Methods for increasing sepiapterin plasma exposure

Abstract

To provide methods of treating BH4-related disorders such as CNS disorder.SOLUTION: A method comprises a step for administering to a subject an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof, without food. Preferably, the effective method should be an amount sufficient to produce a concentration of at least 0.5 ng / mL in a plasma of the subject within one hour of administration.SELECTED DRAWING: None

Description

Background Art

[0001] Sepiapterin is a naturally occurring precursor of tetrahydrobiopterin (BH4), an essential cofactor for important 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 alkyl glycerol monooxygenase (AGMO) (Tietz et al, 1964). The rapid conversion of sepiapterin to BH4 occurs via two-step reduction in the salvage pathway for BH4 synthesis (Sawabe, 2008). Synthetic forms of BH4 (e.g., sapropterin dihydrochloride) are used as therapies for diseases associated with high plasma phenylalanine such as phenylketonuria (PKU). PKU is a congenital metabolic disorder mainly caused by mutations in the PAH gene. BH4 has also been tested as a therapy for various central nervous system symptoms and other diseases associated with PKU, but the effects were limited, probably because BH4 could not effectively cross the blood-brain barrier and / or enter brain cells (Klaiman et al, 2013, Grant et al, 2015).

[0002] Recent studies suggest that peripherally administered sepiapterin has higher permeability to cross membranes compared to BH4, and as a result, it can be more easily accessed by liver, kidney, and brain cells. Sepiapterin is rapidly converted to BH4 intracellularly, and it has been reported that this raises the BH4 levels in the liver, kidney, and brain (Sawabe, 2008). As a result, sepiapterin can serve as a useful therapeutic agent for diseases associated with low intracellular BH4 levels or dysfunction of various BH4-dependent metabolic pathways.

Summary of the Invention

[0003] This invention relates to the fact that administering sepiapterin to a fasted subject, compared to administration with food, improves the plasma Cmax and area under the concentration-time curve (AUC) of sepiapterin in the subject. 0-last The findings are directed towards the unexpected result of lower BH4 plasma (plasma) maximal concentrations (Cmax) despite resulting in increased exposure as measured by ). While not bound by theory, the increased sepiapterin plasma exposure in a fasted state is thought to be due to rapid gastrointestinal absorption, saturation kinetics of hepatocyte membrane-based active sepiapterin transporters (e.g., hENT2), and / or saturation of intracellular sepiapterin reductase and / or dihydrofolate reductase involved in the reduction of sepiapterin to BH4. Furthermore, the increased sepiapterin plasma Cmax results in increased CSF and / or brain exposure, accompanied by subsequent penetration of sepiapterin into brain cells. The present invention features sepiapterin, compositions comprising its salts, and methods for treating BH4-related diseases. In some embodiments, the compositions and methods result in increased plasma, CSF, and / or brain exposure of sepiapterin. In some embodiments, increased brain exposure to sepiapterin is determined by measuring the levels of monoamines in CSF, e.g., dopamine and / or serotonin metabolites (e.g., homovanillic acid or 5-hydroxyindoleacetic acid (5-HIAA)), where an increase compared to a reference (e.g., at least 5%, at least 10%, at least 15%, at least 25%, at least 50%, at least 75%, or at least 100%) indicates increased brain exposure to sepiapterin.

[0004] As is known in the art, food can affect 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 slowing the residence time in the stomach or foregut, reducing access of the compound to the absorption site, altering the dissolution rate of the compound, or altering the pH of the stomach. Because of this effect, it is important to establish a specific administration schedule for drugs that should be administered separately from or with food.

[0005] In one embodiment, the present invention is characterized by a method for treating BH4-related diseases in subjects requiring such treatment by administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof without food (for example, by reducing the peripheral conversion of sepiapterin to BH4).

[0006] In another embodiment, the present invention is characterized by a method for increasing sepiapterin plasma exposure in subjects receiving sepiapterin therapy by administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof without food (for example, by reducing the peripheral conversion of sepiapterin to BH4).

[0007] In a further embodiment, the present invention is characterized by a method for increasing cerebrospinal fluid (CSF) and / or brain exposure of sepiapterin by administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof without food (for example, by reducing the peripheral conversion of sepiapterin to BH4).

[0008] In another aspect, the present invention is characterized by a method for increasing the absorption rate of an oral formulation of sepiapterin and / or reducing its peripheral conversion to BH4, as measured by the concentration of sepiapterin that reaches the plasma over time in a subject, by administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof without food.

[0009] In some embodiments of any of the methods described above, the effective dose is an amount sufficient to produce a sepiapterin plasma concentration of at least 0.5 ng / ml (e.g., at least 1 ng / ml, at least 1.5 ng / ml, at least 2.5 ng / ml, or at least 3.5 ng / ml) in the subject's plasma within one hour of administration without food, for example, the effective dose includes a dose (e.g., 2.5 mg / kg to 100 mg / kg per single dose) that is at least 10% (e.g., at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, or at least 120%) less than an amount sufficient to produce a maximum plasma concentration (Cmax) of at least 0.5 ng / ml (e.g., at least 1 ng / ml, at least 1.5 ng / ml, at least 2.5 ng / ml, or at least 3.5 ng / ml) in the subject's plasma within one hour of administration of sepiapterin with food.

