COMPOSITIONS AND METHODS FOR INCREASING PLASMA EXPOSURE OF TETRAHYDROBIOPTERIN

Abstract

The present invention presents pharmaceutical compositions comprising sepiapterin, or a pharmaceutically acceptable salt thereof, and methods for treating BH4-related disorders. In some embodiments, these compositions and methods result in increased plasma exposure to BH4.

Description

COMPOSITIONS AND METHODS FOR INCREASING PLASMA EXPOSURE OF TETRAHYDROBIOPTERIN Background of the invention Septiapterin is a naturally occurring precursor of tetrahydrobiopterin (BH4), an essential cofactor of critical naturally occurring intracellular enzymes including, but not limited to, phenylalanine hydroxylase (PAH) (Kaufman, 1958), tyrosine hydroxylase (TH) (Nagatsu et al., 1964), tryptophan hydroxylase (TPH) (Ichiyama et al., 1970), nitric oxide synthase (NOS) (Kwon et al., 1989; Mayer et al., 1991), and alkylglycerol monooxygenase (AGMO) (Tietz et al., 1964). The rapid conversion of sepiapterin to BH4 occurs via a two-step reduction in the salvage pathway for BH4 synthesis (Sawabe, 2008). A synthetic form of BH4 (e.g., sapropterin dihydrochloride) is used as a therapy for diseases associated with high plasma phenylalanine, such as phenylketonuria (PKU). PKU is an inborn error of metabolism caused predominantly by mutations in the PAH gene.BH4 was also tested as a therapy for various central nervous system symptoms associated with PKU and other diseases, but showed limited effect, presumably due to BH4's inability to cross the blood-brain barrier effectively (Klaiman et al, 2013; Grant et al, 2015). Recent work has suggested that, compared to BH4, peripherally administered sepiapterin has greater permeability across cell membranes and, as a result, can more easily access liver, kidney, and brain cells. Sepiapterin is reported to be rapidly converted to BH4 intracellularly, thereby raising BH4 levels in the liver, kidney, and brain (Sawabe, 2008). Consequently, sepiapterin may serve as a useful therapeutic agent for diseases associated with low intracellular BH4 levels or with dysfunction of various BH4-dependent metabolic pathways. Brief description of the inventionThe present invention relates to the discovery that administering sepiapterin with food to a subject unexpectedly results in increased BH4 production and the resulting plasma BH4 exposure, CSF exposure, and / or exposure to the subject's brain.Not limited by theory, the increased plasma exposure to BH4 may result from delayed absorption of sepiapterin due to increased gastric residence time, or a prolonged rate of sepiapterin absorption due to increased prior intestinal residence time, or from prolonged intracellular concentrations of sepiapterin below, at, or slightly above the maximum enzymatic activity velocity (Vmax) for sepiapterin reductase or dihydrofolate reductase, or a combination thereof, resulting in a higher percentage of administered sepiapterin being converted to BH4 prior to passive or active transport into circulation for excretion and / or elimination. The present invention presents pharmaceutical compositions comprising sepiapterin, or a salt thereof, and methods for treating BH4-related disorders.In some modalities, these compositions and methods result in an increase in plasma exposure of BH4. RQnQZn / LZnZ / q / YL As is known in the field, food can influence the absorption of compounds. Absorption may be delayed, but not reduced, or the total amount of drug absorbed may be reduced. The effect of food may be due to a slowing of gastric residence time, a slowing of anterior intestinal residence time, decreased access of the compound to absorption sites, altered dissolution rate of the compound, or altered stomach pH. Because of these effects, it is important to establish a specific dosing schedule for drugs that must be administered with or without food. In one aspect, the invention presents a method for treating a BH4-related disorder in a subject in need thereof, by administering an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, with food. In another aspect, the invention presents a method for increasing plasma exposure of BH4 in a subject receiving sepiapterin therapy by administering to the subject an effective amount of sepiapterin, or an acceptable pharmaceutical salt thereof, with food. In a further aspect, the invention presents a method for reducing the absorption rate of an oral dosage form of sepiapterin, as measured by the plasma BH4 concentration achieved over time in a subject requiring its therapeutic effect. The method involves administering an effective amount of sepiapterin, or an acceptable pharmaceutical salt thereof, to the subject with food. In some modalities of any of the above methods, the effective amount is an amount (e.g., 2.5 mg / kg to 100 mg / kg per dose) sufficient to produce a BH4 concentration of at least 50 ng / mL (e.g., at least 60 ng / mL, at least 100 ng / mL, at least 200 ng / mL, at least 400 ng / mL, at least 600 ng / mL, at least 1000 ng / mL, or at least 2000 ng / mL) in the subject's plasma over a 10-hour period of administration with food.The effective amount may include a dose that is at least 5% (at least 10%, at least 20%, at least 50%, at least 70%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%) lower than the dose sufficient to produce a maximum plasma concentration of BH4 (Cmax) of at least 50 ng / mL (e.g., at least 60 ng / mL, at least 100 ng / mL, at least 200 ng / mL, at least 400 ng / mL, at least 600 ng / mL, at least 1000 ng / mL, or at least 2000 ng / mL) in the subject's plasma over a 10-hour period following administration of sepiapterin without food. In some variations of any of the above methods, the food is administered to the subject less than 30 minutes before or after the food is consumed, for example, immediately before eating up to 1 hour after eating. In some variations, the food is administered to the subject at substantially the same time as the food. In some variations of any of the above methods, the food is high in protein. In some variations of any of the above methods, the food is high in fat (for example, at least 25, 30, 40, or 50% of the calories are from fat). In some variations of any of the above methods, the food is high in protein and high in fat. In some variations, the food is high in calories (for example, the food includes at least RQr>Q7ñ / 1 7Γ>7 / 3 / Yl· 100 calories, for example, at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, for example, 500-1500 or 800-1000 calories). In some variations of any of the above methods, the food is a meal, for example, breakfast, lunch, or dinner. In some modalities, administration with food (e.g., occurring less than 30 minutes before or after food consumption, e.g., immediately before food consumption up to 1 hour after consumption) results in an increase (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%) in the Cmax of BH4 compared to administration without food (e.g., occurring more than 2 hours after food consumption up to 30 minutes before additional food consumption). In some modalities, administration with food (e.g., occurring less than 30 minutes before or after food consumption, e.g., immediately before food consumption up to 1 hour after consumption) results in an increase (e.g., at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 110%, at least 120%, at least 130%, at least 140%, or at least 150%) in the extent of BH4 production and resulting plasma exposure (AUCo-ultimate) compared to administration without food (e.g., occurring less than 30 minutes before or after food consumption, e.g., immediately before food consumption up to 1 hour after consumption). consumption). In some embodiments of any of the above, sepiapterin is provided in a separate formulation from the food consumed (e.g., sepiapterin is not incorporated into a food product). In some embodiments of any of the above, food consumption occurs before sepiapterin administration (e.g., food consumption occurs from 1 hour to immediately before sepiapterin administration). In some embodiments, food consumption occurs after sepiapterin administration (e.g., food consumption occurs from immediately after administration to 30 minutes after administration). In a further aspect, the invention presents pharmaceutical compositions of