# US 2020/0392084 A1 · Sulfasalazine salt compositions and methods of using the same

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- Number: US 2020/0392084 A1
- Document ID: US20200392084A1
- Status: Published application
- Kind: A1
- Application number: 16/753,971
- Filed: 2018-10-09
- Published: 2020-12-17
- Earliest claimed: 2017-10-10
- Inventors: Khawla ABU-IZZA; David PEARSON; Lorna KENNEDY; Joseph BENSON
- Web page: https://patentgrep.com/patent/US20200392084A1

## CPC

- C07D 213/76: to which a second hetero atom is attached (nitro radicals C07D213/61)
- A61K 31/655: Azo (—N=N—), diazo (=N2), azoxy (>N—O—N< or N(=O)—N<), azido (—N3) or diazoamino (—N=N—N<) compounds
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- C07B 2200/13: Crystalline forms, e.g. polymorphs
- 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
- C07B: GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR (preparation of carboxylic acid esters by telomerisation C07C67/47; telomerisation C08F)

## Abstract

Sulfasalazine salt compositions are provided. In some cases, the sulfasalazine salts have a crystalline form. The subject crystalline sulfasalazine salts can provide a water soluble form of the active compound that finds use in pharmaceutical compositions and therapeutic applications. The subject crystalline sulfasalazine salts can provide increased solubility as compared to the zwitterionic or free acid form of sulfasalazine. Also provided are pharmaceutical compositions including the subject sulfasalazine salt compositions. Methods of treating a neurological related disease such as refractory epilepsy using the subject crystalline sulfasalazine salts and pharmaceutical compositions are also provided.

## Claims

### Claim 1

A water-soluble crystalline salt of sulfasalazine.

### Claim 2 (depends on 1)

The crystalline salt of claim 1, wherein the crystalline salt:
is substantially non-hygroscopic;
has a solubility of 1 mg/mL or more in an aqueous buffer at about pH 7 and 25° C.;
is polymorphically stable; and/or
is storage stable.

### Claim 3 (depends on 1)

The crystalline salt of claim 1, wherein the crystalline salt is a pharmaceutically acceptable basic salt of sulfasalazine and an acid.

### Claim 4 (depends on 3)

The crystalline salt of claim 3, wherein the acid is an organic sulfonic acid.

### Claim 5 (depends on 3)

The crystalline salt of claim 3, wherein the acid is selected from benzenesulfonic acid, ethanedisulfonic acid, ethane sulfonic acid, methane sulfonic acid, naphthalene-1,5-disulfonic acid, p-toluenesulfonic acid and sulfuric acid.

### Claim 6 (depends on 1)

The crystalline salt of claim 1, wherein the crystalline salt is a pharmaceutically acceptable acid salt of sulfasalazine and an organic amine base.

### Claim 7 (depends on 6)

The crystalline salt of claim 6, wherein the base is selected from diethylamine, L-lysine, triethanolamine, tromethamine, piperazine, benzathine, diethanolamine and L-arginine.

### Claim 8 (depends on 7)

The crystalline salt of claim 7, wherein the crystalline salt is crystalline sulfasalazine diethylamine (1:1) salt.

### Claim 9 (depends on 8)

The crystalline salt of claim 8, wherein the crystalline salt is characterized by the X-ray Powder Diffraction Pattern as shown in FIG. 4, or is characterized by having a differential scanning calorimetry plot comprising one endothermic event with an onset temperature of about 191° C. when heated from about 25° C. to about 300° C.

### Claim 10 (depends on 7)

The crystalline salt of claim 7, wherein the crystalline salt is crystalline sulfasalazine tromethamine (1:1) salt.

### Claim 11 (depends on 10)

The crystalline salt of claim 10, wherein the crystalline salt is characterized by the X-ray Powder Diffraction Pattern as shown in FIG. 7, or is characterized by having a differential scanning calorimetry plot comprising endothermic events with an onset temperature of about 67° C. and about 123° C., when heated from about 25° C. to about 300° C.

### Claim 12 (depends on 1)

A pharmaceutical composition comprising the crystalline salt of claim 1 and a pharmaceutical acceptable carrier, diluent or excipient.

### Claim 13 (depends on 1)

A method of treating disease or condition that is a neurological related disease, a neurodegenerative disease, an inflammatory disease or condition or cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a crystalline salt of claim 1.