[0010] In some embodiments of any of the above-described methods, administration is performed more than 30 minutes before food intake, or at least 2 hours after food intake (e.g., at least 4 hours after food intake, at least 8 hours after food intake, or at least 12 hours after food intake). In some embodiments of any of the above-described methods, sepiapterin or its salt is administered without high-protein food. In some embodiments of any of the above-described methods, sepiapterin or its salt is administered without high-fat food (e.g., food in which at least 25, 30, 40, or 50% of calories come from fat). In some embodiments of any of the above-described methods, sepiapterin or its salt is administered without high-protein and high-fat food. In some embodiments, sepiapterin or a salt thereof is administered without accompanying high-calorie foods (for example, foods containing at least 100 calories, e.g., at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, e.g., 500-1500 or 800-1000 calories). In some embodiments of any of the above methods, sepiapterin or a salt thereof is administered without accompanying foods that constitute a meal (e.g., breakfast, lunch, or dinner).

[0011] In some embodiments, administration (e.g., more than approximately 30 minutes before food intake or at least 2 hours after food intake) results in an increase in maximal plasma concentration, CSF concentration, and / or brain concentration (Cmax) of sepiapterin (e.g., at least 10% (at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, or at least 120%) compared to administration with food (e.g., less than 30 minutes before food intake or less than 2 hours after food intake).

[0012] In some embodiments, administration (e.g., more than 30 minutes before food intake or at least 2 hours after food intake) is associated with a higher degree of sepiapterin absorption (AUC) compared to administration with food (e.g., administration to the subject less than 30 minutes before food intake or less than 2 hours after food intake). 0-lastThis results in an increase (for example, at least 10% (at least 20%, at least 40%, at least 60%, at least 80%, at least 100%, or at least 120%)).

[0013] In one embodiment, the present invention is characterized by a method for increasing the levels of homovanillic acid and / or 5-hydroxyindoleacetic acid in a subject, the method comprising the step of administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof without food. In some embodiments, the levels of homovanillic acid and / or 5-hydroxyindoleacetic acid in the cerebrospinal fluid (CSF) of the subject are increased. In some embodiments, the levels of homovanillic acid and / or 5-hydroxyindoleacetic acid in the subject (e.g., the subject's CSF) are increased by at least 5% compared to the level before administration (e.g., an increase of 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%, or at least 300% compared to the level before administration).

[0014] In some embodiments, prior to administration of sepiapterin or a pharmaceutically acceptable salt thereof, the subject has levels of homovanillic acid and / or 5-hydroxyindoleacetic acid at less than 50% of the average subject level (e.g., less than 40%, less than 30%) (e.g., the subject has a CSF level of homovanillic acid less than 15 ng / ml and / or a CSF level of 5-hydroxyindoleacetic acid less than 5 ng / ml). In some embodiments, the subject has not been diagnosed with BH4-related disease. In some embodiments, the subject does not have symptoms of BH4-related disease. In some embodiments, after administration of sepiapterin or a pharmaceutically acceptable salt thereof, the levels of homovanillic acid and / or 5-hydroxyindoleacetic acid in the subject are greater than 50% of the average subject level (e.g., the subject has a CSF level of homovanillic acid greater than 15 ng / ml and / or a CSF level of 5-hydroxyindoleacetic acid greater than 5 ng / ml).

[0015] In some embodiments of any of the above-described aspects, the subject suffers from and / or is diagnosed with a BH4-related disease.

[0016] In some embodiments of any of the aspects described above, BH4-related disorders include primary BH4 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, and in patients with Parkinson's disease. These include impulsivity, major depression, autism spectrum disorder, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety disorder, aggression in Alzheimer's disease, cerebrovascular disease, convulsions after subarachnoid hemorrhage, myocarditis, coronary spasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infection, endotoxin shock, cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, or hypoglycemia. In some embodiments of any of the above-described aspects, BH4-related disorders include phenylketonuria, BH4 deficiency (e.g., primary BH4 deficiency), CNS disorders (e.g., Segawa syndrome, depression, schizophrenia, autism, or Parkinson's disease), or gastrointestinal motility disorders (e.g., gastroparesis and primary and secondary esophageal motility disorders). In some embodiments, BH4-related diseases are BH4 deficiency or phenylketonuria.

[0017] definition In this application, unless otherwise evident from the context, (i) the term “a” may be understood to mean “at least one,” (ii) the term “or” may be understood to mean “and / or,” (iii) the terms “include” and “inclusive” may be understood to include the listed components or processes, whether presented by themselves or together with one or more additional components or processes, and (iv) the terms “about” and “approximately” may be understood to allow for standard variations as understood by those skilled in the art, and (v) if a range is provided, the endpoint is included.

[0018] As used herein, the term “administration” refers to the administration of a composition to a subject. Administration to an animal subject (e.g., a human) may be by any suitable route. For example, in one embodiment, administration may include bronchial (including bronchial infusion), oral cavity, enteral, interdermal, intra-arterial, intradermal, gastric, intramedullary, intramuscular, intranasal, intraperitoneal, intrathecal, intravenous, intraventricular, mucosal, nasal, oral, rectal, subcutaneous, sublingual, topical, intratracheal (including intratracheal infusion), percutaneous, vaginal, or vitreous.

[0019] The "effective dose" of a compound may vary depending on factors such as the individual's medical condition, age, sex, and weight, as well as the compound's ability to induce the desired response. A therapeutically effective dose encompasses the amount in which the therapeutically beneficial effect outweighs any toxic or harmful effects of the compound. The effective dose also includes an amount sufficient to provide a benefit, such as a clinical benefit.