sepiapterin, or an acceptable pharmaceutical salt thereof, that mimic the effect of administration with food, e.g., compositions formulated to increase gastric residence time (e.g., formulations described in Radhakrishnan et al. Drug Delivery Letters, 2017, 7, 190-200, formulations of which are incorporated by reference). In some modalities, the composition is formulated as a bioadhesive dosage form, a high-density dosage form, an expandable dosage form, a superporous hydrogel dosage form, or a floating dosage form (e.g., a composition including ion exchange resin, a raft system, an inflatable chamber, an effervescent mixture, an expandable hydrocolloid, or a multi-particle system). In another aspect, the invention presents a method for treating a BH4-related disorder in a subject requiring it, the method for administering an effective amount of any of the above pharmaceutical compositions. In another aspect, the invention presents a method for increasing the plasma exposure activity of BH4 in a subject receiving sepiapterin therapy by administering to the subject an effective amount of any of the above pharmaceutical compositions. In a further aspect, the invention presents a method for slowing down or reducing (for example, reducing by at least 5%, at least 10%, at least 20%, at least 30%, at least 40%, or at least 50%) the absorption rate of an oral dosage form of sepiapterin as measured by the BH4 concentration achieved in plasma over time in a subject in need of a therapeutic effect thereof, by administering to the subject an effective amount of any of the above pharmaceutical compositions. In one aspect, the invention presents a method for increasing the level of homovanillic acid and / or 5-hydroxyindoleacetic acid in a subject, the method comprising administering an effective amount of sepiapterin, or an acceptable pharmaceutical salt thereof, with food. In some modalities, the level of homovanillinic acid and / or 5-hydroxyindoleacetic acid in the subject's cerebrospinal fluid (CSF) is increased. In some modalities, the level of homovanillinic acid and / or 5-hydroxyindoleacetic acid in the subject (e.g., in the subject's CSF) is increased by at least 5% compared to the level before administration (e.g., the level is increased by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, at least 200%, at least 250%, at least 300%, compared to the level before administration). In some modalities, prior to administration of sepiapterin, or a pharmaceutically acceptable salt thereof, the subject has homovanillic acid and / or 5-hydroxyindoleacetic acid levels that are less than 50% (e.g., less than 40%, less than 30%) of the levels of an average subject (e.g., the subject has CSF homovanillic acid levels less than 15 ng / mL and / or CSF 5-hydroxyindoleacetic acid levels less than 5 ng / mL). In some modalities, the subject has not been diagnosed with a BH4-related disorder. In some modalities, the subject does not have symptoms of a BH4-related disorder.In some modalities, after administration of sepiapterin, or a pharmaceutically acceptable salt thereof, the levels of homovanillinic acid and / or 5-hydroxyindoleacetic acid in the subject are greater than 50% of the levels of an average subject (e.g., the subject has CSF homovanillinic acid levels greater than 15 ng / mL and / or CSF 5-hydroxyindoleacetic acid levels greater than 5 ng / mL). In some forms of any of the above, the subject is suffering from, and / or has been diagnosed with, a BH4-related disorder. In some forms of any of the above, the BH4-related disorder is primary BH4 deficiency, GTPCH deficiency, 6-pyruvyltetrahydropterine synthase (PTPS) deficiency, DHPR deficiency, sepiapterin reductase deficiency, response dystonia to RQnQ7n / L7n7 / q / Yli dopamine, 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 disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety, aggression in Alzheimer's disease, cerebrovascular disorders, spasm following subarachnoid 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, or hypoglycemia.In some forms of any of the above, the BH4-related disorder is phenylketonuria, a BH4 deficiency (e.g., primary BH4 deficiency), a CNS disorder (such as Segawa syndrome, depression, schizophrenia, autism, or Parkinson's disease), or a gastrointestinal motility disorder (such as gastroparesis and primary and secondary esophageal motility disorders). In some forms, the BH4-related disorder is either a BH4 deficiency or phenylketonuria. Definitions In this application, unless otherwise evident from the context, (i) the terms “a”, “one”, “an” may be understood to mean “at least one”; (ii) the term “or” may be understood to mean “and / or”; (iii) the terms “comprising” and “including” may be understood to encompass the listed components or steps whether presented alone or together with one or more additional components or steps; and (iv) the terms “around” and “approximately” may be understood to allow for standard variation as understood by a person skilled in the art; and (v) where scales are used, endpoints are included. As used herein, the term “administration” refers to the delivery of a composition to a subject. Administration to an animal subject (e.g., a human) may be by any appropriate route. For example, in some modalities, administration may be bronchial (including bronchial instillation), buccal, enteral, interdermal, intra-arterial, intradermal, intragastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, tracheal (including intratracheal instillation), transdermal, vaginal, or vitreous. The “effective amount” of a compound can vary depending on factors such as the disease state, age, sex, and weight of the individual, and the compound's ability to elicit the desired response. A therapeutically effective amount is one in which any toxic or harmful effects of the compound are outweighed by its therapeutically beneficial effects. An effective amount is also one sufficient to confer a benefit, such as a clinical benefit. The term "food," as used herein, refers to solid foods with sufficient bulk and fat content that do not dissolve and are rapidly absorbed in the stomach. For example, a meal, such as breakfast, lunch, or dinner. The term "with food," as used herein, refers to the administration of a composition between approximately 30 minutes before and approximately two hours after eating, for example, a meal. The terms "without food," "fasting," or "on an empty stomach" refer to the condition of not having consumed solid food for at least approximately two hours until approximately 30 minutes before consuming additional solid food. The term “pharmaceutical composition” as used herein refers to a composition containing a compound described herein, formulated with a pharmaceutically acceptable excipient. Pharmaceutical compositions may be formulated, for example, for oral administration in a unit-dose form (e.g., a tablet, capsule, caplet, gel capsule, suspension, solution, or syrup); for topical administration (e.g., as a cream, gel, lotion, or ointment); for intravenous administration (e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use); or in any other pharmaceutically acceptable formulation. As used herein, the term “pharmaceutically acceptable salt” means any pharmaceutically acceptable salt of sepiapterin. For example, pharmaceutically acceptable salts of sepiapterin include those that are within the scope of good medical judgment, suitable for use in contact with human and animal tissues without undue toxicity, irritation, allergic response, and the like, and in accordance with a reasonable risk / benefit ratio. Pharmaceutically acceptable salts are well known in the field. