# US 12,599,570 B2 · Biodegradable extended release microsphere-hydrogel ocular drug delivery system and method

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- Number: US 12,599,570 B2
- Document ID: US12599570B2
- Status: Granted
- Kind: B2
- Application number: 17/673,504
- Filed: 2022-02-16
- Published: 2022-06-02
- Granted: 2026-04-14
- Earliest claimed: 2015-09-25
- Assignees: Jennifer Kang-Mieler
- Applicants: Jennifer J. Kang-Mieler
- Inventors: Jennifer J. Kang-Mieler; Eric Brey; Victor Perez-Luna; Bin Jiang; Christian Osswald
- Web page: https://patentgrep.com/patent/US12599570B2

## CPC

- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 9/5052: {Proteins, e.g. albumin}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0051: {Ocular inserts or implants}
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/501: {Inorganic compounds}
- A61K 9/5015: {Organic compounds, e.g. fats, sugars}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 9/5036: {Polysaccharides, e.g. gums, alginate; Cyclodextrin}
- A61K 31/573: substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/32: Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers {, poly(meth)acrylates, or polyvinyl pyrrolidone}
- C07K 16/22: against growth factors {; against growth regulators}
- A61K 2039/505: {comprising antibodies}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

A hydrogel delivery composition and method, including degradable microcapsules suspended in a degradable thermo-responsive hydrogel. The hydrogel is thermo-responsive at a physiological temperature and changes after application to a more solid state due to body temperatures. The composition includes one or more treatment agents to be released over time as the composition degrades. The composition can be varied to modify the structure and/or release of the treatment agent. The degradable microcapsules include one or more of magnesium hydroxide (Mg(OH)2), bovine serum albumin (BSA), polyethylene glycol (PEG), and sucrose to improve release duration.

## Claims

### Claim 1

A delivery composition, comprising a treatment agent microencapsulated in degradable microcapsules that are suspended in a degradable thermo-responsive hydrogel, wherein the degradable microcapsules comprise magnesium hydroxide (Mg(OH)2) and bovine serum albumin (BSA), wherein the hydrogel is thermo-responsive at a physiological temperature of about 32° C. to about 37° C.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the microcapsules comprise:
0.001% to 20% w/v BSA; and
0.001% to 9% w/v Mg(OH)2.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the microcapsules further comprise polyethylene glycol (PEG) and sucrose.

### Claim 4 (depends on 3)

The composition of claim 3, wherein the microcapsules comprise:
0.001% to 20% w/v BSA;
0.001% to 9% w/v Mg(OH)2;
0.001% to 20% w/v PEG; and
0.001% to 10% w/v sucrose.

### Claim 5 (depends on 3)

The composition of claim 3, wherein the microcapsules comprise:
about 10-14% w/v % BSA;
about 2-4% w/v Mg(OH)2;
about 8-12% w/v PEG; and
about 1.5-3.5% w/v sucrose.

### Claim 6 (depends on 1)

The composition of claim 1, wherein the microcapsules further comprise poly(lactic-co-glycolic acid), poly(lactic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof.

### Claim 7 (depends on 6)

The composition of claim 6, wherein the microcapsules further comprise polyethylene glycol (PEG) and sucrose.

### Claim 8 (depends on 1)

The composition of claim 1, further comprising a non-encapsulated treatment agent dispersed within the hydrogel.

### Claim 9 (depends on 1)

The composition of claim 1, further comprising microcapsules having at least two release rates.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the degradable microcapsules comprise a combination of microparticles and nanoparticles.

### Claim 11 (depends on 10)

The composition of claim 10, wherein the microparticles contain a first treatment agent, and the nanoparticles contain a different second treatment agent.

### Claim 12 (depends on 11)

The composition of claim 11, wherein each of the first and second treatment agents is independently selected from an anti-VEGF agent, an anti-PDGF agent, cells, delivery cells, an antibiotic, a corticosteroid, enzymes, peptides, nucleic acids, or combinations thereof.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the hydrogel comprises poly(N-isopropylacrylamide), poly(lactic acid), polysaccharide chitin, alginate, diacrylate, or combinations or block copolymers thereof.

### Claim 14

A delivery composition, comprising:
a degradable thermo-responsive hydrogel that is thermo-responsive at a physiological temperature of about 32° C. to about 37° C. to provide a liquid-like state at room temperature and more solid state at body temperature;
degradable nanoparticles including a first treatment agent, and suspended in the hydrogel; and
degradable microparticles including a second treatment agent, and suspended in the hydrogel;
wherein each of the degradable nanoparticles and microparticles comprises at least two of: polyethylene glycol (PEG), magnesium hydroxide (Mg(OH)2), bovine serum albumin (BSA), and sucrose.

### Claim 15 (depends on 14)

The composition of claim 14, wherein the microcapsules further comprise:
poly(lactic-co-glycolic acid), poly(lactic acid), polysaccharide chitin, alginate, or combinations or block copolymers thereof;
0.001% to 20% w/v BSA;
0.001% to 9% w/v Mg(OH)2;
0.001% to 20% w/v PEG; and
0.001% to 10% w/v sucrose.

### Claim 16 (depends on 1)

A method of delivering a compound to an eye, the method comprising:
applying to or into an eye of a mammal the delivery composition of claim 1 in a first physicochemical state; and
the composition changing to a second physicochemical state upon administration, wherein the second physicochemical state is more solid than the first physicochemical state, wherein the degradable microcapsules release the microencapsulated treatment agent over time after applying.

### Claim 17 (depends on 16)

The method of claim 16, wherein the microcapsules comprise:
0.001% to 20% w/v BSA; and
0.001% to 9% w/v Mg(OH)2.

### Claim 18 (depends on 16)

The method of claim 16, wherein the microcapsules comprise:
0.001% to 20% w/v BSA;
0.001% to 9% w/v Mg(OH)2;
0.001% to 20% w/v PEG; and
0.001% to 10% w/v sucrose.

### Claim 19 (depends on 16)

The method of claim 16, wherein the second physicochemical state is degradable to release the microencapsulated treatment agent and further comprising controlling the degradation by at least one of: type and/or amount of crosslinking to control the release of the microencapsulated treatment agent, or selection of organic solvent used in microencapsulation of the treatment agent.

### Claim 20 (depends on 16)

The method of claim 16, further comprising applying the composition in a first physicochemical state by intravitreal injection, by periocular or transcleral injection, by topical application, by intracameral application, by suprachoroidal application, within ocular implants, or combinations thereof.