[0020] As used herein, the term “food” refers to solid food having sufficient bulk and fat content so that it is not rapidly dissolved and absorbed in the stomach. For example, a meal such as breakfast, lunch, or dinner. As used herein, the term “with food” refers to administering the composition between approximately 30 minutes before eating (e.g., eating a meal) and approximately 2 hours after eating. The terms “without food,” “fasting,” or “hunger” further refer to a state in which no solid food has been consumed for at least approximately 2 hours, up to approximately 30 minutes before consuming food.

[0021] As used herein, the term “pharmaceutical composition” refers to a composition comprising the compounds described herein, formulated with pharmaceutically acceptable excipients. Pharmaceutical compositions may be formulated, for example, for oral administration of unit formulations (e.g., tablets, capsules, caplets, gel caps, suspensions, solutions, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as sterile solutions of granular embolism-free solvent systems suitable for intravenous use), or in any other pharmaceutically acceptable formulation.

[0022] 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 fall within reasonable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, or allergic reactions, and have a reasonable benefit / risk ratio. Pharmacologically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in Berge et al., J. Pharmaceutical Sciences 66:1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use, (Eds. PH Stahl and CG Wermuth), Wiley-VCH, 2008. Salts can be prepared in situ during the final isolation and purification of the compounds described herein, or separately by reacting the free base group with a suitable organic acid.

[0023] In many cases, compounds are prepared or used as pharmaceutically acceptable salts, which are prepared as addition products of pharmaceutically acceptable acids. Suitable pharmaceutically acceptable acids and methods for preparing suitable salts are well known in the art. Salts may be prepared from pharmaceutically acceptable, non-toxic acids, including inorganic and organic acids.

[0024] Typical acid addition salts include acetate, adipate, alginate, ascorbate, aspatate, benzenesulfonate, benzoate, besylate, bisulfate, borate, butylate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, gentisate, glucoheptate, glycerophosphate, glycolate, hemisulfate, heptonate, hexanate, hydrobromide, hydrochloride, hydroiodide, and 2 This includes hydroxyethanesulfonates, lactobionates, lactates, laurates, lauryl sulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoates, pectinates, parsulfates, 3-phenylpropionates, phosphates, picates, pivalates, propionates, stearates, succinates, sulfates, tarates, thiocyanates, toluenesulfonates, undecanoates, and valverate salts.

[0025] As used herein, the terms “subject” or “patient” mean any organism to which a compound or composition according to the present invention may be administered, for example, for experimental, diagnostic, preventive, and / or therapeutic purposes. Typical subjects include any animal (e.g., mammals such as mice, rats, rabbits, non-human primates, and humans). A subject may be a human or animal that requires treatment, is receiving treatment, may receive treatment in the future, or is being cared for by a specialist trained for a particular disease or condition.

[0026] As used herein, the term "BH4-related disorder" refers to any disease or disorder for which a therapeutic benefit can be obtained from modulating the level or activity of BH4. BH4-related disorders include, but are not limited to, primary BH4 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 in Parkinson's disease, impulsivity in Parkinson's disease patients, major depression, autism spectrum, ADHD, schizophrenia, bipolar disorder, cerebral ischemia, restless leg syndrome, obsessive-compulsive disorder, anxiety disorder, aggression in Alzheimer's disease, cerebrovascular disorder, spasm after subarachnoid hemorrhage, myocarditis, coronary vasospasm, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infectious disease, endotoxin shock, cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, or hypoglycemia. In some embodiments of any of the above aspects, the BH4-related disorder is phenylketonuria, BH4 deficiency (e.g., primary BH4 deficiency), CNS disorder (e.g., Segawa syndrome, depression, schizophrenia, autism, or Parkinson's disease), or gastrointestinal motility disorder (e.g., gastric hypomotility and primary and secondary esophageal motility disorders). In some embodiments, the BH4-related disorder is BH4 deficiency or phenylketonuria.

[0027] As used herein, the terms "treating," "treated," or "treatment" mean both therapeutic treatment and prophylactic or inhibitory measures, the purpose of which is to inhibit or slow down (mitigate) an undesirable physiological condition, disorder, or disease, or to obtain a beneficial or desirable clinical outcome. Beneficial or desirable clinical outcomes include alleviation of symptoms, reduction in the degree of a condition, disorder, or disease, stabilization (i.e., not worsening) of a condition, disorder, or disease, onset or delay of the progression of a condition, disorder, or disease, improvement of a condition, disorder, or pathological condition or remission (partial or total), whether or not detectable, improvement of at least one measurable physical parameter, which need not be distinguishable by the patient, or improvement or amelioration of a condition, disorder, or disease, but are not limited thereto. Treatment includes eliciting a clinically significant response without undue levels of side effects. Treatment also includes prolonging survival as compared to expected survival in the absence of treatment.

Brief Description of the Drawings

[0028] [Figure 1] Figure 1 is a graph showing the mean plasma concentration of BH4 over time in fed and fasted subjects. [Figure 2] Figure 2 is a graph showing the mean plasma concentration of sepiapterin over time in fed and fasted subjects.

Modes for Carrying Out the Invention

[0029] The inventors have discovered that administration of sepiapterin or a pharmaceutically acceptable salt thereof without food increases plasma, CSF, and / or brain exposure of sepiapterin in a subject. Accordingly, the present invention features a composition comprising sepiapterin or a pharmaceutically acceptable salt thereof, and a method of treating BH4-related diseases that results in plasma, CSF, and / or brain exposure of sepiapterin.