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977 and in Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008.The salts can be prepared in situ during the final isolation and purification of the compounds described herein or separately by reacting a free base group with a suitable organic acid. Often, compounds are prepared or used as pharmaceutically acceptable salts prepared as addition products of pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acids and methods for preparing the appropriate salts are well known. Salts can be prepared from pharmaceutically acceptable, non-toxic acids, including both inorganic and organic acids. Representative acid addition sales include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butyrate, alkamphorate, alkamphorsulfonate and citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, gencisate, glucoheptonate, glycerophosphate, glycolate, hemisulfate, heptonate, hexanoate, hydrogen bromide, hydrochloride, hydroioduro, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, methansulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate and valerate salts. As used herein, the term “subject” or “patient” refers to any organism to which a compound or composition according to the invention may be administered, for example, for experimental, diagnostic, prophylactic, and / or therapeutic purposes. Typical subjects include any animal (for example, mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be seeking or needing treatment, requiring treatment, receiving treatment, being to receive treatment in the future, or be a human or animal under the care of a trained professional for a particular disease or condition. The term “BH4-related disorder” or as used herein refers to any disease or disorder that may gain therapeutic benefit from modulating the level of BH4. BH4-related disorders include, but are not limited to, primary BH4 deficiency, GTPCH deficiency, 6-pyruvyltetrahydropterine synthase (PTPS) deficiency, DHPR deficiency, sepiapterin reductase deficiency and 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 disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety, aggression in Alzheimer's disease, cerebrovascular disorders, spasm following subarachnoid hemorrhage, and myocarditis.Coronary vasospasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infections, endotoxin shock, hepatic cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, or hypoglycemia. In some forms of any of the above, the BH4-related disorder is phenylketonuria, a BH4 deficiency (e.g., primary BH4 deficiency), a CNS disorder (such as Segawa syndrome, depression, schizophrenia, autism, or Parkinson's disease), or a gastrointestinal motility disorder (such as gastroparesis and primary and secondary esophageal motility disorder). In some forms, the BH4-related disorder is either a BH4 deficiency or phenylketonuria. As used herein, the terms “treat,” “treated,” or “to treat” mean both therapeutic and prophylactic or preventive treatment, where the objective is to prevent or lessen (reduce) an unwanted physiological condition, disorder, or disease, or to achieve beneficial or desired clinical outcomes. Beneficial or desired clinical outcomes include, but are not limited to, alleviating symptoms; lessening the severity of a condition, disorder, or disease; stabilizing (i.e., not worsening) the state of the condition, disorder, or disease; delaying the onset or slowing the progression of the condition, disorder, or disease; improving the state or achieving remission of the condition, disorder, or disease; an improvement in at least one measurable physical parameter, not necessarily discernible by the patient; or improving the condition, disorder, or disease. Treatment includes producing a clinically significant response without excessive levels of side effects.The treatment also includes prolonging survival compared to expected survival without treatment. Brief description of the drawings Figure 1 is a graph illustrating the mean plasma concentration of BH4 over time in fed and fasting subjects. Figure 2 is a graph illustrating the mean plasma concentration of sepiapterin over time in fed and fasted subjects. RQnozn / Lznz / q / Yl· Detailed description of the invention The present inventors have discovered that administering sepiapterin, or a pharmaceutically acceptable salt thereof, with food unexpectedly results in an increase in a subject's plasma BH4 exposure. Therefore, the present invention presents pharmaceutical compositions comprising sepiapterin, or a pharmaceutically acceptable salt thereof, and methods for treating BH4-related disorders. These compositions and methods may result in an increase in plasma BH4 exposure. Sepiapterin Sepiapterin enters the cell and is converted to 7,8-dihydrobiopterin by sepiapterin reductase. 7,8-Dihydrobiopterin is then converted to BH4 by reduction by dihydrofolate reductase. Not limited by theory, administering sepiapterin with food results in increased plasma BH4 exposure, for example, by reducing the absorption rate of sepiapterin. If the administered sepiapterin is rapidly absorbed, for example, when administered on an empty stomach, the sepiapterin reductase and / or dihydrofolate reductase in cells can become saturated above Vmax, resulting in at least some of the administered sepiapterin leaving the cell without being reduced to 7,8-dihydrobiopterin and subsequently to BH4.This excess sepiapterin can then be excreted without ever being converted to BH4, resulting in lower plasma BH4 levels compared to sepiapterin administration with food. This reduces the rate of, or prolongs, sepiapterin absorption and results in reaction rates below, at, or slightly above Vmax for substrate saturation of the sepiapterin reductase and / or dihydrofolate reductase enzymes. Sepiapterin administration with food unexpectedly results in an increase in the maximum plasma concentration (Cmax) of BH4 and the degree of exposure, as measured by the area under the concentration-time curve from time zero to the ultimate concentration (AUCo-ultimate) of BH4, compared to administration without food. Sepiapterin has the following structure: Sepiapterin Sepiapterin, or a pharmaceutically acceptable salt thereof, can be formulated into a pharmaceutical composition. In some embodiments, the pharmaceutical composition of the invention includes 20 to 30% by total weight of sepiapterin or a salt thereof, for example, 20%, 22%, 25%, 27%, or 30%. In some embodiments, the pharmaceutical compositions include more than 20% sepiapterin by total weight, for example, more than 25%, more than 30%, more than 40%, more than 50%, more than 60%, more than 70%, more than 80%, or more than 90%. In some embodiments, the pharmaceutical composition includes less than 20% sepiapterin by total weight, for example, less than 15%, less than 10%, or less than 5%. In some embodiments, the invention comprises a pharmaceutical composition that includes sepiapterin or a salt thereof, and less than 10% by total weight of an antioxidant, for example, 9%, 7%, 5%, 3%, 1%, 0.5%, 0.25%, or 0.1%. The antioxidant may be ascorbic acid. In some embodiments, the ratio of sepiapterin, or a pharmaceutically acceptable salt thereof, to the antioxidant is 1:1, for example, 2:1, 5:1, 7:1, or 10:1. The pharmaceutical composition may include 20% to 30% sepiapterin, or a pharmaceutically acceptable salt thereof, by total weight, for example, 20%, 22%, 25%, 27%, or 30%. The pharmaceutical composition may further include a dispersant, for example, croscarmellose sodium. The pharmaceutical composition may include 0.1 to 1.5% dispersant by total weight, for example, 0.1%, 0.5%, 1% or 1.5%.In some formulations, the pharmaceutical composition includes at least one anti-caking agent, for example, colloidal silicon dioxide or microcrystalline cellulose. The pharmaceutical composition may include 65 to 75% anti-caking agent by total weight, for example, 65%, 67%, 70%, 73%, or 75%. In some formulations, the pharmaceutical composition includes both colloidal silicon dioxide and microcrystalline cellulose. In some formulations, the pharmaceutical composition includes 60 to 65% by total weight of microcrystalline cellulose and 5 to 7% by total weight of colloidal silicon dioxide. In some formulations, the crystalline form of sepiapterin is formulated as particles smaller than 140 µm, for example, 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 forms, the pharmaceutical composition includes less than 1% of an impurity such as lactoylpterin, for example, 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%. In some forms, sepiapterin is a salt of sepiapterin, for example, with sulfuric acid, p-toluenesulfonic acid, methanesulfonic acid, benzenesulfonic acid, malonic acid, tartaric acid (for example, L-tartaric acid), phosphoric acid, gentisic acid, fumaric acid, glycolic acid, acetic acid, or nicotinic acid. In some embodiments, sepiapterin or