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Methods and Compositions for Reducing Neurodegeneration in Amyotrophic Lateral Sclerosis

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Methods and Compositions for Reducing Neurodegeneration in Amyotrophic Lateral Sclerosis (19) & (11) EP 2 255 812 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 01.12.2010 Bulletin 2010/48 A61K 31/575 (2006.01) A61K 47/36 (2006.01) A61K 9/00 (2006.01) A61P 25/16 (2006.01) (2006.01) (21) Application number: 10176111.2 A61P 25/28 (22) Date of filing: 31.10.2005 (84) Designated Contracting States: (72) Inventor: Yoo, Seo Hong AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Wyckoff, HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI New Jersey 07481 (US) SK TR (74) Representative: Lucas, Brian Ronald (30) Priority: 01.11.2004 US 624100 P Lucas & Co. 16.11.2004 US 628421 P 135 Westhall Road Warlingham, (62) Document number(s) of the earlier application(s) in Surrey CR6 9HJ (GB) accordance with Art. 76 EPC: 05820886.9 / 1 814 558 Remarks: This application was filed on 10-09-2010 as a (71) Applicant: Yoo, Seo Hong divisional application to the application mentioned Wyckoff, under INID code 62. New Jersey 07481 (US) (54) Methods and compositions for reducing neurodegeneration in amyotrophic lateral sclerosis (57) A composition comprising a clear aqueous so- (c) water, wherein the first material and the carbohydrate lution comprising: both remain in solution for any subset of the range of pH (a) a first material selected from soluble ursodeoxycholic values obtainable in an aqueous system sufficient for a acid or a sodium salt oftauroursodeoxycholic acid (TUD- pharmaceutical formulation to remain in solution from CA); preparation, to administration, to absorption in the body; (b) a carbohydrate selected from the group consisting of an aqueous soluble starch conversion product or an for use in the treatment of at least one symptom of a aqueous soluble non-starch polysaccharide; neurodegenerative disease or at least one symptom of a motor neuron disease in a subject. EP 2 255 812 A1 Printed by Jouve, 75001 PARIS (FR) (Cont. next page) EP 2 255 812 A1 2 1 EP 2 255 812 A1 2 Description closure with riluzole may reduce riluzole toxicity or side effects in some embodiments. TECHNICAL FIELD [0006] Compositions of the present disclosure may in- clude (1) a bile acid, a bile acid derivative, a bile acid salt, [0001] The present disclosure is related to composi- 5 or a bile acid conjugate with an amine, (2) water, and (3) tions and methods for ameliorating or treating at least a sufficient quantity of an aqueous soluble starch con- one symptom of a neurodegenerative process or dis- version product such that the bile acid and the starch ease. conversion product remain in solution at any pH within a selected pH range. BACKGROUND 10 [0007] The disclosure also relates to a composition which comprises (1) a bile acid, a bile acid derivative, a [0002] At any given time, as many as 30,000 Ameri- bile acid salt, or a bile acid conjugate with an amine, (2) cans suffer with Amyotrophic Lateral Sclerosis (ALS), water, and (3) a sufficient quantity of an aqueous soluble which is nearly always fatal. ALS, also known as Lou non-starch polysaccharide such that the bile acid and the Gehrig’s Disease, is a progressive neurodegenerative 15 polysaccharide remain in solution at any pH within a se- disease that attacks motor neurons in the brain and spinal lected pH range. cord and results in muscle weakness and atrophy. Early [0008] The disclosure further relates to a pharmaceu- symptoms include loss of dexterity and gait. As the dis- tical composition which comprises (1) a bile acid, a bile ease progresses, patients becomeparalyzed and require acid derivative, a bile acid salt, or a bile acid conjugate respiratory support. The life expectancy of ALS patients 20 with an amine, (2) water, (3) a pharmaceutical compound is usually 3 to 5 years after diagnosis with the leading in a pharmaceutically appropriate amount, and (4) a suf- cause of death being loss of respiratory function. ficient quantity of an aqueous soluble starch conversion [0003] ALS etiology is only partially understood. Fa- product or an aqueous soluble non-starch polysaccha- milial (inherited) cases make up only about 5-10% of ALS ride such that the bile acid, the pharmaceutical com- patients overall. Within this subset of ALS patients, one 25 pound, and the carbohydrate remain in solution at any in five carry the only genetic defect identified to date, a pH level within a selected pH range. According to some mutation in the SOD1 gene. The mutant allele leads to non-limiting embodiments, the pharmaceutical com- production of a protein believed to be toxic to motor neu- pound may be any drug that has beneficial effect when rons. Most cases, i.e., the remaining 90-95%, arise administered to a subject having a neurodegenerative seemingly spontaneously and without an identifiable pat- 30 disease. According to one non-limiting embodiment of tern. Thus, ALS appears to be capable of striking anyone the disclosure, the pharmaceutical compound may be at any time. Effective