[0030] Sepiapterin Sepiapterin passes into 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.

[0031] While not bound by theory, administering sepiapterin without food may lead to increased plasma, CSF, and / or brain exposure of sepiapterin due to its increased absorption rate. Because sepiapterin efficiently crosses cell membranes, rapid absorption of administered sepiapterin (e.g., by administration on an empty stomach) can saturate the intracellular sepiapterin active transporter and / or sepiapterin reductase, resulting in at least some of the administered sepiapterin not entering the cell and / or leaving the cell without being reduced to 7,8-dihydrobiopterin. This excess sepiapterin in the plasma then crosses the blood-brain barrier (BBB) ​​and enters brain cells before being converted to BH4, resulting in higher levels of BH4 in the brain (and / or CSF) compared to administration with food. Furthermore, it may reduce the absorption rate of sepiapterin and prevent saturation of sepiapterin transporters and intracellular sepiapterin reductase. Thus, administration of sepiapterin without food may result in higher maximum plasma, CSF, and / or brain concentrations (Cmax) and / or absorption rates (AUC) of sepiapterin compared to administration with food. 0-last This unexpectedly leads to an increase in sepiapterin levels in plasma, CSF, and / or brain. Increased sepiapterin levels may be beneficial in the treatment of some BH4 disorders, e.g., BH4-related CNS disorders.

[0032] Sepiapterin has the following structure. JPEG0007841005000001.jpg2942

[0033] Sepiapterin or a pharmaceutically acceptable salt thereof may be incorporated into the pharmaceutical composition. In some embodiments, the pharmaceutical composition of the present invention contains 20-30% of sepiapterin or a salt thereof by total weight, for example, 20%, 22%, 25%, 27%, or 30%. In some embodiments, the pharmaceutical composition contains more than 20% of 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 contains less than 20% of sepiapterin by total weight, for example, less than 20%, less than 15%, less than 10%, or less than 5%.

[0034] In some embodiments, the present invention features a pharmaceutical composition comprising sepiapterin or a salt thereof and an antioxidant in an amount less than 10% (e.g., 9%, 7%, 5%, 3%, 1%, 0.5%, 0.25%, or 0.1%) of the total weight. 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 contain sepiapterin or a pharmaceutically acceptable salt thereof in an amount of 20-30% of the total weight, for example, 20%, 22%, 25%, 27%, or 30%. The pharmaceutical composition may further contain a dispersant, for example, croscamerose sodium. The pharmaceutical composition may contain a dispersant in an amount of 0.1-1.5% of the total weight, for example, 0.1%, 0.5%, 1%, or 1.5%. In some embodiments, the pharmaceutical composition comprises at least one anticaking agent, such as colloidal silicon dioxide or microcrystalline cellulose. The pharmaceutical composition may contain the anticaking agent in an amount of 65-75% of the total weight, for example, 65%, 67%, 70%, 73%, or 75%. In some embodiments, the pharmaceutical composition comprises both colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, the pharmaceutical composition comprises 60-65% microcrystalline cellulose and 5-7% colloidal silicon dioxide by weight. In some embodiments, the crystalline form of sepiapterin is formulated as particles less 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 embodiments, the pharmaceutical composition contains less than 1% of an impurity such as lactoylpterin, for example, 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%.

[0035] In some embodiments, sepiapterin is a salt of sepiapterin, for example, a salt 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.

[0036] In some embodiments, sepiapterin or its pharmaceutically acceptable salts are in crystalline form. The crystalline form of crystalline sepiapterin-free base or salts of sepiapterin may occur as anhydrous (e.g., without any bound water or solvent or hydration or solvation), or as hydrates, partial hydrates (e.g., hemihydrate, sesquihydrate, etc.), dihydrates, trihydrates, etc., where the crystalline form binds the hydration water or solvent molecules associated with the crystalline form of sepiapterin or its salts. In one embodiment, crystalline sepiapterin occurs as a monohydrate or hemihydrate.

[0037] In some embodiments, sepiapterin or a pharmaceutically acceptable salt thereof exists in crystalline form. In some embodiments, the crystalline form of sepiapterin is characterized by a powder X-ray diffraction pattern obtained by irradiation with CuKα X-rays having peaks represented by 2θ at at least about 9.7°, about 10.2°, and about 11.3°. In other embodiments, the crystalline form of sepiapterin is characterized by a powder X-ray diffraction pattern obtained by irradiation with CuKα X-rays having peaks represented by 2θ at at least about 9.7°, about 10.2°, about 11.3°, about 14.0°, about 14.6°, about 19.9°, about 22.2°, about 25.3°, and about 32.4°.

[0038] The present invention provides a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof.

[0039] Pharmaceutically acceptable excipients may be any of those conventionally used, and are limited only by physicochemical considerations such as solubility and route of administration. Those skilled in the art will understand that, in addition to the pharmaceutical compositions described below, sepiapterin can be formulated as inclusion complexes such as cyclodextrin inclusion complexes, or as liposomes.

[0040] The pharmaceutically acceptable excipients described herein, such as vehicles, adjuvants, excipients, or diluents, are well known to those skilled in the art and readily available. Preferably, the pharmaceutically acceptable excipients are chemically inert to sepiapterin and do not have adverse side effects or toxicity under the conditions of use.