its pharmaceutically acceptable salt is found in crystalline form. The free crystalline base of sepiapterin or a crystalline form of a sepiapterin salt may occur as an anhydrate (i.e., having no bound water or solvent, or hydration or solvation) or as a hydrate, a partial hydrate (i.e., hemihydrate, sesquihydrate, and the like), a dihydrate, a trihydrate, or the like, wherein the crystalline form is bound to water of hydration or a solvent molecule associated with the crystalline form of sepiapterin or its salt. In one embodiment, crystalline sepiapterin occurs as a monohydrate or as a hemihydrate. In some forms, sepiapterin is found in crystalline form. In some forms, the crystalline form of sepiapterin is characterized by an X-ray powder diffraction pattern obtained by X-ray irradiation of CuKa that has peaks expressed as 2Θ at least approximately 9.7, approximately 10.2, and approximately 11.3°. In other forms, the crystalline form of sepiapterin is characterized by an X-ray powder diffraction pattern obtained by X-ray irradiation of CuKa that has peaks expressed as 2Θ at least approximately 9.7, approximately 10.2, approximately 11.3, approximately 14.0, approximately 14.6, approximately 19.9, approximately 22.2, approximately 25.3 and approximately 32.4°. The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable excipient may be any of those conventionally used and is limited only by physicochemical considerations such as solubility and the route of administration. It will be appreciated by those skilled in the art that, in addition to the following pharmaceutical compositions described, sepiapterin may be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes. The pharmaceutically acceptable vehicles described herein, such as carriers, adjuvants, excipients, or diluents, are well known to practitioners and readily available to the public. It is preferred that the pharmaceutically acceptable excipient be chemically inert to sepiapterin and have no harmful side effects or toxicity under the conditions of use. Formulations that increase the residence time in the anterior and / or gastric intestine Gastro-retention drug administration is an approach where the drug formulation is designed to remain in the stomach longer, for example, until drug release is complete. Bioadhesive dosage forms utilize polymers that can adhere to surfaces and result in controlled drug release. Bioadhesive polymers can be anionic (e.g., carboxymethylcellulose, alginic acid, polyacrylic acid, pectin, carrageenan, polycarbophil, or carbomer); cationic (e.g., chitosan, polylysine, or polybrene); or nonionic (e.g., polyethylene glycol, polyvinylpyrrolidone, dextran, or hydroxypropyl methylcellulose). High-density dosage forms are designed to remain in the stomach at a level lower than the pyloric sphincter, thereby preventing gastric emptying. Suitable excipients for high-density dosage forms include iron powder, barium sulfate, zinc oxide, and titanium oxide. Expandable dosage forms are designed to expand in the stomach to be larger than the pyloric sphincter, thereby preventing gastric emptying. For example, dosage forms that include a drug core, a swellable hydrocolloid, and an outer semipermeable polymer are suitable for expandable dosage forms. Superporous hydrogel dosage forms are designed, similarly to expandable dosage forms, to expand in the stomach to be larger than the pyloric sphincter. Superporous hydrogel dosage forms may include polymers such as croscarmellose sodium. Floating dosage forms are designed to have a lower density than gastric fluid. Floating dosage forms may include compositions such as ion-exchange resin, a raft system, an inflatable chamber, an effervescent mixture, an inflatable hydrocolloid, or a multi-particle system. Antioxidants Sepiapterin is prone to rapid oxidation when exposed to air. Therefore, the pharmaceutical composition of the invention may include antioxidants. The antioxidant can minimize the oxidative degradation of sepiapterin. Examples of antioxidants include, but are not limited to, ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetylcysteine, glutathione, ethylenediaminetetraacetic acid, sodium bisulfite, sodium metabisulfite, thiourea, butylated hydroxytoluene, butylated hydroxyanisole, and vitamin E. In some embodiments, the pharmaceutical compositions of the invention include ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetylcysteine, glutathione, butylated hydroxytoluene, and / or butylated hydroxyanisole as antioxidants. In some formulations, the pharmaceutical composition includes less than 10% antioxidant by weight, for example, less than 9%, less than 8%, less than 7%, less than 6%, less than 5%, less than 4%, less than 3%, less than 2%, less than 1%, or substantially antioxidant-free. In some formulations, the pharmaceutical composition includes 2 to 9% total weight of antioxidant, for example, 2 to 4%, 3 to 5%, 4 to 6%, 5 to 7%, 6 to 8%, or 7 to 9%. In some formulations, the pharmaceutical composition includes 5 to 100% of the USP Maximum Daily Intake of the antioxidant; for example, in some formulations, the pharmaceutical composition comprises 5%, 10%, 15%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% of the USP Maximum Daily Intake of the antioxidant. In some forms, the ratio between sepiapterin and antioxidant is at least 1:1, for example, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1 or 10:1. Dispersants In some embodiments, the pharmaceutical composition of the invention includes at least one dispersant. The dispersant can cause the particles of the formulation to separate, for example, to release their medicinal substances upon contact with moisture. Examples of dispersants include, but are not limited to, cross-linked polyvinylpyrrolidone, carboxymethylcellulose (for example, a salt of croscarmellose, e.g., croscarmellose sodium), starch (for example, 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 to 1.5% by total weight of dispersant, for example, 0.1%, 0.5%, 1%, or 1.5%. In some embodiments, the pharmaceutical composition includes less than 1.5% of dispersant, for example, less than 1%, less than 0.5%, or less than 0.1%. Anti-caking agentsIn 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. Examples of anti-caking agents include colloidal silicon dioxide, microcrystalline cellulose, tricalcium phosphate, microcrystalline cellulose, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, colloidal silicon dioxide, calcium silicate, magnesium trisilicate, talc powder, sodium aluminosilicate, potassium aluminosilicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, and polydimethylsiloxane. In some embodiments, the anti-caking agent is either colloidal silicon dioxide or microcrystalline cellulose.In some formulations, the pharmaceutical composition may include 65 to 75% by total weight of an anti-caking agent, for example, 65%, 67%, 70%, 73%, or 75%. In some formulations, the pharmaceutical composition includes both colloidal silicon dioxide and microcrystalline cellulose. In some formulations, the pharmaceutical composition includes 60 to 65% by total weight of microcrystalline cellulose and 5 to 7% by total weight of colloidal silicon dioxide. Management vehicle In some embodiments, the pharmaceutical compositions of the invention are combined with a dosage vehicle prior to administration, for example, a dosage vehicle with a viscosity of approximately 50–1750 centipoise (cP). One type of suspending agent that may be used is a combination of glycerin and sucrose in water (for example, MEDISCA® oral mixture with 2.5% glycerin and 27% sucrose in water). An appropriate amount of the composition may be added to the dosage vehicle mixture and shaken to suspend the composition just before administration. Other suspending agents may also be used as delivery vehicles. Exemplary suspending agents include agar, alginic acid, sodium carboxymethylcellulose, carrageenan, dextrin, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose, methylcellulose, polyethylene glycol, povidone, tragacanth, xanthan gum, or other suspending agents known in the art. Dosage Sepiapterin or its pharmaceutically acceptable salt can be used at any suitable dose. Appropriate doses and dosage regimens can be determined using conventional titration-finding