# US 2014/0154246 A1 · Cai-based systems and methods for the localized treatment of ocular and other diseases

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- Number: US 2014/0154246 A1
- Document ID: US20140154246A1
- Status: Published application
- Kind: A1
- Application number: 14/174,080
- Filed: 2014-02-06
- Published: 2014-06-05
- Earliest claimed: 2004-09-24
- Assignees: RFE Pharma LLC
- Applicants: RFE Pharma LLC
- Inventors: Gary Robinson; Gideon Shapiro; Alan J. Franklin; Simona Jurczyk
- Web page: https://patentgrep.com/patent/US20140154246A1

## CPC

- A61K 31/4192: 1,2,3-Triazoles
- A61K 9/0048: {Eye, e.g. artificial tears}
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61K 47/38: Cellulose; Derivatives thereof
- A61K 47/44: Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin (synthetic glycerides, e.g. medium-chain triglycerides, A61K47/14)
- A61K 47/6951: {using cyclodextrin (cyclodextrins used as simple excipients A61K47/40)}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 7/02: Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
- 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 17/04: Antipruritics
- A61P 17/06: Antipsoriatics
- A61P 17/10: Anti-acne agents
- A61P 17/12: Keratolytics, e.g. wart or anti-corn preparations
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 25/04: Centrally acting analgesics, e.g. opioids
- A61P 25/08: Antiepileptics; Anticonvulsants
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61P 27/02: Ophthalmic agents
- A61P 27/06: Antiglaucoma agents or miotics
- A61P 27/12: for cataracts
- A61P 27/14: Decongestants or antiallergics
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- 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 subject invention provides CAI compounds and formulations thereof, and methods for their use in the localized treatment of non-life threatening diseases. Formulations of CAI compounds of the subject invention include CAI free base and CAI prodrug microcrystallines, microparticles, emulsions, and the like. The subject invention further provides methods for treating non-life threatening diseases using the CAI compounds of the invention (i.e., novel delivery systems and combination therapies), that are effective and are associated with little or no adverse side effects.

## Claims

### Claim 1

A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:
(a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and
(b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation with hydroxypropyl β-cyclodextrin.

### Claim 2

A method for treating a patient suffering from age-related macular degeneration or diabetic retinopathy comprising:
(a) diagnosing age-related macular degeneration, diabetic retinopathy- or symptom thereof in a patient; and
(b) ocularly administering to said patient a sterile, aqueous suspension formulation free of organic solvents comprising a therapeutically effective amount of suspended solid microparticulates of CAI (5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide) free base form, wherein the effective amount comprises a dose of 0.1 to 30 mg/ml of CAI in formulation.

### Claim 3 (depends on 1)

The method of claim 1, wherein the local ocular administration is assisted by sonophoresis or iontophoresis.

### Claim 4 (depends on 1)

The method of claim 1, wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound.

### Claim 5 (depends on 1)

The method of claim 1, wherein the local ocular administration is intravitreal injection.

### Claim 6 (depends on 5)

The method of claim 5, wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound.

### Claim 7 (depends on 1)

The method of claim 1, wherein the aqueous suspension formulation further comprises any one or combination of substances selected from the group consisting of pharmaceutically acceptable carriers, auxiliary substances, diluents, surfactants, detergents, stabilizers, buffers, excipients, isotonicity adjusting auxiliary substances, preservatives, antioxidants, and delivery-enhancing agents.

### Claim 8 (depends on 1)

The method of claim 1, wherein the aqueous formulation further comprises one or more polymeric surfactants, sterile water, saline or phosphate buffered saline.

### Claim 9 (depends on 8)

The method of claim 8, wherein the polymeric surfactants are polysorbates, cellulosic polymers, polyethylene glycols and polyoxyethylene-polyoxypropylene block copolymers.

### Claim 10 (depends on 1)

The method of claim 1, wherein the aqueous formulation is formulated to be isotonic with said patient's blood.