[0041] Antioxidants Sepiapterin tends to oxidize rapidly when exposed to air. Therefore, the pharmaceutical composition of the present invention may contain antioxidants. The antioxidants may minimize the oxidative degradation of sepiapterin. Examples of antioxidants, but not limited to, include 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 composition of the present invention contains ascorbic acid, tocopherol, retinol, ascorbyl palmitate, N-acetylcysteine, glutathione, butylated hydroxytoluene, and / or butylated hydroxyanisole as antioxidants.

[0042] In some embodiments, the pharmaceutical composition contains less than 10% by weight of the antioxidant, for example, less than 9% by weight, less than 8% by weight, less than 7% by weight, less than 6% by weight, less than 5% by weight, less than 4% by weight, less than 3% by weight, less than 2% by weight, less than 1% by weight, or substantially no antioxidant. In some embodiments, the pharmaceutical composition contains 2 to 9% of the antioxidant by weight, for example, 2 to 4%, 3 to 5%, 4 to 6%, 5 to 7%, 6 to 8%, or 7 to 9%. In some embodiments, the pharmaceutical composition contains 5 to 100% of the USP maximum daily dose of the antioxidant, for example, in some embodiments, the pharmaceutical composition contains 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 to 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.

[0043] Dispersant In some embodiments, the pharmaceutical composition of the present invention comprises at least one dispersant. The dispersant may separate particles in the formulation, for example, by releasing its active ingredient upon contact with water. Examples of dispersants include, but are not limited to, cross-linked 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 carboxymethylcellulose, such as a pharmaceutically acceptable salt of croscarmellose. In some embodiments, the pharmaceutical composition may contain 0.1 to 1.5% (e.g., 0.1%, 0.5%, 1%, or 1.5%) of the dispersant based on the total weight. In some embodiments, the pharmaceutical composition contains less than 1.5% (e.g., less than 1%, less than 0.5%, or less than 0.1%) of the dispersant.

[0044] Anti-caking agent In some embodiments, the pharmaceutical composition of the present invention comprises at least one anticaking agent. In some embodiments, the pharmaceutical composition of the present invention comprises at least two anticaking agents. Exemplary anticaking 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, at least one anticaking agent is colloidal silicon dioxide or microcrystalline cellulose. In some embodiments, the pharmaceutical composition may contain 65-75% (e.g., 65%, 67%, 70%, 73%, or 75%) of the anticaking agent based on the total weight. In some embodiments, the pharmaceutical composition contains both colloidal silicon dioxide and microcrystalline cellulose. In some embodiments, the pharmaceutical composition contains 60-65% microcrystalline cellulose and 5-7% colloidal silicon dioxide by weight.

[0045] Administration vehicle In some embodiments, the pharmaceutical composition of the present invention is combined with an administration vehicle before administration (e.g., an administration vehicle having a viscosity of about 50 to 1750 centipoise (cP)). One type of suspension that can be used is a combination of glycerin and sucrose in water (e.g., MEDISCA containing 2.5% glycerin and 27% sucrose in water). (R) (Oral mix). An appropriate amount of the composition can be added to the administration vehicle mixture and stirred to suspend the composition immediately before administration.

[0046] Other suspensions may also be used as administration vehicles. Exemplary suspensions include agar, alginic acid, sodium carboxymethylcellulose, carrageenan, dextrin, gelatin, guar gum, hydroxyethylcellulose, hydroxypropylcellulose, hypermellose, methylcellulose, polyethylene glycol, povidone, tragacanth, xanthan gum, or other suspensions known in the art.

[0047] dose Sepiapterin or its pharmaceutically acceptable salts can be used in any appropriate dose. Appropriate doses and dose regimens can be determined within the scope of the prior art. Generally, treatment is initiated with a dose lower than the optimal dose. The dose is then gradually increased until the optimal effect is achieved under the circumstances. For convenience, the total daily dose can be divided and administered throughout the day if desired. With appropriate doses and appropriate administration of specific compounds, the present invention provides a wide range of responses. Typically, doses range from about 2.5 to about 500 mg / kg body weight / day of the patient being treated. For example, in the embodiment, sepiapterin, or a pharmaceutically acceptable salt thereof, can be administered once or more times a day at doses of approximately 20 mg / kg to approximately 150 mg / kg, approximately 40 mg / kg to approximately 100 mg / kg, approximately 100 mg / kg to approximately 150 mg / kg, approximately 60 mg / kg to approximately 120 mg / kg, approximately 80 mg / kg to approximately 100 mg / kg, approximately 40 mg / kg to approximately 60 mg / kg, approximately 2.5 mg / kg to approximately 20 mg / kg, approximately 2.5 mg / kg to approximately 10 mg / kg, or approximately 2.5 mg / kg to approximately 5 mg / kg of target body weight / day, in order to obtain the desired therapeutic effect.

[0048] In some embodiments, the dose is sufficient to generate levels of BH4 in the CNS (e.g., the brain), for example, as measured in the CSF, and / or sufficient to produce a therapeutic outcome, such as an increase in serotonin or dopamine in the CNS. In some embodiments, the increase in BH4 in the CNS is measured by determining the levels of metabolites of monoamines in the CSF, such as serotonin and / or dopamine (e.g., homovanillic acid or 5-hydroxyindoleacetic acid (5-HIAA)). Here, an increase in the metabolites in the CSF indicates an increase in BH4 levels in the CNS (e.g., the brain). In some embodiments, the dose is sufficient to increase the level of BH4, as measured in plasma or the organ of interest (e.g., the liver of the interest), to at least twice the level of BH4 before administration.