techniques. Treatment is generally initiated with smaller doses that are less than the optimum dose. The dose is then increased in small increments until the optimum effect is achieved under the circumstances. For convenience, the total daily dose can be divided and administered in portions throughout the day if desired. At appropriate doses and with proper administration of certain compounds, the present invention provides a wide range of responses. Typically, doses range from approximately 2.5 to approximately 150 mg / kg of treated patient body weight / day.For example, in the modalities, sepiapterin, or its pharmaceutically acceptable salt, can be administered from about 20 mg / kg to about 150 mg / kg, from about 40 mg / kg to about 100 mg / kg, from about 100 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, or from about 2.5 mg / kg to about 5 mg / kg, of the subject's body weight per day, once or more times a day, to obtain the desired therapeutic effect. In some modalities, the dose is sufficient to produce levels of BH4 in the CNS (e.g., the brain), as measured in the CSF, and / or sufficient to produce a therapeutic outcome and / or response, such as increased levels of serotonin or dopamine in the CNS. In some modalities, the increase in BH4 in the CNS is measured by determining the level of metabolites of a monoamine, such as serotonin or dopamine (e.g., homovanillic acid or 5-hydroxyindoleacetic acid (5-HIAA)), in the CSF, where the increase in metabolites in the CSF indicates an increase in BH4 levels in the CNS (e.g., the brain).In some modalities, the dose is an amount sufficient to increase BH4 levels at least twice as high (e.g., at least 10 times higher, at least 20 times higher, at least 50 times higher, at least 100 times higher, or at least 150 times higher) than the BH4 levels before administration as measured in the subject's plasma or an organ, e.g., the subject's liver. In some formulations, sepiapterin or a pharmaceutically acceptable salt thereof may be formulated in solid oral unit-dose forms, such as particles. In these formulations, each solid oral unit-dose form may comprise any suitable amount of sepiapterin or its pharmaceutically acceptable salt. For example, each solid oral dose form may comprise approximately 2.5 mg, approximately 5 mg, approximately 10 mg, approximately 20 mg, approximately 30 mg, approximately 40 mg, approximately 50 mg, approximately 60 mg, approximately 70 mg, approximately 80 mg, approximately 90 mg, approximately 100 mg, approximately 125 mg, approximately 150 mg, approximately 175 mg, approximately 200 mg, approximately 225 mg, approximately 250 mg, approximately 275 mg, approximately 300 mg, approximately 325 mg, approximately 350 mg, approximately 375 mg, approximately 400 mg, approximately 425 mg, approximately 450 mg, approximately 475 mg, or approximately 500 mg. Sepiapterin, or a pharmaceutically acceptable salt thereof, may be used in the preparation of liquid formulations, such as in the form of a solution, suspension, or emulsion. Suitable oral formulations may consist of: a) capsules, sachets, tablets, lozenges, and lozenges, 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 solution, or orange juice; d) suspensions in a suitable liquid; and e) suitable emulsions. Solid oral dosage forms such as capsules, tablets, and powders are preferred. Capsule forms may be of the common hard or soft gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.Tablet forms may include one or more of lactose, sucrose, mannitol, maize 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, wetting agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms may comprise the active ingredient in a flavoring, generally sucrose and acacia or tragacanth, as well as lozenges 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, excipients known in the art. Suitable compositions for oral and / or parenteral administration include aqueous and non-aqueous solutions, sterile isotonic solutions for injection, which may contain antioxidants, buffers, bacteriostatics and solutes that make the formulation isotonic with the blood of the desired recipient; and sterile aqueous and non-aqueous suspensions which may include suspending agents, solubilizers, thickening agents, stabilizers and preservatives.The compound may be administered in a physiologically acceptable diluent in a pharmaceutical excipient, such as a sterile liquid or a mixture of liquids, including water, saline solution, 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 detergent, a suspending agent such as pectin, carbomers, methylcellulose, hydroxypropyl methylcellulose or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants. The present invention presents pharmaceutical compositions in an orally tolerable formulation containing a therapeutically effective amount of sepiapterin and less than 10% antioxidant. In some embodiments, the pharmaceutical composition is a granular formulation dispersed in a pharmaceutically acceptable excipient; for example, the composition may be mixed with 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's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA, 22nd ed., 2010. Whenever any conventional excipient is incompatible with the active ingredient, its use in the pharmaceutical compositions is contemplated.In addition, for administration to animals (e.g., humans), it will be understood that the preparations must comply with the standards of sterility, pyrogenicity, general safety, and purity required by the FDA Office of Biologics Standards. Oils that can be used in parenteral formulations include petrolatum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral oils. 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 salts, ammonium, and triethanolamine, and suitable detergents include: a) cationic detergents, such as, for example, dimethyl-dialkylammonium halides and alkylpyridinium halides; b) anionic detergents, such as, for example, alkyl, aryl, and olefin sulfonates, olefin, ether, and monoglyceride, 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, alkylbeta-aminopropionates, and quaternary ammonium salts of 2-alkylimidazole, and mixtures thereof. Parenteral formulations typically contain 20 to 30% by weight of sepiapterin, or an acceptable pharmaceutical salt thereof, in solution. Suitable preservatives and buffers may be used in such formulations. To minimize or eliminate irritation at the injection site, these compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic (HLB) ratio of approximately 12 to approximately 17. The amount of surfactant in such formulations ranges from approximately 5% to approximately 15% by weight. Suitable surfactants include fatty acid esters of polyethylene sorbitan, such as sorbitan monooleate, and high-molecular-weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.Parenteral formulations may be presented in sealed unit-dose or multi-dose containers, such as ampoules and vials, and may be stored in a cryo-dried (lyophilized) condition requiring only the addition of a sterile liquid excipient, e.g., water for injection, immediately before use. Extemporaneous injectable solutions and suspensions may be prepared from sterile powders, granules, and tablets of the type described above. The sepiapterin, or a pharmaceutically acceptable salt thereof, of the present invention can be produced in injectable formulations. The requirements for effective pharmaceutical excipients for injectable compositions are well known to those skilled in the art. See Remington: The Science and Practice of Pharmacy, 22nd Edition, Lippincott Williams & Wilkins, (2012); and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and J.C. Boylan, 2006, Marcel Dekker, New York, each of which is incorporated herein by reference. Topical formulations, including those useful for the transdermal release of drugs, are well known to those skilled in the art and are suitable in the context of the invention for application to the 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, gingiva, and nasal mucosa. In some embodiments, the composition contains sepiapterin, or a pharmaceutically acceptable salt thereof, and a suitable vehicle or excipient. It may also contain other components, such as an antiirritant. The excipient may be liquid, solid, or semisolid. In