therapies are scarce or non-exist- riluzole or pharmaceutically active or activatable metab- ent. olites, pro-drugs, derivatives or analogs of riluzole. [0009] The disclosure further relates to solution dos- SUMMARY 35 age forms of bile acid compositions. Advantages of these solution dosage forms include improved bioavailability [0004] Accordingly, a need has arisen for methods and and absorbability of a bile acid. Additional advantages of compositions useful for ameliorating or eliminating pro- solution dosage forms include improved bioavailability gression of a neurodegenerative process or disease in- and absorbability of a pharmaceutical compound. cluding, without limitation, ALS. 40 [0010] In some embodiments of the disclosure, a com- [0005] The present disclosure relates to compositions position is provided which comprises (1) a bile acid, a and methods for ameliorating or treating at least one bileacid derivative, a bile acid salt, or a bile acid conjugate symptom of a neurodegenerative process or disease. For with an amine, (2) water, and (3) a sufficient quantity of example, in some embodiments, the disclosure provides carbohydrate such that the bile acid component and the compositions and methods for ameliorating or eliminat- 45 carbohydrate remain in solution at any pH within a se- ing progression of a neurodegenerative process or dis- lected pH range, wherein the carbohydrate is a combi- ease. In some embodiments of the disclosure, a clear nation of an aqueous soluble starch conversion product stable solution of a bile acid may be administered to a and an aqueous soluble non-starch polysaccharide. In subject having a progressive neurodegenerative disor- embodiments containing both soluble starchnon- der. According to some embodiments, a bile acid solution 50 polysaccharide and high molecular weight starch con- may further comprise another pharmaceutical ( e.g., rilu- version product, the amounts of each are such that when zole). In some embodiments, a bile acid solution of the combined together in the composition they are sufficient disclosure may be administered to a subject having to allow the bile acid component, the high molecular amyotrophic lateral sclerosis. According to some embod- weight starch conversion product, the soluble non- starch iments, coadministration of a bile acid with riluzole may 55 polysaccharide and the pharmaceutical compound, if result in a surprisingly-improved outcome over adminis- any, to remain in solution at any pH within a selected pH tration of either pharmaceutical alone. In some embodi- range. ments, coadministration of a bile composition of the dis- [0011] In some embodiments of the disclosure, a com- 3 3 EP 2 255 812 A1 4 bination therapy composition is provided which may in- been identified as familial ALS (FALS). In about a fifth of crease the intensity of response to or efficacy of a phar- FALS cases, the mutant gene is a cytoplasmic enzyme, maceutical. More specifically, administration of a com- Cu/Zn superoxide dismutase- 1 (SOD). More than 90 mu- position of the disclosure comprising a bile acid and rilu- tations inCu/Zn SOD have been identified andare spread zole to a subject suffering from a neurodegenerative dis- 5 across over 30 sites. These mutations may give rise to order may have more than an additive effect of adminis- a new adverse function that leads to FALS as opposed tration of either compound alone. to simply impairing a normal function of the gene product. For example, in experiments with transgenic mice that BRIEF DESCRIPTION OF THE DRAWINGS overexpress a mutant human Cu/Zn SOD (A4V, G93A, 10 G85R, G37R), there was no correlation between loss of [0012] Some specific example embodiments of the SOD1 activity and the onset or severity of disease. disclosure may be understood by referring, in part, to the [0014] The symptoms and pathology of FALS patients following description and the accompanying drawings, with SOD1 mutations closely resemble those of patients wherein: with SALS. The clinical progression and pathologic alter- 15 ations in motor neurons from mice expressing mutant FIGURE 1A is life expectancy and its result is shown SOD1 are also strikingly similar to those found in SALS as the percent of survival on time when animal died; patients, suggesting that the mechanisms of neurode- FIGURE 1B is Rotarod test and its result is shown generation for SALS and FALS may share common com- as the time they remained on the rod before sliding ponents. Mitochondria play a pivotal role in many meta- off on every week until dying; 20 bolic and apoptotic pathways that regulate the life and FIGURE 2 is a bar graph showing the results of a death of cells. Mitochondria also are the site of initiation cell viability assay with wildtype cells, A4V cells, and of the intrinsic apoptotic cascade, which can be activated G93A cells in which the cells were untreated (left by the release of pro- apoptotic factors that may act both panel) or incubated with 200 nM of solubilized UDCA in a caspase-dependent or caspase-independent man- in solution of the disclosure (center panel), or 20 PM 25 ner.
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