[0049] In some embodiments, sepiapterin or a pharmaceutically acceptable salt thereof can be formulated as a unit solid oral dosage form, such as particles. In these embodiments, each unit solid oral dosage form may contain any appropriate amount of sepiapterin or a pharmaceutically acceptable salt thereof. For example, each unit solid oral dosage form may contain 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.

[0050] Sepiapterin or a pharmaceutically acceptable salt thereof can be used to prepare liquid formulations such as solutions, suspensions, or emulsions. Formulations suitable for oral administration may consist of (a) solid or granular forms, each containing a predetermined amount of the active ingredient, such as capsules, sachets, tablets, lozenges, and troches; (b) powders; (c) liquid formulations such as an effective amount of the compound dissolved in a diluent such as water, saline, or orange juice; (d) suspensions in a suitable liquid; and (e) suitable emulsions. Preferably, solid oral formulations such as capsules, tablets, and powders. Capsules may be of the usual hard or soft shell-like gelatin type, containing, for example, a surfactant, lubricant, and inert filler, such as lactose, sucrose, calcium phosphate, and corn starch. The tablet form may contain 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 one or more other excipients, colorants, diluents, buffers, disintegrants, wetting agents, preservatives, flavorings, and pharmacologically suitable excipients. The lozenge form may contain the active ingredient in addition to a flavor (usually sucrose and acacia or tragacanth), and similarly, pastilles may contain the active ingredient in an inert base such as gelatin and glycerin, or sucrose and acacia, emulsion, or gel, and such excipients are known in the art.

[0051] Formulations suitable for oral and / or parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions, which may contain antioxidants, buffers, bacteriostags, and solutes and suspensions that make the formulation isotonic with the recipient's blood, as well as aqueous and non-aqueous sterile suspensions, solubilizers, thickeners, stabilizers, and preservatives. The compounds of the present invention can be administered in a physiologically acceptable diluent in a sterile liquid or mixture of liquids containing pharmaceutical excipients, such as water, physiological saline, glucose aqueous solution and related sugar solutions, alcohols such as ethanol, benzyl alcohol, or hexadecyl alcohol, glycols such as propylene glycol or polyethylene glycol and polyethylene alcohol, glycerol ketals such as 2,2-dimethyl-1,3-dioxolane-4-methanol, ethers such as poly(ethylene glycol) 400, oils, fatty acids, fatty acid esters or glycerides, or acetylated fatty acid glycerides with or without the addition of pharmaceutically acceptable surfactants such as soap or detergent, suspending agents such as pectin, carbohydrates, methylcellulose, hydroxypropyl methylcellulose, or carboxymethylcellulose, or emulsifiers, and other pharmaceutical adjuvants.

[0052] The present invention features pharmaceutical compositions of orally acceptable formulations comprising a therapeutically effective amount of sepiapterin and less than 10% of an antioxidant. In some embodiments, the pharmaceutical composition is a granular formulation dispersed in pharmaceutically acceptable excipients, for example, the composition can be mixed with water and ingested by a patient (e.g., within 5 to 10 minutes). Preferred formulations for use in the present invention are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, PA 22nd ed., 2010. Unless any conventional excipient is incompatible with the active ingredient, its use in the pharmaceutical compositions of the present invention is intended. Furthermore, for animal (e.g., human) administration, it will be understood that the formulation should meet sterility, pyrogenicity, general safety, and purity standards as required by the FDA Office's biological standards.

[0053] Oils that can be used in parenteral formulations include petroleum, animal, plant, and synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and minerals. Fatty acids suitable 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 acid alkali metals, ammonium, and triethanolamine salts; suitable detergents include (A) cationic detergents (e.g., dimethyldialkylammonium halides and alkylpyridinium halides); (B) anionic detergents (e.g., alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates); (C) nonionic detergents (e.g., fatty amine oxides, fatty acid alkanolamides, and polyoxyethylene-polypropylene copolymers); (D) amphoteric detergents (e.g., alkyl-β-aminopropionates and 2-alkyl-imidazopeake quaternary ammonium salts); and mixtures thereof.

[0054] Parenteral formulations may typically contain about 20% to about 30% by weight of sepiapterin or a pharmaceutically acceptable salt thereof in solution. Suitable preservatives and buffers may be used in such formulations. To minimize or eliminate irritation at the injection site, such compositions may contain one or more nonionic surfactants having a hydrophilic-lipophilic balance (HLB) of about 12 to about 17. The amount of surfactant in such compositions is in the range of about 5% to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters such as sorbitan monooleate, and high molecular weight adducts of hydrophobic bases and ethylene oxide formed by the condensation of propylene oxide and propylene glycol. Parenteral formulations can be placed in unit-dose or multi-dose sealed containers such as ampoules and vials and can be stored in a lyophilized state requiring only the addition of a sterile liquid excipient for injection, such as water, immediately before use. Immediate injection solutions and suspensions can be prepared from the types of sterile powders, granules, and tablets described above.

[0055] The sepiapterin or a pharmaceutically acceptable salt thereof of the present invention can be prepared as an injectable formulation. The requirements for effective pharmaceutically acceptable excipients for injectable compositions are well known to those skilled in the art. Remington: The Science and Practice of Pharmacy, 22 nd See Edition, Lippincott Williams & Wilkins, (2012), and Encyclopedia of Pharmaceutical Technology, eds. J. Swarbrick and JC Boylan, 2006, Marcel Dekker, New York (these are incorporated herein by reference).