some embodiments, the composition is an aqueous solution. Alternatively, the composition may be a dispersion vehicle, emulsion, gel, lotion, or cream for the various components.In one embodiment, the primary vehicle is water or a biocompatible solvent that is substantially neutral or has been made substantially neutral. The liquid vehicle may include other materials, such as buffers, alcohols, glycerin, and mineral oils, with various emulsifiers or dispersing agents known in the art to achieve the desired pH, consistency, and viscosity. Compositions may also be produced as solids, such as powders or granules. The solids may be applied directly or dissolved in water or a biocompatible solvent prior to use to form a solution that is substantially neutral or has been made substantially neutral, and which can then be applied to the target site.In some embodiments of the invention, the vehicle for topical application to the skin may include water, buffer solutions, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oils, phosphoglycerides, collagen, gelatin, and silicone-based materials. Sepiapterin, or a salt thereof, alone or in combination with other suitable components, can be produced in aerosol formulations for administration by inhalation. These aerosol formulations can be placed in acceptable pressurized propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They can also be formulated as pharmaceutical products for non-pressurized preparations, such as in a nebulizer or atomizer. Additionally, sepiapterin, or a pharmaceutically acceptable salt thereof, can be produced in suppositories by mixing it with a variety of bases, such as emulsifying or water-soluble bases. Suitable formulations for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams, or sprays containing, in addition to the active ingredient, excipients, which are known in the art as appropriate. Solid dosage form for oral administration Oral formulations include particles containing the active ingredient(s) in a mixture with pharmaceutically acceptable nontoxic excipients, and such formulations are known to those skilled in the art (e.g., U.S. Patent 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, which are incorporated herein 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, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinylpyrrolidone or polyethylene glycol); and lubricating, sliding, anti-adherent agents (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, magnesium stearate, sodium bicarbonate, sodium ferrocyanide, potassium ferrocyanide, calcium ferrocyanide, calcium phosphate, sodium silicate, colloidal silicon dioxide, calcium silicate, magnesium trisilicate, talc powder, sodium aluminosilicate, potassium aluminosilicate, calcium aluminosilicate, bentonite, aluminum silicate, stearic acid, polydimethylsiloxane). Other pharmaceutically acceptable excipients may include colorants, flavoring agents, plasticizers, humectants, and buffering agents. In some embodiments, the excipients (e.g., flavoring agents) are packaged with the composition. In some embodiments, the excipients (e.g., flavorings) are packaged separately from the composition (e.g., they are combined with the composition prior to administration). 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 to the solid dosage form in a manner similar to that described in the Encyclopedia of Pharmaceutical Technology, supra. Powders and granules can be prepared using the above-mentioned ingredients in the conventional way, using, for example, a mixer, a fluid bed apparatus, a melt-freeze apparatus, a rotary granulator, an extruder / spheronizer, or spray-drying equipment. Treatment methods Sepiapterin may serve as a useful therapy for diseases associated with low intracellular levels of BH4 or with alteration of various BH4-dependent metabolic pathways, including, but not limited to, primary BH4 deficiency, GTPCH deficiency, 6-pyruvoyl-tetrahydropterin synthase (PTPS) deficiency, DHPR deficiency, sepiapterin reductase deficiency, dopamine-responsive dystocia, 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 disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety, aggression in Alzheimer's disease, cerebrovascular disorders, spasm following subarachnoid hemorrhage, myocarditis, coronary vasospasm, cardiac hypertrophy, arteriosclerosis, hypertension,Thrombosis, infections, endotoxic shock, hepatic cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal failure, impotence, and hypoglycemia. In this way, the various forms of sepiapterin or a salt thereof according to the present invention can be administered to a patient in an effective quantity to obtain treatment or mitigation of the disease, disorder, or condition. In some variations of any of the above methods, the food is a high-protein food. In some variations of any of the above methods, the food is a high-fat food (e.g., at least 25, 30, 40, or 50% of the calories are from fat). In some variations of any of the above methods, the food is a high-protein, high-fat food. In some variations, the food is a high-calorie food (e.g., the food contains at least 100 calories, at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, or 500–1500 or 800–1000 calories). In some variations of any of the above methods, the food is a meal, such as breakfast, lunch, or dinner. The actual dose of a composition of the present invention administered to a patient may be determined by physical and physiological factors, such as body weight, severity of the condition, the type of disease being treated, prior or concurrent therapeutic interventions, patient idiopathic status, and the route of administration. Depending on the dose and route of administration, the number of administrations of a preferred dose and / or an effective amount may vary according to the subject's response. The physician responsible for administration will, in any case, determine the concentration of the active ingredients of a composition and the appropriate doses for the individual subject. In some regimens, 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. Patients may receive the pharmaceutical composition containing sepiapterin once, twice, or three times daily during treatment. In some regimens, patients continue their other current medications for the BH4-related disorder (e.g., L-dopa / carbidopa, 5-HTP, 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 known medications that inhibit folate synthesis (e.g., methotrexate, pemetrexed, or trimetrexate). In some embodiments, patients taking BH4 discontinue BH4 administration (i.e., BH4 washout). Blood samples for Phe concentrations can be obtained during the BH4 washout period on days 7, 5, 3, and 1 before treatment with the pharmaceutical composition of the invention, or until blood Phe levels are >360 pmol / L at any time point during the BH4 washout. In some embodiments, pre-dose blood samples are analyzed for sepiapterin, Phe, BH4, and tyrosine (Tyr). Equivalents and Scope Skilled workers will recognize or be able to determine, using only routine experimentation, various equivalents to the specific modalities according to the invention described herein. It is not proposed that the scope of the present invention be limited to the foregoing description, but rather as set forth in the appended claims. Furthermore, it should be understood that any particular embodiment of the present invention that falls within the prior art may be explicitly excluded from one or more of the claims. Since such embodiments are considered to be known to a person skilled in the art, they may be excluded even if the exclusion is not explicitly stated herein. Any particular embodiment of the compositions of the invention (e.g., any compound; any method of production; any method of use; etc.) may be excluded from one or more of the claims for any reason, whether or not related to the existence of the prior art. Examples Example 1. Evaluation of the effect of food on sepiapterin administration Method: Subjects received two oral doses of sepiapterin (10 mg / kg) separated by one week, in both fed and fasted states. Subjects were fed a standard high-fat (approximately 50 percent of the total caloric content of the meal) and high-calorie (approximately 800 to 1000 calories) meal starting 30 minutes before receiving