PHARMACEUTICALLY ACCEPTABLE SALTS OF SEPIAPTERIN

Abstract

The present invention relates to new pharmaceutical salts and/or co-crystals of sepiapterin which exhibit improved properties. In particular, the invention relates to salts of sepiapterin with improved stability. The invention also relates to pharmaceutical compositions including a pharmaceutically effective amount of one or more salts and/or co-crystals of sepiapterin, as well as methods of treating tetrahydrobiopterin-related disorders including administration of a sepiapterin salt and/or co-crystal of the invention to a subject in need thereof.

Claims

1. A pharmaceutically acceptable salt and/or co-crystal of sepiapterin, wherein the pharmaceutically acceptable salt and/or co-crystal is a methanesulfonate salt and/or co-crystal, a nicotinate salt and/or co-crystal, a toluenesulfonate salt and/or co-crystal, a benzenesulfonate salt and/or co-crystal, a sulfate salt and/or co-crystal, a phosphate salt and/or co-crystal, a malonate salt and/or co-crystal, a tartrate salt and/or co-crystal, a fumarate salt and/or co-crystal, a gentisate salt and/or co-crystal, or a glycolate salt and/or co-crystal.

2. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a phosphate salt and/or co-crystal, a tartrate salt and/or co-crystal, a glycolate salt and/or co-crystal, a fumarate salt and/or co-crystal, a gentisate salt and/or co-crystal, a malonate salt and/or co-crystal, or a nicotinate salt and/or co-crystal.

3. The pharmaceutically acceptable salt and/or co-crystal of claim 1 or 2, wherein the pharmaceutically acceptable salt and/or co-crystal is a nicotinate, phosphate, or tartrate salt and/or co-crystal.

4. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a nicotinate salt and/or co-crystal.

5. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a phosphate salt and/or co-crystal.

6. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a tartrate salt and/or co-crystal.

7. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is methanesulfonate salt and/or co-crystal.

8. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a toluenesulfonate salt and/or co-crystal.

9. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is benzenesulfonate salt and/or co-crystal.

10. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a sulfate salt and/or co-crystal.

11. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a malonate salt and/or co-crystal.

12. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is a fumarate salt and/or co-crystal.

13. The pharmaceutically acceptable salt and/or co-crystal of claim 12, wherein the fumarate salt and/or co-crystal is a 2:1 fumarate salt and/or co-crystal.

14. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is gentisate salt and/or co-crystal.

15. The pharmaceutically acceptable salt and/or co-crystal of claim 1, wherein the pharmaceutically acceptable salt and/or co-crystal is glycolate salt and/or co-crystal.

16. The pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 15, wherein the salt and/or co-crystal is crystalline.

17. The pharmaceutically acceptable salt and/or co-crystal of claim 16 comprising less than 40% by weight of amorphous compound.

18. A pharmaceutical composition comprising the pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 and a pharmaceutically acceptable excipient.

19. A method for treating a tetrahydrobiopterin-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

20. The method of claim 19, wherein the tetrahydrobiopterin-related disorder is phenylketonuria or a tetrahydrobiopterin deficiency.

21. A method of increasing tetrahydrobiopterin levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

22. A method of decreasing phenylalanine levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

23. A method of increasing the activity of phenylalanine hydroxylase in a subject, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

24. A method of treating phenylketonuria in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

25. A method of increasing serotonin levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

26. A method of increasing the activity of tryptophan hydroxylase in a subject, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

27. A method of increasing dopamine levels in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

28. A method of increasing the activity of tyrosine hydroxylase in a subject, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

29. A method of increasing the activity of nitric oxide synthases in a subject, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

30. A method of increasing the activity of alkylglycerol monooxygenase in a subject, the method comprising administering to the subject an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

31. The method of any one of claims 19 to 30, wherein the effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18 comprises an amount sufficient to increase the level of tetrahydrobiopterin in the plasma of the subject by at least a factor of two compared to the level of tetrahydrobiopterin prior to administration.

32. The method of any one of claims 19 to 30 wherein the effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18 comprises an amount sufficient to increase the level of tetrahydrobiopterin in the CSF and/or brain of the subject by at least a factor of two compared to the level of tetrahydrobiopterin prior to administration.

33. A method of increasing the level of homovanillic acid and/or 5-hydroxyindoleacetic acid in a subject, the method comprising administering an effective amount of a pharmaceutically acceptable salt and/or co-crystal of any one of claims 1 to 17 or a pharmaceutical composition of claim 18.

34. The method of claim 33, wherein the level of homovanillic acid and/or 5-hydroxyindoleacetic acid in the CSF of the subject is increased.

35. The method of claim 33 or 34, wherein the level of homovanillic acid and/or 5-hydroxyindoleacetic acid in the subject is increased at least 100% compared to the level prior to administration.

36. The method of any one of claims 19 to 35, wherein the subject is human.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0108] FIG. 1 is an IR spectrum of a free base of sepiapterin.

[0109] FIG. 2 is an IR spectrum of a hydrochloride salt and/or co-crystal of sepiapterin.

[0110] FIG. 3 is an IR spectrum of a methanesulfonate salt and/or co-crystal of sepiapterin.

[0111] FIG. 4 is an IR spectrum of a nicotinate salt and/or co-crystal of sepiapterin.