[0056] Topical formulations, including those useful for transdermal drug release, are well known to those skilled in the art and are suitable for application to the skin in the context of the present invention. Compositions applied topically are typically in the form of liquids, creams, pastes, lotions, and gels. Topical administration includes application to oral mucosa, including the oral cavity, oral epithelium, palate, gingiva, and nasal mucosa. In some embodiments, the composition comprises sepiapterin, or a pharmaceutically acceptable salt thereof, and a suitable vehicle or excipient. It may also contain other components, such as an anti-irritant. The excipient may be a liquid, solid, or semi-solid. In embodiments, the composition is an aqueous solution. Alternatively, the composition may be a dispersion, emulsion, gel, lotion, or cream vehicle of various components. In one embodiment, the primary vehicle is water or a substantially neutral or substantially neutralized biocompatible solvent. The liquid vehicle may contain buffers, alcohols, glycerin, mineral oils, and other materials, along with various emulsifiers or dispersants known in the art, to obtain the desired pH, invariance, and viscosity. The composition can be manufactured as a solid, such as a powder or granules. This solid can be applied directly before use, or dissolved in water or a biocompatible solvent to form a substantially neutral or substantially neutralized solution, which can then be applied to the target site. In embodiments of the present invention, the vehicle for topical application to the skin may include water, a buffer solution, various alcohols, glycols such as glycerin, lipid materials such as fatty acids, mineral oil, phosphoglycerides, collagen, gelatin, and silicone-based materials.

[0057] Sepiapterin or its salts can be prepared alone or in combination with other suitable ingredients as aerosol formulations for administration by inhalation. These aerosol formulations can be mounted on pressurized, acceptable propellants such as dichlorodifluoromethane, propane, or nitrogen. They may also be formulated as pharmaceuticals for non-pressurized formulations, such as nebulizers or atomizers.

[0058] Furthermore, the sepiapterin of the present invention or a pharmaceutically acceptable salt thereof may be mixed with various bases, such as emulsifying bases or water-soluble bases, to produce suppositories. Formulations suitable for vaginal administration may exist as pessaries, tampons, creams, gels, pastes, foams, or spray formulations, containing the active ingredient in addition to excipients known to be appropriate in the art.

[0059] Oral solid dosage form Formulations for oral use comprise particles containing the active ingredient in a mixture with non-toxic, pharmaceutically acceptable excipients, and such formulations are known to those skilled in the art (e.g., US 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 include, for example, inert diluents or fillers (e.g., sucrose, sorbitol, sugar, mannitol, microcrystalline cellulose, starch containing potato starch, calcium carbonate, sodium chloride, lactose, calcium phosphate, calcium sulfate, or sodium phosphate), granulating and disintegrating agents (e.g., cellulose derivatives containing microcrystalline cellulose, starch containing potato starch, croscarmellose sodium, alginates, or alginic acid), binders (e.g., sucrose, glucose, sorbitol, acacia, alginic acid, sodium alginate, gelatin, starch, pre-gelatinized starch, microcrystalline cellulose, magnesium aluminum silicate, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethylcellulose, polyvinyl pyropropylcellulose) The excipients may be lydone (or polyethylene glycol), lubricants, anti-adhesion agents (e.g., magnesium stearate, zinc stearate, stearic acid, silica, hydrogenated vegetable oil, or talc), and anticaking 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, or polydimethylsiloxane). Other pharmaceutically acceptable excipients may be colorants, fragrances, plasticizers, humectants, and buffers. In some embodiments, the excipients (e.g., fragrances) are packaged together with the composition.In some embodiments, excipients (e.g., fragrances) are packaged separately from the composition (e.g., combined with the composition before administration).

[0060] The solid composition of the present invention may include a coating adapted to protect the composition from undesirable chemical changes (e.g., chemical decomposition before the release of the active substance). The coating may be applied to the solid dosage form in a manner similar to that described in the Encyclopedia of Pharmaceutical Technology above.

[0061] Using the above components, powders and granules may be prepared by conventional methods, for example, using a mixer, fluidized bed apparatus, melt-solidification apparatus, rotor granulator, extrusion / spheroidization apparatus, or spray drying apparatus.

[0062] Treatment method Sepiapterin is used to treat disorders associated with decreased intracellular BH4 levels, including primary BH4 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 associated with Parkinson's disease, impulsivity in Parkinson's disease patients, major depressive disorder, autism spectrum disorder, and ADHD. It may be useful in treating a variety of diseases associated with dysfunction of BH4-dependent metabolic pathways, including but not limited to schizophrenia, bipolar disorder, cerebral ischemia, restless legs syndrome, obsessive-compulsive disorder, anxiety disorders, aggression in Alzheimer's disease, cerebrovascular disease, convulsions after subarachnoid hemorrhage, myocarditis, coronary spasms, cardiac hypertrophy, arteriosclerosis, hypertension, thrombosis, infections, endotoxin shock, cirrhosis, hypertrophic pyloric stenosis, gastric mucosal injury, pulmonary hypertension, renal dysfunction, impotence, and hypoglycemia. Therefore, various forms of sepiapterin, or salts thereof, of the present invention can be administered to a patient in an effective amount to obtain treatment or improvement of a disease, disorder, or condition.