their second oral dose of sepiapterin on Day 8. Sampling for PK analysis was presented pre-dose on Days 1 and 8 (within a 30-minute period prior to dosing) and 0.5 h, 1 h, 2 h, 4 h, 8 h, 12 h, and 24 h post-dose on Days 1 and 8. Blood concentrations of sepiapterin and BH4 were analyzed by MNG Labs. Cerebrospinal fluid (CSF) from selected subjects is collected by lumbar puncture on Day 1 (before dosing) and Day 7 (i.e., after daily dosing for 7 days) approximately 30 minutes from the time of the maximum observed plasma concentration of BH4 (Tmax) as determined from blood testing. Cerebrospinal fluid (CSF) is analyzed by MNG Labs. Descriptive statistics are provided to characterize any changes in neurotransmitter metabolism between the Day 1 and Day 7 sample results. Results: As shown in Tables 1 and 2 below and Figure 1, surprisingly, the plasma Cmax of BH4 was much higher in subjects who had been fed prior to administration compared to subjects who had fasted prior to administration. Furthermore, there was a decrease in plasma sepiapterin concentration, but an increase in BH4 concentration, when sepiapterin was administered in the fed versus fasted state (Figure 1). The geometric mean ratios (fasted / fed, 90% CI) for plasma sepiapterin were 1.29 (0.84 to 2.00) for AUCutima and 1.57 (1.21 to 2.0) for Cmax. The corresponding ratios (90% CI) for plasma BH4 were 0.58 (0.47 to 0.71) for AUCo-inf, and 0.55 (0.45 to 0.68) for Cmax. Overall BH4 exposure as measured by AUCo-inf and AUCultimate increased by 1.7-fold when sepiapterin was administered in the fed state compared to the fasted state. Table 1. Summary of BH4 concentration in plasma of fasting subjects Time (hours) 0 0.5 1 2 4 8 12 24 Average (nM) 7.62 25.65 154.63 413.48 624.34 248.09 85.87 18.33 SD (nM) 1.26 14.20 42.65 104.49 210.24 118.04 39.26 8.65 Average (nM) 7.75 22.85 147.30 370.40 635.05 232.55 75.30 15.35 Minimum (nM) 5.00 13.80 98.50 271.40 379.00 90.20 38.90 8.50 Maximum (nM) 9.00 66.50 223.10 617.90 1127.90 457.30 162.00 37.40 Table 2. Summary of BH4 concentration in plasma of fed subjects Time (hours) 0 0.5 1 2 4 8 12 24 Average (nM) 8.43 33.32 165.79 586.90 1098.85 520.33 161.39 19.27 SD (nM) 1.45 21.70 82.02 249.26 289.74 192.50 58.43 8.20 Average (nM) 8.50 30.95 160.00 554.00 1010.60 485.00 142.30 16.15 Minimum (nM) 6.00 8.90 42.30 298.90 750.80 252.70 90.40 12.10 Maximum (nM) 11.00 76.40 369.00 1199.90 1566.70 926.30 261.10 40.10 Furthermore, as shown in Tables 3 and 4 below and Figure 2, surprisingly, the Cmax of sepiapterin in plasma was much lower in subjects when they fed before administration compared to subjects who fasted before administration. Table 3. Summary of sepiapterin concentration in plasma of fasting subjects Time (hours) 0 0.5 1 2 4 8 12 24 Average (nM) 0 2.85 5.43 4.63 1.88 0 0 0 SD (nM) 0 2.67 2.22 1.36 1.48 0 0 0 Average (nM) 0 2.32 4.82 4.71 2.37 0 0 0 Minimum (nM) 0 0 3.15 2.52 0 0 0 0 Maximum (nM) 0 7.23 10.19 6.65 3.93 0 0 0 Table 4. Summary of sepiapterin concentration in plasma of fed subjects Time (hours) 0 0.5 1 2 4 8 12 24 Average (nM) 0 0.63 2.38 2.96 2.96 0.18 0 0 SD (nM) 0 1.17 1.66 1.88 1.53 0.63 0 0 Average (nM) 0 0 2.42 2.91 2.50 0 0 0 Minimum (nM) 0 0 0 0 0 0 0 0 Maximum (nM) 0 3.22 4.57 5.92 5.56 2.19 0 0 Example 2. Comparison of adverse events in fed and fasted subjects Method: Twelve subjects were given a single dose (10 mg / kg) of sepiapterin under fasted conditions and then 7 days later under fed conditions. Standard definitions of adverse events (AEs) were used. All-cause AEs were those occurring at any time; treatment-emergent adverse events (TEAEs) were those occurring at or after the time of study treatment administration. Study drug-related TEAEs were based on investigator judgment. Serious AEs were defined as life-threatening or resulting in death, hospitalization or prolongation of existing hospitalization, or a persistent or significant disability or substantial disruption of the ability to carry out normal life functions, or a congenital anomaly / birth defect. Results: As shown in Table 5, surprisingly, there was a reduced incidence of adverse events when sepiapterin was administered to fed subjects compared to fasted subjects. Table 5. Comparison of adverse events under fasted and fed conditions Sepiapterin 10 mg / kg Fasted Fed >1 AE 5 1 TEAE 4 1 Study drug related TEAE 1 0 Example 3. Determination of CSF neurotransmitter levels after sepiapterin administration Method: Cerebrospinal fluid (CSF) samples were analyzed from subjects administered 60 mg / kg of sepiapterin or placebo. The following analytes were measured: sepiapterin, BH4, BH2, homovanillic acid (HVA), and 5-hydroxyindoleacetic acid (HIAA). Descriptive statistics (n, mean, SD, median, minimum, maximum) were determined for these analytes on day 1 and day 7 ± 30 minutes from Tmax and the change from the baseline on day 7 for each analyte. Results: Sepiapterin was not detected in CSF on day 1 or day 7 + / - 30 minutes from BH4 Tmax. CSF BH4 concentration increased by 4,102 ng / mL in subjects treated with sepiapterin, while it remained unchanged in subjects receiving placebo (change from baseline of 0.010 ng / mL). Similarly, CSF BH2 concentration increased by 1,368 ng / mL in subjects treated with sepiapterin, while it remained unchanged in subjects receiving placebo (change from baseline of -0.020 ng / mL). Changes in neurotransmitter concentrations relative to Day 1 also differed between subjects treated with sepiapterin and those receiving placebo. HVA concentration increased by 1,378 ng / mL in subjects treated with sepiapterin compared to a decrease of 0,630 ng / mL in subjects receiving placebo. 5-HIAA concentration decreased in both arms, but to a lesser extent in subjects treated with sepiapterin than in subjects receiving placebo (1,142 ng / mL versus -2,440 ng / mL). It should be noted that the pre-dose HVA (10.02 ng / mL) and 5-HIAA (3.69 ng / mL) concentrations for one subject were approximately one-third of the concentrations observed in the other subjects (HVA: 22.45 ng / mL to 44.72 ng / mL; 5-HIAA: 9.49 ng / mL to 19.70 ng / mL). However, on Day 7, the HVA (29.93 ng / mL) and 5-HIAA (9.53 ng / mL) concentrations for this subject were close to the range observed in the other subjects administered sepiapterin (HVA: 30.64 ng / mL to 43.19 ng / mL; 5-HIAA: 10.10 ng / mL to 21.59 ng / mL). The concentrations of HVA and 5-HIAA for the subject on day 7 were both higher than the mean concentrations for subjects treated with placebo on day 7. The information is summarized in Table 6 below. Table 6. Analyte concentrations in the CSF of the subjects. Analyte Day Treatment Mean Concentration (ng / mL) 5-HIAA 1 sepiapterin 14.6 placebo 11.9 7 sepiapterin 13.4 placebo 9.5 BH2 1 sepiapterin 0.5 placebo 0.5 7 sepiapterin 1.9 placebo 0.5 BH4 1 sepiapterin 4.4 placebo 3.2 7 sepiapterin 8.5 placebo 3.2 HVA 1 sepiapterin 32.3 placebo 25.1 7 sepiapterin 33.7 placebo 24.5 Sepiapterin 1 sepiapterin 0 placebo 0 7 sepiapterin 0 placebo 0 Example 4. Pharmacokinetic analysis of multiple-dose administration of sepiapterin Methods: Three cohorts of eight fed subjects each were randomized to receive sepiapterin or placebo once daily for 7 days in a 6:2 ratio. A sentinel dose strategy was also used for administration of the highest sepiapterin dose. Results: Plasma concentrations of sepiapterin and BH4 were similar after 1 and 7 days of sepiapterin treatment, with no drug accumulation. Pharmacokinetic data are shown in Table 7 below. Table 7. Summary of pharmacokinetic data for multiple administrations of sepiapterin Sepiapterin Dose (mg / kg) Parameter Compound Day 5 20 60 Cmax (ng / mL) sepiapterin 1 0.6 1.2 2.7 7 0.6 1.3 2.8 BH4 1 147 496 597 7 152 516 678 Tmax (h) sepiapterin 1 3.0 2.6 3.3 7 3.0 2.7 3.0 BH4 1 4.0 4.0 4.6 7 4.0 4.0 4.0 AUCo-24 (ng.h / mL) sepiapterin 1 NC NC 23 7 NC NC 23 BH4 1 994 3031 4560 7 1070 3718 4864 ABCo— (ng-h / mL) sepiapterin 1 1.0 3.9 21.2 7 0.7 4.3 16.0 BH4 1 1014 3085 4668 7 NC NC NC NC=Not calculated Other modalities It is understood that, although the present disclosure has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not to limit the scope of this disclosure, which is defined by the scope of the appended claims. Other aspects, advantages, and alterations are within the scope of the following claims.

