# US 8,367,701 B2 · Crystalline pharmaceutical and methods of preparation and use thereof

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 8,367,701 B2
- Document ID: US8367701B2
- Status: Granted
- Kind: B2
- Application number: 13/289,172
- Filed: 2011-11-04
- Published: 2012-05-03
- Granted: 2013-02-05
- Earliest claimed: 2008-04-15
- Assignees: Sarcode Bioscience Inc.
- Applicants: John Burnier; Thomas Gadek; Frederic Naud
- Inventors: John Burnier; Thomas Gadek; Frederic Naud
- Web page: https://patentgrep.com/patent/US8367701B2

## CPC

- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- A61K 9/06: Ointments; Bases therefor; {Other semi-solid forms, e.g. creams, sticks, gels (composition of ointments, creams or gels A61K47/00)}
- A61K 9/08: Solutions {(composition of solutions A61K47/00)}
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/4725: containing further heterocyclic rings
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/02: Inorganic compounds
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61K 47/14: Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
- A61K 47/22: Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
- A61K 47/38: Cellulose; Derivatives thereof
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 17/06: Antipsoriatics
- A61P 17/08: Antiseborrheics
- A61P 17/14: for baldness or alopecia
- A61P 27/02: Ophthalmic agents
- A61P 27/04: Artificial tears; Irrigation solutions
- 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]
- C07C 317/48: the carbon skeleton being further substituted by singly-bound nitrogen atoms, not being part of nitro or nitroso groups
- C07D 217/02: with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
- C07D 217/04: with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
- C07D 217/26: Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
- C07D 405/10: linked by a carbon chain containing aromatic rings
- A61K 47/183: {Amino acids, e.g. glycine, EDTA or aspartame}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS

## Abstract

Novel crystalline polymorphic forms, Forms A, B, C, D, and E of a compound of Formula I, which has been found to be a potent inhibitor of LFA-1, are disclosed. Methods of preparation and uses thereof in the treatment of LFA-1 mediated diseases are also disclosed in this invention.

## Claims

### Claim 1

A composition comprising a compound of Formula I:
comprising a purity of greater than about 90%, and/or a pharmaceutically acceptable salt thereof.

### Claim 2 (depends on 1)

The composition of claim 1, wherein the purity is greater than about 98%.

### Claim 3 (depends on 1)

The composition of claim 1, wherein the compound comprises at least about 95% of an S-enantiomer.

### Claim 4 (depends on 1)

The composition of claim 1, wherein the compound is not the calcium salt of the free acid.

### Claim 5 (depends on 1)

The composition of claim 1, wherein the compound is a crystalline form (Form A) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 18.2, 21.4, and 22.7 degrees.

### Claim 6 (depends on 5)

The composition of claim 5, wherein the form undergoes a predominant endotherm at about 145° C.

### Claim 7 (depends on 5)

The composition of claim 5, wherein the form is produced by isolating the form from a suspension of the compound in an organic solvent which is acetonitrile, methyl ethyl ketone, or water.

### Claim 8 (depends on 1)

The composition of claim 1, wherein the compound is a crystalline form (Form B) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 12.1, 17.1, and 18.5 degrees.

### Claim 9 (depends on 1)

The composition of claim 1, wherein the compound is a crystalline form (Form C) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 4.8, 17.8, and 21.5 degrees.

### Claim 10 (depends on 1)

The composition of claim 1, wherein the compound is a crystalline form (Form D) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 17.6, 21.7, and 24.8 degrees.

### Claim 11 (depends on 1)

The composition of claim 1, wherein the compound is a crystalline form (Form E) comprising an X-ray powder diffraction pattern having characteristic peaks at a reflection angle 2θ of about 5.12, 8.26, and 17.8 degrees.

### Claim 12 (depends on 1)

The composition of claim 1, wherein the compound is an amorphous form.

### Claim 13 (depends on 1)

The composition of claim 1, wherein the compound comprises less than 0.5% of any one byproduct of chemical synthesis of the compound.

### Claim 14 (depends on 1)

The composition of claim 1, wherein the compound comprises less than a total of 1.5% of all byproducts of the chemical synthesis.

### Claim 15 (depends on 5)

A method of producing the form of the compound of claim 5:
comprising the steps of:
a) suspending the compound of Formula I in a solvent;
b) filtering the suspension to isolate a crystalline product; and
c) washing the crystalline product with water thereby obtaining the form of the compound of claim 5.

### Claim 16 (depends on 15)

The method of claim 15 wherein the solvent is acetonitrile or methyl ethyl ketone.

### Claim 17 (depends on 1)

A pharmaceutical composition comprising a pharmaceutically acceptable carrier and the compound of claim 1.

### Claim 18 (depends on 17)

The pharmaceutical composition of claim 17, wherein said compound has been converted to a salt.

### Claim 19 (depends on 17)

The pharmaceutical composition of claim 17, wherein said compound comprises the amorphous form or any of crystalline Forms A, B, C, D, or E, or a combination thereof, of said compound.

### Claim 20 (depends on 17)

The pharmaceutical composition of claim 17, wherein said carrier further comprises one or more pharmaceutically acceptable excipients.

### Claim 21 (depends on 17)

The pharmaceutical composition of claim 17, further comprising at least one additional therapeutic agent.