[0112] FIG. 5 is an IR spectrum of a toluenesulfonate salt and/or co-crystal of sepiapterin.

[0113] FIG. 6 is an IR spectrum of a benzenesulfonate salt and/or co-crystal of sepiapterin.

[0114] FIG. 7 is an IR spectrum of a sulfate salt and/or co-crystal of sepiapterin.

[0115] FIG. 8 is an IR spectrum of a phosphate salt and/or co-crystal of sepiapterin.

[0116] FIG. 9 is an IR spectrum of a L-tartrate salt and/or co-crystal of sepiapterin.

[0117] FIG. 10 is an IR spectrum of a glycolate salt and/or co-crystal of sepiapterin.

[0118] FIG. 11 is an IR spectrum of a malonate salt and/or co-crystal of sepiapterin.

[0119] FIG. 12 is an IR spectrum of a gentisate salt and/or co-crystal of sepiapterin.

[0120] FIG. 13 is an IR spectrum of a fumarate salt and/or co-crystal of sepiapterin.

DETAILED DESCRIPTION

[0121] The present invention features pharmaceutically acceptable salts and/or co-crystals of sepiapterin, compositions thereof, and methods for the treatment of tetrahydrobiopterin-related disorders with such compositions. The present inventors have surprisingly found that some salts and/or co-crystals of sepiapterin have improved properties, e.g., improved stability, purity, exposure, and/or bioavailability.

Compounds

[0122] Sepiapterin

[0123] The pharmaceutical compositions of the invention comprise sepiapterin, or a pharmaceutically acceptable salt and/or co-crystal thereof. Sepiapterin has the structure:

##STR00001##

[0124] In some embodiments, a pharmaceutically acceptable salt and/or co-crystal of sepiapterin is present in a pharmaceutical composition of the invention in a crystalline form, as described herein.

[0125] In some embodiments, a pharmaceutical composition of the invention includes 20-30% of a pharmaceutically acceptable salt and/or co-crystal of sepiapterin by total weight, e.g., 20%, 22%, 25%, 27%, or 30%. In some embodiments, a pharmaceutical composition includes greater than 20% of a pharmaceutically acceptable salt and/or co-crystal of sepiapterin by total weight, e.g., greater than 25%, greater than 30%, greater than 40%, greater than 50%, greater than 60%, greater than 70%, greater than 80%, or greater than 90%.

[0126] Tetrahydrobiopterin

[0127] Sepiapterin, upon administration to a subject, is converted to tetrahydrobiopterin. Tetrahydrobiopterin has the structure:

##STR00002##

[0128] Lactoylpterin

[0129] An impurity that may be present in sepiapterin preparations is lactoylpterin, which may result from oxidation of sepiapterin. Lactoylpterin has the structure:

##STR00003##

Excipients

[0130] Antioxidants

[0131] Sepiapterin is prone to rapid oxidation when exposed to air. Accordingly, a pharmaceutical composition of the invention may include an antioxidant. The antioxidant may minimize the oxidative degradation of sepiapterin. Examples of antioxidants include, but are not limited to, 4-chloro-2,6-di-tert-butylphenol, tocopherol, alpha-tocopherol, alkylated diphenylamines, ascorbic acid, ascorbyl myristate, ascorbyl palmitate, ascorbyl stearate, beta-carotene, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, cysteine, D-alpha-tocopheryl polyethylene glycol 1000 succinate, deferoxamine methanesulfonate, dodecyl gallate, ethylparaben, folic acid, fumaric acid, gallic acid, glutathione, lecithin, malic acid, methylparaben, monothioglycerol, N-acetyl cysteine, nordihydroguaiaretic acid, octyl gallate, p-phenylenediamine, potassium ascorbate, potassium metabisulfite, potassium sorbate, propionic acid, propyl gallate, retinol, sorbic acid, sodium ascorbate, sodium bisulfite, sodium hydrosulfite, sodium isoascorbate, sodium metabisulfite, sodium sulfite, sodium thiosulfate, tartaric acid, tert-butylhydroquinone, tocopheryl acetate, vitamin A, vitamin B6, vitamin 12, or vitamin E. In some embodiments, a pharmaceutical composition of the invention includes ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetyl cysteine, glutathione, butylatedhydroxytoluene, and/or butylatedhydroxyanisole as antioxidant.

[0132] In some embodiments, the pharmaceutical composition includes less than 10% antioxidant by weight, e.g., less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, or less than 1%. In some embodiments, the pharmaceutical composition includes 2-9% antioxidant by total weight, e.g., 2-4%, 3-5%, 4-6%, 5-7%, 6-8%, or 7-9%. In some embodiments, the pharmaceutical composition includes 5-100% of the USP maximum daily dose of the antioxidant, e.g., in some embodiments, the pharmaceutical composition includes 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the USP maximum daily dose of the antioxidant. In some embodiments, the ratio of sepiapterin or pharmaceutically acceptable salt and/or co-crystal thereof to antioxidant is at least 1:1, e.g., 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1 wt/wt. In some embodiments of any of the foregoing compositions, the composition includes an antioxidant (e.g., ascorbic acid), wherein the ratio of the pharmaceutically acceptable salt and/or co-crystal of sepiapterin to antioxidant is greater than 4:1 (e.g., greater than 5:1, greater than 6:1, greater than 7:1, greater than 8:1, greater than 9:1, greater than 10:1, greater than 15:1, or greater than 20:1) by weight (e.g., the weight of the salt to antioxidant).

