# US 10,369,124 B2 · Dendrimer compositions and their use in treatment of diseases of the eye

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- Number: US 10,369,124 B2
- Document ID: US10369124B2
- Status: Granted
- Kind: B2
- Application number: 15/307,284
- Filed: 2015-04-30
- Published: 2017-02-16
- Granted: 2019-08-06
- Earliest claimed: 2014-04-30
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Kannan Rangaramanujam; Gerard Lutty; Siva Pramodh Kambhampati; Manof Mishra; Imran Bhutto
- Web page: https://patentgrep.com/patent/US10369124B2

## CPC

- 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 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 9/0048: {Eye, e.g. artificial tears}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- 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 47/595: {Polyamides, e.g. nylon (polyamino acids A61K47/62)}
- A61K 49/0032: {Methine dyes, e.g. cyanine dyes}
- A61K 49/0054: {Macromolecular compounds, i.e. oligomers, polymers, dendrimers}
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 9/12: Antihypertensives
- A61P 25/02: for peripheral neuropathies
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/04: Antibacterial agents
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- 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

The treatment of many ocular disorders is hampered because of poor penetration of systemically administered drugs into the eye. The tight junctional complexes (zonulae occludens) of the retinal pigment epithelium and retinal capillaries are the site of the blood-ocular barrier. This barrier inhibits penetration of substances, including antibiotics, into the vitreous. Over the last 18 years we have evaluated the nontoxic doses of various drugs. These include antibiotics and antifungals for treatment of bacterial and fungal endophthalmitis, antivirals for treatment of viral retinitis (specifically, when medication with these drugs poses the threat of toxicity to other organs). Intravitreal antineoplastic drugs have been studied to prevent cell proliferation in the vitreous cavity after retinal attachment surgery, which can lead to proliferative vitreoretinopathy (PVR). Furthermore, we evaluated the anti-inflammatory action of dexamethasone and cyclosporine A to reduce intraocular inflammation after intraocular surgery or in uveitis. Because these studies had been performed in the presence of the vitreous, which can slow down the diffusion of the drugs toward the retina, it was necessary to reevaluate the concentration of drugs which could be administered intravitreally in the vitrectomized eye. The nontoxic dose of numerous drugs when added to vitrectomy infusion fluid has also been evaluated. Furthermore, the role of vitrectomy in the treatment of bacterial fungal endophthalmitis has been studied and the role of vitrectomy in this ocular disorder is defined.

## Claims

### Claim 1

A method for treating an inflammatory and/or angiogenic disease in the eye of the subject in need thereof, comprising injecting for systemic delivery a dendrimer composition in an effective amount to treat the inflammatory and/or angiogenic disease in the eye of the subject,
wherein the dendrimer composition comprises hydroxyl-terminated poly(amidoamine) (PAMAM) dendrimers covalently linked to one or more therapeutic agents, which can be the same or different.

### Claim 2 (depends on 1)

The method of claim 1, wherein the dendrimers are included in a formulation comprising liposomes, microcapsules, nanoparticles, or nanocapsules.

### Claim 3 (depends on 1)

The method of claim 1, wherein the PAMAM dendrimer is a G3, G4, G5, G6, G7, G8, G9 or G10 PAMAM dendrimer.

### Claim 4 (depends on 1)

The method of claim 1, wherein the inflammatory disease of the eye is selected from the group consisting of age-related macular degeneration (AMD), retinitis pigmentosa, optic neuritis, infection, uveitis, sarcoid, sickle cell disease, retinal detachment, temporal arteritis, retinal ischemia, arteriosclerotic retinopathy, hypertensive retinopathy, retinal artery blockage, retinal vein blockage, hypotension, diabetic retinopathy, macular edema, and choroidal neovascularization.

### Claim 5 (depends on 1)

The method of claim 1, wherein the dendrimer composition is repeatedly administered to the subject daily, weekly, biweekly, monthly, or bimonthly.

### Claim 6 (depends on 1)

The method of claim 1, wherein the one or more therapeutic agents are selected from the group consisting of proteins, oligonucleotides, and small molecules.

### Claim 7 (depends on 6)

The method of claim 6, wherein the one or more therapeutic agents are selected from the group consisting of vitamin A, vitamin C, vitamin E, and beta-carotene.

### Claim 8 (depends on 6)

The method of claim 6, wherein the one or more therapeutic agents are anti-inflammatory agents selected from the group consisting of triamcinolone acetonide, methyl prednisone, dexamethasone, COX-2 inhibitors, gold compound anti-inflammatory agents, salicylate anti-inflammatory agents, N-acetyl cysteine, minocycline, aflibercept, rapamycin, and anti-VEGF agents.

### Claim 9 (depends on 6)

The method of claim 6, wherein the one or more therapeutic agents are antibodies selected from the group consisting of daclizumab, basiliximab, ranibizumab, and pegaptanib sodium.

### Claim 10 (depends on 6)

The method of claim 6, wherein the one or more therapeutic agents are selected from the group consisting of enzymes, receptor antagonists or agonists, hormones, growth factors, and antibodies.

### Claim 11 (depends on 6)

The method of claim 6, wherein the oligonucleotides are selected from the group consisting of siRNAs, and microRNAs.

### Claim 12 (depends on 1)

The method of claim 1, wherein the composition is administered in combination with one or more additional therapeutically active agents.

### Claim 13 (depends on 1)

The method of claim 1, wherein the composition is administered intravenously.