### Claim 11 (depends on 1)

The method of claim 1, wherein the aqueous formulation further comprises any one or combination of anionic, cationic or zwitterionic detergents.

### Claim 12 (depends on 1)

The method of claim 1, wherein the microparticulates of CAI are surface stabilized particles.

### Claim 13 (depends on 12)

The method of claim 12, wherein the surface stabilization of the surface stabilized particles of CAI is provided by a pharmaceutically acceptable surface active agent selected from the group consisting of lecithin, charged or uncharged phospholipids, polymeric surfactants, non-polymeric surfactants, charged surfactants, uncharged surfactants, and one or more of bile acids and their salts.

### Claim 14 (depends on 13)

The method of claim 13, wherein the aqueous suspension formulation further comprises any one or combination of materials selected from the group consisting of pharmaceutically acceptable diluents, viscosity-modifiers, and stabilizers.

### Claim 15 (depends on 1)

The method of claim 1, wherein the formulation further comprises an ocular therapeutic substance selected from the group consisting of: a VEGF binding molecule and a tyrosine receptor kinase inhibitor, wherein the ocular disease is neovascular disease.

### Claim 16 (depends on 1)

The method of claim 1, wherein the VEGF binding molecule is selected from the group consisting of ranibizumab (Lucentis®) and pegatanib (Macugen®).

### Claim 17 (depends on 2)

The method of claim 2, wherein the local ocular administration is assisted by sonophoresis or iontophoresis.

### Claim 18 (depends on 2)

The method of claim 2, wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound.

### Claim 19 (depends on 2)

The method of claim 2, wherein the local ocular administration is intravitreal injection.

### Claim 20 (depends on 19)

The method of claim 19, wherein the effective amount of the CAI compound is a dose of 0.1 to 10 mg of the CAI compound.

### Claim 21 (depends on 2)

The method of claim 2, wherein the aqueous suspension formulation further comprises any one or combination of substances selected from the group consisting of pharmaceutically acceptable carriers, auxiliary substances, diluents, surfactants, detergents, stabilizers, buffers, excipients, isotonicity adjusting auxiliary substances, preservatives, antioxidants, and delivery-enhancing agents.

### Claim 22 (depends on 2)

The method of claim 2, wherein the aqueous formulation further comprises one or more polymeric surfactants, a sterile water, saline or phosphate buffered saline.

### Claim 23 (depends on 22)

The method of claim 22, wherein the polymeric surfactants are polysorbates, cellulosic polymers, polyethylene glycols and polyoxyethylene-polyoxypropylene block copolymers.

### Claim 24 (depends on 2)

The method of claim 2, wherein the aqueous formulation is formulated to be isotonic with said patient's blood.

### Claim 25 (depends on 2)

The method of claim 2, wherein the aqueous formulation further comprises any one or combination of anionic, cationic or zwitterionic detergents.

### Claim 26 (depends on 2)

The method of claim 2, wherein the microparticulates of CAI are surface stabilized particles.

### Claim 27 (depends on 26)

The method of claim 26, wherein the surface stabilization of the surface stabilized particles of CAI is provided by a pharmaceutically acceptable surface active agent selected from the group consisting of lecithin, charged or uncharged phospholipids, polymeric surfactants, non-polymeric surfactants, charged surfactants, uncharged surfactants, and one or more of bile acids and their salts.

### Claim 28 (depends on 27)

The method of claim 27, wherein the aqueous suspension formulation further comprises any one or combination of materials selected from the group consisting of pharmaceutically acceptable diluents, viscosity-modifiers, and stabilizers.

### Claim 29 (depends on 2)

The method of claim 2, wherein the formulation further comprises an ocular therapeutic substance selected from the group consisting of: a VEGF binding molecule and a tyrosine receptor kinase inhibitor, wherein the ocular disease is neovascular disease.

### Claim 30 (depends on 2)

The method of claim 2, wherein the VEGF binding molecule is selected from the group consisting of ranibizumab (Lucentis®) and pegatanib (Macugen®).