[0133] As previous formulations of sepiapterin included as much as 50% antioxidant (e.g., ascorbic acid) or more, it is surprising that compositions including less than 10% antioxidant or even no antioxidant are effective at stabilizing pharmaceutically acceptable salts and/or co-crystals of sepiapterin.

[0134] Dispersants

[0135] In some embodiments, a pharmaceutical composition of the invention includes at least one dispersant. The dispersant may cause particles in the formulation to separate, e.g., release their medicinal substances on contact with moisture. Examples of dispersant include, but are not limited to, crosslinked polyvinylpyrrolidone, carboxymethylcellulose (e.g., croscarmellose salt, e.g., croscarmellose sodium), starch (e.g., sodium starch glycolate), or alginic acid. In some embodiments, the dispersant in the pharmaceutical composition is a carboxymethylcellulose such as a pharmaceutically acceptable salt of croscarmellose. In some embodiments, the pharmaceutical composition may include 0.1-1.5% dispersant by total weight, e.g., 0.1%, 0.5%, 1%, or 1.5%. In some embodiments, the pharmaceutical composition includes less than 1.5% dispersant, e.g., less than 1%, less than 0.5%, or less than 0.1%.

[0136] Anti-Caking Agents

[0137] Sepiapterin has been found to clump when added to aqueous solutions. Anti-caking agents are often added to pharmaceutical compositions to prevent the formation of lumps, e.g., in solutions. Accordingly, in some embodiments, the pharmaceutical compositions of the invention include at least one anti-caking agent. In some embodiments, the pharmaceutical compositions include at least two anti-caking agents. Exemplary anti-caking agents include colloidal silicon dioxide, microcrystalline cellulose, tricalcium phosphate, microcrystalline cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, colloidal silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, and polydimethylsiloxane. In some embodiments, the at least one anti-caking agent is colloidal silicon dioxide or microcrystalline cellulose. In some embodiments, the pharmaceutical composition may include 65-75% anti-caking agent by total weight, e.g., 65%, 67%, 70%, 73%, or 75%. In some embodiments, the pharmaceutical composition includes both colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, the pharmaceutical composition includes 60-65% microcrystalline cellulose by total weight and 5-7% colloidal silicon dioxide by total weight.

[0138] Dosing Vehicle

[0139] In some embodiments, a pharmaceutical composition of the invention is combined with a dosing vehicle prior to administration. In some embodiments of any of the foregoing compositions, the composition may be administered in a dosing vehicle with a viscosity of approximately 50-1750 centipoise (cP), e.g., to aid suspension and dosing of the pharmaceutical composition. One type of suspending agent that can be used is a combination of glycerin and sucrose in water (e.g., MEDISCA® oral mix with 2.5% glycerin and 27% sucrose in water). An appropriate quantity of composition can be added to the dosing vehicle mixture and agitated to suspend the composition just prior to administration.

[0140] Other suspending agents may also be used as a dosing vehicle. Exemplary suspending agents include agar, alginic acid, sodium carboxymethyl cellulose, carrageenan, dextrin, gelatin, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, methyl cellulose, polyethylene glycol, povidone, tragacanth, xanthan gum, or other suspending agents known in the art.

[0141] Formulations

[0142] In some embodiments, the invention features a pharmaceutical composition including a pharmaceutically acceptable salt and/or co-crystal of sepiapterin, e.g., and less than 10% by total weight of an antioxidant, e.g., 9%, 7%, 5%, 3%, 1%, 0.5%, 0.25%, or 0.1%. The antioxidant may be ascorbic acid. In some embodiments, the ratio of the pharmaceutically acceptable salt and/or co-crystal of sepiapterin to the antioxidant is 1:1, e.g., 2:1, 5:1, 7:1, or 10:1 wt/wt. In some embodiments of any of the foregoing compositions, the composition includes an antioxidant (e.g., ascorbic acid), wherein the ratio of the pharmaceutically acceptable salt and/or co-crystal of sepiapterin to antioxidant is greater than 4:1 (e.g., greater than 5:1, greater than 6:1, greater than 7:1, greater than 8:1, greater than 9:1, greater than 10:1, greater than 15:1, or greater than 20:1) by weight (e.g., the weight of the salt to antioxidant). A pharmaceutical composition may include 20-30% a pharmaceutically acceptable salt and/or co-crystal of sepiapterin by total weight, e.g., 20%, 22%, 25%, 27%, or 30%. A pharmaceutical composition can further include a dispersant, e.g., croscarmellose sodium. The pharmaceutical composition may include 0.1-1.5% dispersant by total weight, e.g., 0.1%, 0.5%, 1%, or 1.5%. In some embodiments, a pharmaceutical formulation includes at least one anti-caking agent, e.g., colloidal silicon dioxide or microcrystalline cellulose. A pharmaceutical composition may include 65-75% anti-caking agent by total weight, e.g., 65%, 67%, 70%, 73%, or 75%. In some embodiments, a pharmaceutical composition includes both colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, a pharmaceutical composition includes 60-65% microcrystalline cellulose by total weight and 5-7% colloidal silicon dioxide by total weight. In some embodiments, the pharmaceutically acceptable salt and/or co-crystal of sepiapterin is formulated as particles less than 140 μm in size, e.g., 120 μm, 110 μm, 100 μm, 90 μm, 80 μm, 70 μm, 60 μm, 50 μm, 40 μm, 30 μm, 20 μm, 10 μm, or 5 μm. In some embodiments, a pharmaceutical composition includes less than 1.3%, e.g., less than 1%, of an impurity such as lactoylpterin, e.g., the composition includes less than 0.9%, less than 0.8%, less than 0.7%, less than 0.6%, less than 0.5%, less than 0.4%, less than 0.3%, or less than 0.2%.