Claims

1. A method for treating a BH4-related disorder in a subject in need thereof, the method comprising administering to the subject an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, with food.

2. A method for increasing plasma exposure of BH4 in a subject receiving sepiapterin therapy comprising administering to the subject an effective amount of sepiapterin, or an acceptable pharmaceutical salt thereof, with food.

3. A method for reducing the absorption rate of an oral dosage form of sepiapterin, or a pharmaceutically acceptable salt thereof, as measured by the BH4 concentration achieved in the plasma over time in a subject in need thereof, the method comprising administering to the subject an effective amount of sepiapterin, or a pharmaceutically acceptable salt thereof, with food.

4. The method according to any of claims 1 to 3, wherein the effective amount is an amount sufficient to produce a concentration of at least 50 ng / mL in the subject's plasma within a 10-hour administration period.

5. The method according to claim 4, wherein the effective amount comprises a dose that is at least 20% lower than the dose sufficient to produce a maximum plasma concentration (Cmax) of BH4 of at least 50 ng / mL in the subject's plasma within a 10-hour period following administration of sepiapterin, or a pharmaceutically acceptable salt thereof, without food.

6. The method according to any of claims 1 to 5, wherein the effective amount RQnQ7n / L7n7 / q / Yli is from 2.5 mg / kg to 100 mg / kg per dose.

7. The method according to any of claims 1 to 6, administration to the subject is presented less than 30 minutes before consuming the food. wherein the 8. The method of administration according to any of the claims to the subject is substantially at the same time as the food.

9. The method according to any of claims a 7, wherein the administration is immediately after food consumption up to 2 hours after consumption.

10. The method according to any of claims 1 to 9, wherein the effective amount results in an increase in the maximum plasma concentration (Cmax) of BH4 compared to administration without food.

11. The method according to any of claims 1 to 10, wherein the effective amount results in an increase in the area under the concentration time curve from time zero to the ultimate concentration (AUCo-ultimate) of BH4 compared to administration without food.

12. A pharmaceutical composition comprising sepiapterin, or an acceptable pharmaceutical salt thereof, wherein the composition is formulated to increase the residence time in the anterior and / or gastric intestine.

13. The pharmaceutical composition according to claim 12, wherein the composition is formulated as a bioadhesive dosage form, a high-density dosage form, an expandable dosage form, a superporous hydrogel dosage form, or a floating dosage form.

14. The pharmaceutical composition according to claim 13, wherein the floating dosage form comprises an ion exchange resin, a raft system, an inflatable chamber, an effervescent mixture, an inflatable hydrocolloid, or a multi-particle system.

15. A method of treating a BH4-related disorder in a subject requiring it, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to any of claims 12 to 14.

16. A method for increasing plasma exposure of BH4 in a subject, the method comprising administering to the subject an effective amount of a pharmaceutical composition according to any of claims 12 to 14.

17. A method for reducing the absorption rate of an oral dosage form of sepiapterin, or a pharmaceutically acceptable salt thereof, as measured by the plasma BH4 concentration achieved over time in a subject in need thereof, the method comprising administering to the subject an effective amount of a pharmaceutical composition of any of claims 12 to 14.

18. The method according to any of claims 1 to 15, wherein the disorder related to BH4 is a BH4 deficiency disorder or phenylketonuria.

19. A method for increasing the level of homovanillic acid and / or 5-hydroxyindoleacetic acid in a subject, the method comprising administering an effective amount of sepiapterin, or an acceptable pharmaceutical salt thereof, with food.

20. The method according to claim 19, wherein the level of homovanillic acid and / or 5-hydroxyindoleacetic acid in the subject's CSF is increased.

21. The method according to claim 19 or 20, wherein the level of homovanillic acid and / or 5-hydroxyindoleacetic acid in the subject is increased by at least 100% compared to the level before administration.