### Claim 22 (depends on 21)

The pharmaceutical composition of claim 21, wherein the additional therapeutic agent is an antioxidant, antiinflammatory agent, antimicrobial agent, antiangiogenic agent, anti-apoptotic agent, vascular endothelial growth factor inhibitor, antiviral agent, calcineurin inhibitor, corticosteroid, antihistamine, mast cell stabilizing agent, or immunomodulator.

### Claim 23 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a gel comprising about 1% W/V of said compound; and further wherein said pharmaceutically acceptable carrier comprises up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol, up to about 0.15% W/V Methylparaben; up to about 0.05% W/V Propylparaben; up to about 1% W/V Hydroxyethyl Cellulose; and water.

### Claim 24 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is an ointment comprising about 1% W/V of said compound; and further wherein said pharmaceutically acceptable carrier comprises up to about 10% W/V Dimethyl Isosorbide; up to about 0.02% W/VButylated Hydroxytoluene; up to about 2% W/V Span 80; up to about 10% W/VWhite Wax; and White Petrolatum.

### Claim 25 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a water based lotion comprising about 1% W/V of said compound; and further wherein said pharmaceutically acceptable carrier comprises up to about 15% W/V Dimethyl Isosorbide; up to about 25% W/V Transcutol; up to about 12% W/V Hexylene glycol; up to about 5% W/V Propylene Glycol; and pH 6.0 25% Trolamine, wherein the lotion is buffered to a pH of about pH 4.0 to about pH 7.5.

### Claim 26 (depends on 1, 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is an aqueous solution buffered to a pH of about 6.0 to about 8.0 with Sodium Phosphate, Monobasic, and further wherein said pharmaceutically acceptable carrier comprises about 1% W/V of the compound of claim 1, up to about 0.1% W/V EDTA, and, optionally, up to about 0.4% w/w Methylparaben, and optionally, up to about 0.02% w/w Propylparaben.

### Claim 27 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is a biocompatible solid or gel.

### Claim 28 (depends on 27)

The pharmaceutical composition of claim 27 wherein the biocompatible solid is biodegradable.

### Claim 29 (depends on 17)

The pharmaceutical composition of claim 17, wherein the composition is suitable for administration via instillation, via aerosol, via inhalation, orally, topically, transdermally, via insert, or via injection.

### Claim 30 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is formulated to deliver a therapeutically effective amount of the compound of Formula I locally.

### Claim 31 (depends on 17)

The pharmaceutical composition of claim 17, wherein the pharmaceutical composition is formulated to deliver less than a therapeutically effective amount of the compound of Formula I systemically.

### Claim 32 (depends on 17)

A method of treating disease in a subject, comprising the steps of administering an effective amount of the pharmaceutical composition of claim 17 to the subject in need thereof, wherein said disease is an inflammation-mediated disease.

### Claim 33 (depends on 32)

The method of claim 32, wherein the disease is an inflammatory eye disorder which is intraocular, periocular and ocular surface inflammation, Keratoconjunctivitis, keratoconjunctivitis sicca (KCS, aka Dry Eye), KCS in patients with Sjogren's syndrome, allergic conjunctivitis, uveitis, inflammation of the eye, the cornea and periocular tissue from contact lens wear, inflammation of the eye following surgery including LASIK, intraocular inflammation including inflammation of the retina and the anterior and posterior segments of the eye, uveitis, retinitis, edema and retinopathies including diabetic macular edema and diabetic retinopathy, corneal inflammation including rejection of corneal transplants Graves' disease (Basedow disease), or Graves ophthalmopathy.

### Claim 34 (depends on 32)

The method of claim 32, wherein the disease is an allergic disease which is allergic conjunctivitis, allergic rhinitis, allergic asthma, or allergic contact dermatitis.

### Claim 35 (depends on 32)

The method of claim 32, wherein the disease is psoriasis, irritant contact dermatitis, eczematous dermatitises, seborrhoeic dermatitis, cutaneous manifestations of immunologically-mediated disorders, alopecia, alopecia areata, or scar formation.

### Claim 36 (depends on 27)

The pharmaceutical composition of claim 27, comprising a compound of Formula I:
which comprises a purity greater than about 90% and a pharmaceutically acceptable biocompatible matrix wherein the compound comprises a solid form within the biocompatible matrix.

### Claim 37 (depends on 36)

The pharmaceutical composition of claim 36, wherein the solid form is the amorphous form or any of crystalline Forms A, B, C, D, or E, or a combination thereof, of said compound.

### Claim 38 (depends on 36)

The pharmaceutical composition of claim 36, wherein the biocompatible matrix is a polyacrylate, methacyrlate, polyolefin, polyamide, fluoropolymer, cellulose derivative, polyvinyl alcohol, polyvinylpyrrolidone, coated zeolite, or PLGA microsphere or nanosphere.

### Claim 39 (depends on 36)

The pharmaceutical composition of claim 36, wherein the biocompatible matrix is biodegradable.

### Claim 40 (depends on 36)

The pharmaceutical composition of claim 36, wherein a release of the compound from the biocompatible matrix comprises a slow release profile or a sustained release profile.

### Claim 41

A compound of the formula:
or its pharmaceutically acceptable salts.