[0143] A pharmaceutically acceptable salt and/or co-crystal of sepiapterin may serve as a useful therapeutic for diseases associated with low intracellular BH4 levels or with dysfunction of various BH4 dependent metabolic pathways including, but not limited to, primary tetrahydrobiopterin deficiency, GTPCH deficiency, 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, DHPR deficiency, sepiapterin reductase deficiency, dopamine responsive dystonia, Segawa Syndrome, tyrosine hydroxylase deficiency, phenylketonuria, DNAJC12 deficiency, Parkinson's Disease, depression due to Parkinson's Disease, impulsivity in Parkinson's patients, major depression, Autism spectrum, ADHD, schizophrenia, Bipolar disorder, cerebral ischemia, restless leg syndrome, Obsessive Compulsive Disorder, anxiety, aggression in Alzheimer's disease, cerebrovascular disorders, spasm after subarachnoidal hemorrhage, myocarditis, coronary vasospasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infections, endotoxin shock, hepatic cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, and hypoglycemia. Thus, the various forms of sepiapterin in accordance with the present invention can be administered to a patient in an effective amount to obtain a treatment or amelioration of the disease, disorder or condition.

[0144] In some embodiments, the salt and/or co-crystal is a salt and/or co-crystal of sepiapterin with sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, tartaric acid (e.g., L-tartaric acid), phosphoric acid, gentisic acid, fumaric acid, glycolic acid, acetic acid, or nicotinic acid.

[0145] In some embodiments, the pharmaceutical composition comprises a crystalline salt and/or co-crystal of sepiapterin. The crystalline salt and/or co-crystal of sepiapterin can occur as an anhydrate (e.g., without having any bound water or solvent or hydration or solvation) or as a hydrate, a partial hydrate (e.g., hemihydrate, sesquihydrate), as a dihydrate, a trihydrate, wherein the crystalline form binds a water of hydration or a solvent molecule associated with the crystalline form of sepiapterin or salt and/or co-crystal thereof. In an embodiment, crystalline salt and/or co-crystal of sepiapterin occurs as a monohydrate or as a hemihydrate.

[0146] The present invention provides a pharmaceutical composition including a pharmaceutically acceptable carrier and an effective amount, e.g., a therapeutically effective amount, including a prophylactically effective amount, of a pharmaceutically acceptable salt and/or co-crystal of sepiapterin.

[0147] The pharmaceutically acceptable carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical compositions; a pharmaceutically acceptable salt and/or co-crystal of sepiapterin can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.

[0148] The pharmaceutically acceptable carriers described herein, for example, vehicles, adjuvants, excipients, or diluents, are well known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one which is chemically inert to the active compounds and one which has no detrimental side effects or toxicity under the conditions of use.

Dosage

[0149] A pharmaceutically acceptable salt of sepiapterin can be used in any suitable dose. Suitable doses and dosage regimens can be determined by conventional range finding techniques. Generally treatment is initiated with smaller dosages, which are less than the optimum dose. Thereafter, the dosage is increased by small increments until optimum effect under the circumstances is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired. In proper doses and with suitable administration of certain compounds, the present invention provides for a wide range of responses. Typically, the dosages range from about 2.5 to about 150 mg/kg body weight of the patient being treated/day. For example, in embodiments, a pharmaceutically acceptable salt of sepiapterin, may be administered from about 20 mg/kg to about 200 mg/kg, from about 40 mg/kg to about 150 mg/kg, from about 60 mg/kg to about 120 mg/kg, from about 80 mg/kg to about 100 mg/kg, from about 40 mg/kg to about 60 mg/kg, from about 2.5 mg/kg to about 20 mg/kg, from about 2.5 mg/kg to about 10 mg/kg, from about 2.5 mg/kg to about 5 mg/kg, of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0150] In some embodiments, the dose is an amount sufficient to produce levels of BH4 in the CNS, e.g., as measured in the CSF and/or brain and/or sufficient to produce a therapeutic results, e.g., increased levels of serotonin or dopamine in the CNS. In some embodiments, the dose is an amount sufficient to increase levels of BH4 at least two times greater than the levels of BH4 prior to administration as measured in the plasma or an organ of the subject, e.g., the liver of the subject.

[0151] In some embodiments, a pharmaceutically acceptable salt and/or co-crystal of sepiapterin can be formulated into unit solid oral dosage forms such as particles. In these embodiments, each unit solid oral dosage form can comprise any suitable amount of a pharmaceutically acceptable salt and/or co-crystal of sepiapterin. For example, each solid oral dosage form can comprise about 2.5 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 125 mg, about 150 mg, about 175 mg, about 200 mg, about 225 mg, about 250 mg, about 275 mg, about 300 mg, about 325 mg, about 350 mg, about 375 mg, about 400 mg, about 425 mg, about 450 mg, about 475 mg, or about 500 mg.