### Claim 14 (depends on 13)

The method of claim 13, wherein the disease or condition is:
a) a neurological related disease that is epilepsy;
b) an epilepsy selected from Dravet syndrome, Lennox-Gastaut syndrome, Doose syndrome, West syndrome, Angelman Syndrome, Benign Rolandic Epilepsy, CDKL5 Disorder, Childhood and Juvenile Absence Epilepsy, Doose Syndrome, Dravet Syndrome, Epilepsy with Myoclonic-Absences, Glut 1 Deficiency Syndrome, Infantile Spasms and West's Syndrome, Juvenile Myoclonic Epilepsy, Lafora Progressive Myoclonus Epilepsy, Landau-Kleffner Syndrome, Lennox-Gastaut Syndrome, Ohtahara Syndrome, Panayiotopoulos Syndrome, PCDH19 Epilepsy, Rasmussen's Syndrome, Ring Chromosome 20 Syndrome, Reflex Epilepsies, TBCK-related ID Syndrome, Hypothalamic Hamartoma, Frontal Lobe Epilepsy, Epilepsy with Generalized Tonic-Clonic Seizures Alone, Progressive Myoclonic Epilepsies, Temporal Lobe Epilepsy, Tuberous Sclerosis Complex, Focal Cortical Dysplasia and epileptic encephalopathies. In another aspect of the method, the seizure disease or disorder is selected from the group consisting of Childhood and Juvenile Absence Epilepsy, Infantile Spasms and West's Syndrome, Juvenile Myoclonic Epilepsy, Frontal Lobe Epilepsy, Epilepsy with Generalized Tonic-Clonic Seizures Alone, Progressive Myoclonic Epilepsies, Temporal Lobe Epilepsy, Tuberous Sclerosis Complex, Rasmussen's Syndrome, Hypothalamic Hamartoma, Focal Cortical Dysplasia, epileptic encephalopathies, and Long-term epilepsy associated tumors (LEATs) for example ganglioglioma, oligodendroglioma, and dysembryoplastic neuroepithelial tumors (DNETs);
c) a neurodegenerative disease selected from Alexander disease, Alzheimer's disease (AD), frontotemporal dementia, HIV-associated dementia and other dementias, amyotrophic lateral sclerosis, epilepsy, Huntington's disease (HD), ischemic stroke, Motor neurone diseases (MND), neuropathic pain, Parkinson's disease (PD) and PD-related disorders, Prion disease, Rett syndrome, Spinal muscular atrophy (SMA), Spinocerebellar ataxia (SCA), traumatic brain injury, tuberous sclerosis, progressive multiple sclerosis (P-MS), amyotrophic lateral sclerosis (ALS) and neuropathic pain;
d) an inflammatory disease or condition selected from inflammatory bowel diseases, ulcerative colitis, Crohn's disease, inflammatory arthritis diseases, ankylosing spondylitis, rheumatoid arthritis and psoriatic arthritis; or
e) a cancer selected from glial tumors, glioblastoma, lymphoma and pancreatic cancer.

### Claim 15 (depends on 14)

The method of claim 14, wherein the disease or condition is refractory epilepsy.

### Claim 16 (depends on 13)

The method of claim 13, wherein the subject is diagnosed as having intractable seizures.

### Claim 17 (depends on 13)

The method of claim 13, wherein the crystalline salt is administered at a dosage and/or frequency effective to reduce the occurrence of side effects of sulfasalazine.

### Claim 18 (depends on 13)

The method of claim 13, further comprising co-administering to the subject an antiepileptic agent or an ABCG2 inhibitor.

### Claim 19

A method of preparing a crystalline sulfasalazine salt, the method comprising:
a) combining sulfasalazine and an organic amine base in an organic solvent under conditions sufficient to crystallize a sulfasalazine salt; and
b) isolating the sulfasalazine salt;
wherein the organic amine base is selected from diethylamine, L-lysine, triethanolamine, tromethamine, piperazine, benzathine, diethanolamine and L-arginine.

### Claim 20 (depends on 19)

The method of claim 19, wherein:
a) the organic amine base is diethylamine and the solvent is ethanol
b) the organic amine base is L-lysine and the solvent is acetone;
c) the organic amine base is triethanolamine and the solvent is acetone; or
d) the organic amine base is tromethamine and the solvent is ethanol.