Routes of Administration

[0152] The choice of carrier will be determined in part by the particular active agent, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intra-arterial, intramuscular, intraperitoneal, intrathecal, rectal, and vaginal administration are merely exemplary and are in no way limiting.

[0153] A pharmaceutical composition may be a liquid formulation, such as in the form of a solution, suspension, or emulsion. Formulations suitable for oral administration can consist of (a) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (b) powders; (c) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Preferred are solid oral dosage forms such as capsule forms, tablet forms, and powder forms. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and cornstarch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible carriers. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such carriers as are known in the art.

[0154] Formulations suitable for oral and/or parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The compound can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, benzyl alcohol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol and other polyethylene alcohols, glycerol ketals, such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers, such as poly(ethylene glycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants.

[0155] Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-beta-aminopropionates, and 2-alkyl-imidazopeak quaternary ammonium salts, and (3) mixtures thereof.

[0156] The parenteral formulations will typically contain from about 20 to about 30% by weight of sepiapterin or pharmaceutically acceptable salt and/or co-crystal thereof in solution. Suitable preservatives and buffers can be used in such formulations. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations ranges from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

[0157] A pharmaceutical composition may be an injectable formulation. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art. See Remington: The Science and Practice of Pharmacy, (22nd ed.) ed. L. V. Allen, Jr., 2013, Pharmaceutical Press, Philadelphia, Pa.

[0158] Topical formulations, including those that are useful for transdermal drug release, are well-known to those of skill in the art and are suitable in the context of the invention for application to skin. Topically applied compositions are generally in the form of liquids, creams, pastes, lotions and gels. Topical administration includes application to the oral mucosa, which includes the oral cavity, oral epithelium, palate, gingival, and the nasal mucosa. In some embodiments, the composition contains sepiapterin and a suitable vehicle or carrier. It may also contain other components, such as an anti-irritant. The carrier can be a liquid, solid or semi-solid. In embodiments, the composition is an aqueous solution. Alternatively, the composition can be a dispersion, emulsion, gel, lotion or cream vehicle for the various components. In one embodiment, the primary vehicle is water or a biocompatible solvent that is substantially neutral or that has been rendered substantially neutral. The liquid vehicle can include other materials, such as buffers, alcohols, glycerin, and mineral oils with various emulsifiers or dispersing agents as known in the art to obtain the desired pH, consistency and viscosity. It is possible that the compositions can be produced as solids, such as powders or granules. The solids can be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or that has been rendered substantially neutral and that can then be applied to the target site. In embodiments of the invention, the vehicle for topical application to the skin can include water, buffered solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin and silicone based materials.

[0159] A pharmaceutical composition may be an aerosol formulation to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also may be formulated as pharmaceuticals for non-pressured preparations, such as in a nebulizer or an atomizer.

[0160] Additionally, a pharmaceutical composition may be a suppository. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or spray formulas containing, in addition to the active ingredient, such carriers as are known in the art to be appropriate.

[0161] Solid Dosage Form for Oral Administration

[0162] Formulations for oral use include particles containing the active ingredient(s) in a mixture with non-toxic pharmaceutically acceptable excipients, and such formulations are known to the skilled artisan (e.g., U.S. Pat. Nos. 5,817,307, 5,824,300, 5,830,456, 5,846,526, 5,882,640, 5,910,304, 6,036,949, 6,036,949, 6,372,218, hereby incorporated by reference). Excipients may be, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starches including potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate); granulating and disintegrating agents (e.g., cellulose derivatives including microcrystalline cellulose, starches including potato starch, croscarmellose sodium, alginates, or alginic acid); binding agents (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pregelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, carboxymethylcellulose sodium, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone, or polyethylene glycol); and lubricating agents, glidants, anti-adhesives (e.g., magnesium stearate, zinc stearate, stearic acid, silicas, hydrogenated vegetable oils, or talc), and anti-caking agents (e.g., colloidal silicon dioxide, microcrystalline cellulose, tricalcium phosphate, microcrystalline cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, colloidal silicon dioxide, calcium silicate, magnesium trisilicate, talcum powder, sodium aluminosilicate, potassium aluminum silicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane). Other pharmaceutically acceptable excipients can be colorants, flavoring agents, plasticizers, humectants, and buffering agents. In some embodiments, excipients (e.g., flavoring agents) are packaged with the composition. In some embodiments, excipients (e.g., flavorings) are packaged separately from the composition (e.g., are combined with the composition prior to administration).

[0163] The solid compositions of the invention may include a coating adapted to protect the composition from unwanted chemical changes, (e.g., chemical degradation prior to the release of the active substances). The coating may be applied on the solid dosage form in a similar manner as that described in Remington: The Science and Practice of Pharmacy, (22nd ed.) ed. L. V. Allen, Jr., 2013, Pharmaceutical Press, Philadelphia, Pa.

[0164] Powders and granulates may be prepared using the ingredients mentioned above in a conventional manner using, e.g., a mixer, a fluid bed apparatus, melt congeal apparatus, rotor granulator, extrusion/spheronizer, or spray drying equipment.

Methods of Treatment

[0165] The present invention features pharmaceutical compositions, e.g., in an orally tolerable formula that contains a therapeutically effective amount of a pharmaceutically acceptable salt and/or co-crystal of sepiapterin, e.g., and less than 10% antioxidant. In some embodiments, the pharmaceutical composition is a granular formulation that is dispersed in a pharmaceutically acceptable carrier, for example the composition can be mixed into water and ingested by a patient (e.g., over the course of 5 to 10 minutes). Suitable formulations for use in the present invention are found in Remington: The Science and Practice of Pharmacy, (22nd ed.) ed. L. V. Allen, Jr., 2013, Pharmaceutical Press, Philadelphia, Pa. Except insofar as any conventional carrier is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated. Moreover, for animal (e.g., human) administration, it will be understood that preparations should meet sterility, pyrogenicity, general safety and purity standards as required by regulatory agencies.

[0166] The actual dosage amount of a composition of the present invention administered to a patient can be determined by physical and physiological factors such as body weight, severity of condition, the type of disease being treated, previous or concurrent therapeutic interventions, idiopathy of the patient and on the route of administration. Depending upon the dosage and the route of administration, the number of administrations of a preferred dosage and/or an effective amount may vary according to the response of the subject. The practitioner responsible for administration will, in any event, determine the concentration of active ingredient(s) in a composition and appropriate dose(s) for the individual subject.

[0167] In some embodiments, patients receive 2.5 mg/kg/day, 5 mg/kg/day 10 mg/kg/day 20 mg/kg/day, 40 mg/kg/day, 60 mg/kg/day, or 80 mg/kg/day of a pharmaceutically acceptable salt and/or co-crystal of sepiapterin. Patients may receive the pharmaceutical composition including sepiapterin once daily, twice daily or three times daily during treatment In some embodiments, patients continue their other current medications for BH4-related disorder (e.g., L-dopa/carbidopa, 5HTP, melatonin, MAO inhibitors, and dopamine receptor agonists as prescribed) except for BH4 supplementation (if they are taking BH4). Patients may not be permitted to take any drugs known to inhibit folate synthesis (e.g., methotrexate, pemetrexed, or trimetrexate).

[0168] In some embodiments, patients taking BH4 therapy prior to study entry undergo a “washout” period during screening prior to administration of the pharmaceutical composition of the invention. Patients may be instructed to maintain a consistent diet, with respect to protein and phenylalanine (Phe) intake. Diet records may be reviewed by a qualified dietician. Total Phe concentrations for the 3-day period may be calculated by the dietician and recorded.

[0169] In some embodiments, patients who are taking BH4 discontinue administration of BH4 (i.e., BH4 washout). Blood samples for Phe concentrations may be obtained during the BH4 washout period at 7, 5, 3, and 1 day before the treatment with the pharmaceutical composition of the invention or until blood Phe levels are >360 μmol/L at any time point during BH4 washout. In some embodiments, pre-dose blood sample are tested for sepiapterin, Phe, BH4, and tyrosine (Tyr).

Methods of Producing Formulations

[0170] In some embodiments, a pharmaceutical composition of the invention may be produced by mixing sepiapterin or pharmaceutically acceptable salt and/or co-crystal thereof and an antioxidant with one or more excipients, e.g., a dispersant and one or more anti-caking agents. In some embodiments, each of the components of the composition are passed through a size exclusion filter (e.g., a filter having pores of 200 μm or less) prior to mixing. In some embodiments, the anti-caking agents are mixed together prior to the addition of the components (e.g., the sepiapterin, dispersant, and antioxidant).

[0171] In some embodiments, the pharmaceutical composition is produced by:

[0172] (a) passing at least one anti-caking agent through a size exclusion filter (e.g., a filter having pores less than 200 μm);

[0173] (b) combining the sepiapterin, antioxidant, and optionally a dispersant with the at least one anti-caking agent (e.g., by mixing in a blender); and

[0174] (c) passing the combination of step b through a size exclusion filter (e.g., a filter having pores less than 150 μm).

[0175] In some embodiments, the at least one anti-caking agent of step a includes more than one anti-caking agent (e.g., two anti-caking agents) that have been mixed together prior to be passed through the size exclusion filter.

EXAMPLES

[0176] While certain features of the invention have been illustrated and described herein, many modifications, substitutions, changes, and equivalents will now occur to those of ordinary skill in the art. It is, therefore, to be understood that the appended claims are intended to cover all such modifications and changes as fall within the true spirit of the invention. As such, the following examples are provided to teach various aspects of the present invention. These examples represent individual embodiments of the aspects of this invention and one skilled in the art will recognize that additional examples can be generated in order to equally teach the aspects of the present invention.

Example 1. Preparation of Salts of Sepiapterin

[0177] Salts and/or co-crystals of sepiapterin and hydrochloric acid, methanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, nicotinic acid, sulfuric acid, phosphoric acid, malonic acid, L-tartric acid, fumaric acid, gentisic acid, and glycolic acid were produced by slurrying the free base of sepiapterin and the acid in acetone/water (9/1, v/v) or methanol for 2-17 days.

[0178] The salts were analyzed by DSC, TGA, HPLC, IR, and XRPD. The results are summarized in Table 15 below. The IR spectra are shown in FIGS. 1-13.

TABLE-US-00015 TABLE 15 Summary of sepiapterin salt and/or co-crystal analysis TGA Weight DSC Molar Weight loss Endotherm ratio Residual Salt form (mg) (%) (° C., onset) Purity (%) (FB:acid) solvent HCl Salt 190.9 3.6 218.3 93.94 1:1.3 Negligible Acetone Methanesulfonate 188.0 4.23 182.3 91.14 1:1.0 Negligible MeOH Nicotinate 246.0 1.27 220.4 97.16 1:0.9 None Toluenesulfonate 256.4 0.5 190.3, 262.9 96.84 1:1.0 None Benzenesulfonate 173.3 1.54 192.7, 206.2 90.20 1:1.0 Negligible MeOH Sulfate 227.5 2.6 196.5 97.33 1:0.6 None Phosphate 235.8 11.2 144.0, 206.8 96.75 1:1.1 None Malonate 95.8 3.83 175.1 99.45 TBD None L-Tartrate 232.2 1.14 156.5, 174.6 99.75 1:1.0 Negligible Acetone Fumarate 217.3 4.81 77.3, 132.8, 99.46 1:0.6 Negligible 190.1 Acetone Gentisate 98.1 6.92 83.2, 133.8, 94.35 1:0.5 None 149.0 Glycolate 135.4 20.15 79.3, 90.0, 99.19 1:0.3 None 132.3, 151.6 FB = free base

Example 2. Stability Analysis of Salts and/or Co-Crystals of Sepiapterin

[0179] The stability of the prepared salts and/or co-crystals was analyzed after 1 and 2 weeks at 25° C. and 60% relative humidity and 40° C. and 75% relative humidity. The results are summarized in Table 16 below. Surprisingly, of all the salts and/or co-crystals tested, the phosphate salt and/or co-crystal, the tartrate salt and/or co-crystal, and the nicotinate salt and/or co-crystal were noticeably more stable than the others. None of the phosphate, tartrate, or nicotinate salts and/or co-crystals underwent a form change during the stability testing, and each of them retained greater than 97% purity over the two weeks of the study. In fact, both the tartrate and nicotinate both retained greater than 99% purity.

TABLE-US-00016 TABLE 16 Summary of stability study results Purity vs. Time Purity initial Salt point Condition Form change (Area %) (%) Phosphate Initial NA NA 96.75 NA 1 week 25° C./60% No 95.35 98.6 RH 40° C./75% No 95.91 99.1 RH 2 weeks 25° C./60% No 95.87 99.1 RH 40° C./75% No 94.50 97.7 RH L-Tartrate Initial NA NA 99.75 NA 1 week 25° C/60% No 98.61 99.9 RH 40° C./75% No 99.06 99.3 RH 2 weeks 25° C/60% No 99.39 99.6 RH 40° C/75% No 99.00 99.3 RH Glycolate Initial NA NA 99.19 NA 1 week 25° C./60% Glycolate and free 98.93 99.7 RH base 40° C./75% Glycolate and free 98.54 99.3 RH base 2 weeks 25° C./60% Glycolate and free 98.86 99.7 RH base 40° C./75% Glycolate and free 98.52 99.3 RH base Fumarate Initial NA NA 99.46 NA 1 week 25° C./60% No 99.39 99.9 RH 40° C./75% No 99.15 99.7 RH 2 weeks 25° C./60% Fumarate and free 99.25 99.7 RH base 40° C./75% Fumarate and free 98.98 99.5 RH base Gentisate Initial NA NA 94.35 NA 1 week 25° C./60% Gentisate and free 97.66 103.5 RH base 40° C/75% Gentisate and free 96.89 102.7 RH base 2 weeks 25° C/60% Gentisate and free 97.00 102.8 RH base 40° C/75% Gentisate and free 93.37 102.1 RH base Malonate Initial NA NA 99.45 NA 1 week 25° C./60% Malonate and free 99.39 99.9 RH base 40° C./75% Malonate and free 99.14 99.7 RH base 2 weeks 25° C./60% Malonate and free 99.23 99.8 RH base 40° C./75% Malonate and free 97.81 98.3 RH base HCl Initial NA NA 93.94 NA 1 week 25° C./60% No 97.19 103.5 RH 40° C./75% No 89.25 95.0 RH 2 weeks 25° C./60% No 91.84 97.8 RH 40° C./75% No 84.16 89.6 RH Methanesulfonate Initial NA NA 91.14 NA 1 week 25° C./60% No 95.26 104.5 RH 40° C./75% No 88.68 97.3 RH 2 weeks 25° C./60% No 91.95 100.9 RH 40° C./75% No 85.97 94.3 RH Nicotinate Initial NA NA 97.16 NA 1 week 25° C./60% No 97.43 100.3 RH 40° C./75% No 97.30 100.2 RH 2 weeks 25° C./60% No 97.45 100.3 RH 40° C./75% No 97.41 100.3 RH Toluenesulfonate Initial NA NA 96.84 NA 1 week 25° C./60% No 94.19 97.3 RH 40° C./75% No 89.11 92.0 RH 2 weeks 25° C./60% No 91.40 94.4 RH 40° C./75% No 88.12 91.0 RH Benzenesulfonate Initial NA NA 90.20 NA 1 week 25° C./60% No 90.68 100.5 RH 40° C./75% No 82.63 91.6 RH 2 weeks 25° C./60% No 86.37 95.8 RH 40° C./75% No 82.65 91.6 RH Sulfate Initial NA NA 97.33 NA 1 week 25° C./60% No 95.22 97.8 RH 40° C./75% No 89.44 91.9 RH 2 weeks 25° C./60% No 93.46 96.0 RH 40° C./75% No 88.20 90.6 RH NA—Not applicable; RH—relative humidity

Example 3. Solubility and Disproportionation of Various Sepiapterin Salts and/or Co-Crystals

[0180] The kinetic solubility was evaluated for nicotinate, phosphate, L-tartrate, and fumarate salts and/or co-crystals of sepiapterin in water and Medisca Oral Mix. X-ray powder diffraction (XRPD) was performed for the residual solids to identify form change/disproportionation. Solids were suspended into the media with target conc. of ˜7 mg/mL (calculated by freebase). The suspensions were agitated on a rolling incubator at 25 rpm for 1, 4 and 24 hrs. At each time point, 1 mL of the suspension was pipetted out for centrifugation at 10000 rpm (2 min) and filtration through 0.45 μm membrane to obtain supernatant for HPLC solubility and pH tests, the residual solids were analyzed by XRPD. The solubility results are summarized in Tables 17-20.

TABLE-US-00017 TABLE 17 Solubility summary of nicotinate salt and/or co-crystal Time point Temp. Solubility Purity Ob- Form Media (hr) (° C.) (mg/mL)* (area %).sup.# servation change pH Water 1 RT 1.5 98.97 Turbid Yes 2.1 4 2.3 99.04 Turbid Yes 2.1 24 1.8 96.54 Turbid Yes 2.1 Medisca 1 2.6 99.76 Turbid Yes 3.1 Oral 4 3.1 99.60 Turbid Yes 3.1 Mix 24 3.5 97.00 Turbid Yes 3.1 *Calculated using freebase. .sup.#Excess amount of salt sample was dosed for solubility measurement, which may lead to impurity enrichment in supernatant, so the purity data is for reference only.

TABLE-US-00018 TABLE 18 Solubility summary of phosphate salt and/or co-crystal Time point Temp. Solubility Purity Ob- Form Media (hr) (° C.) (mg/mL)* (area %).sup.# servation change pH Water 1 RT 1.7 89.92 Turbid Yes  2.1 4 2.0 89.52 Turbid Yes  2.1 24 1.9 82.64 Turbid Yes  2.1 Medisca 1 2.5 99.23 Turbid Yes** 3.1 Oral 4 3.2 98.95 Turbid Yes** 3.1 Mix 24 2.1 87.63 Turbid Yes** 3.1 *Calculated using freebase. **Low crystallinity. .sup.#Excess amount of salt sample was dosed for solubility measurement, which may lead to impurity enrichment in supernatant, so the purity data is for reference only.

TABLE-US-00019 TABLE 19 Solubility summary of L-tartrate salt and/or co-crystal Time point Temp. Solubility Purity Ob- Form Media (hr) (° C.) (mg/mL)* (area %).sup.# servation change pH Water 1 RT 1.6 99.34 Turbid Yes 2.5 4 1.8 99.07 Turbid Yes 2.5 24 1.8 95.61 Turbid Yes 2.5 Medisca 1 2.0 99.68 Turbid Yes 3.3 Oral 4 2.5 99.54 Turbid Yes 3.3 Mix 24 3.2 95.67 Turbid Yes 3.3 *Calculated using freebase. .sup.#Excess amount of salt sample was dosed for solubility measurement, which may lead to impurity enrichment in supernatant, so the purity data was for reference only.

TABLE-US-00020 TABLE 20 Solubility summary of fumarate salt and/or co-crystal Time point Temp. Solubility Purity Ob- Form Media (hr) (° C.) (mg/mL)* (area %).sup.# servation change pH Water 1 AT 1.2 98.39 Turbid No  3.1 4 1.4 98.19 Turbid No  3.1 24 1.5 95.43 Turbid No  3.1 Medisca 1 2.2 99.74 Turbid No** 4.0 Oral 4 3.1 99.60 Turbid No** 4.0 Mix 24 2.9 96.54 Turbid No** 4.0 *Calculated using freebase. **Low crystallinity impurity .sup.#Excess amount of salt sample was dosed for solubility measurement, which may lead to enrichment in supernatant, so the purity data was for reference only.

[0181] Results: For the nicotinate, phosphate, and L-tartrate salts and/or co-crystals, the residual solids converted to freebase in water and Medisca Oral Mix after 1 hour. For the fumarate salt and/or co-crystal, no form change was observed for the residual solids in water while the crystallinity of residual solids decreased after 1 hour in Medisca Oral Mix. Surprisingly, of the twelve different salt and/or co-crystal forms studied, the fumarate salt and/or co-crystal was the only salt and/or co-crystal found to have high stability in the solid form stability study of Example 2 and show no evidence of disproportionation in the disproportionation study.

OTHER EMBODIMENTS

[0182] While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure that come within known or customary practice within the art to which the invention pertains and may be applied to the essential features herein before set forth.