[0063] Sepiapterin or its salt is administered without food. In some embodiments of any of the above methods, separatepiapterin or its salt is administered without high-protein food. In some embodiments of any of the above methods, separatepiapterin or its salt is administered without high-fat food (e.g., food in which at least 25, 30, 40, or 50% of calories come from fat). In some embodiments of any of the above methods, separatepiapterin or its salt is administered without high-protein and high-fat food. In some embodiments, separatepiapterin or its salt is administered without high-calorie food (e.g., food containing at least 100 calories, e.g., at least 200 calories, at least 300 calories, at least 400 calories, at least 500 calories, e.g., 500-1500 or 800-1000 calories). In some embodiments of any of the above methods, separatepiapterin or its salt is administered without a meal (e.g., breakfast, lunch, or dinner).

[0064] The actual dose of the composition of the present invention administered to a patient may be determined by physical and physiological factors such as body weight, severity of condition, type of disease being treated, previous or concurrent therapeutic interventions, patient idiopathy, and route of administration. Depending on the dose and route of administration, the preferred dose and / or number of effective doses may vary depending on the subject's response. In any case, the person responsible for administration may determine the concentration of the active ingredient in the composition and the appropriate dose for each individual subject.

[0065] In some embodiments, the patient receives 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. The patient may receive the pharmaceutical composition containing sepiapterin once or twice daily during treatment. In some embodiments, the patient continues other current medications for BH4-related disorders (e.g., prescribed L-dopa / carbidopa, 5-HTP, melatonin, MAO inhibitors, and dopamine receptor agonists), except for BH4 supplements (if taking BH4). The patient may be permitted to take medications known to inhibit folate synthesis (e.g., methotrexate, pemetrexed, trimethrexate, etc.).

[0066] In some embodiments, patients taking BH4 discontinue BH4 administration (i.e., BH4 washout). Blood samples for Phe concentration may be obtained during the BH4 washout period 7, 5, 3, and 1 day prior to treatment with the pharmaceutical composition of the present invention, or at any point during the BH4 washout until the blood Phe concentration reaches >360 μmol / L. In some embodiments, pre-administration blood samples are tested for sepiapteprine, Phe, BH4, and tyrosine (Tyr).

[0067] Equivalents and scope Those skilled in the art will recognize many equivalents to the specific embodiments of the present invention described herein, or can verify them by routine experimentation alone. The scope of the present invention is not intended to be limited to the foregoing description, but rather as set forth in the appended claims.

[0068] Furthermore, it is understood that any particular embodiment of the present invention that constitutes prior art may be expressly excluded from one or more of the claims. Such embodiments are considered to be known to those skilled in the art and may be excluded even if the exclusion is not expressly provided herein. Any particular embodiment of the composition of the present invention (e.g., any compound, any production method, any use) may be excluded from one or more claims for any reason, whether or not it relates to the existence of prior art. [Examples]

[0069] Example 1. Evaluation of the effects of food on sepiapterin administration Methods: Subjects were orally administered sepiapterin (10 mg / kg) twice a week, once in a fasted state and once in a fed state. On day 8, starting 30 minutes before the second oral administration of sepiapterin, subjects were given a standard high-fat (approximately 50 percent of the total calories in the meal) and high-calorie (approximately 800-1000 calories) meal.

[0070] Sampling for PK analysis was performed before administration (within 30 minutes prior to administration) on days 1 and 8, and at 0.5 hours, 1 hour, 2 hours, 4 hours, 8 hours, 12 hours, and 24 hours after administration on days 1 and 8. Blood concentrations of sepiapterin and BH4 were analyzed at MNG Laboratory.

[0071] The cerebrospinal fluid (CSF) of the selected subject is collected by lumbar puncture approximately 30 minutes after the point at which the maximum observed plasma BH4 concentration (Tmax) determined by blood analysis is reached, on day 1 (before administration) and on day 7 (i.e., after 7 days of daily administration).

[0072] Cerebrospinal fluid (CSF) was analyzed in the MNG laboratory. Descriptive statistics are provided to characterize changes in neurotransmitter metabolism between sample results on day 1 and day 7.

[0073] Results: Surprisingly, as shown in Tables 1 and 2 and Figure 1 below, the Cmax of BH4 in plasma was significantly lower in subjects who fasted before administration compared to subjects who ate before administration. [Table 1] [Table 2]

[0074] Furthermore, as shown in Tables 3 and 4 and Figure 2 below, surprisingly, the Cmax of sepiapterin in plasma was significantly higher in subjects who fasted before administration compared to those who ate before administration. [Table 3] [Table 4]

[0075] Furthermore, as shown in Table 5, in fasted subjects administered sepiapterin, the AUC was higher compared to subjects administered BH4. 0-24 and AUC 0-inf The rate was very high. In each group that underwent this treatment, 6 subjects received sepiapterin and 3 subjects received BH4. [Table 5]

[0076] Other embodiments This specification is provided in conjunction with a detailed description, but it will be understood that the above description is intended to be illustrative and not to limit the scope of the disclosure herein as defined by the appended claims. Other embodiments, advantages, and modifications are within the scope of the following claims.

Claims

1. A composition comprising sepiapterin or a pharmaceutically acceptable salt thereof for use in the treatment of BH4-related CNS disorder in subjects requiring such treatment, wherein the treatment comprises the step of orally administering an effective amount of sepiapterin or a pharmaceutically acceptable salt thereof to the subject once daily without food, wherein the administration to the subject is performed more than 30 minutes before or more than 2 hours after food intake.

2. The composition for use according to claim 1, wherein the effective amount is sufficient to produce a sepiapterin concentration of at least 0.5 ng / ml in the plasma of the subject within 1 hour of administration.

3. The composition for use according to claim 2, wherein the effective amount comprises a dose at least 20% lower than a dose sufficient to produce a maximum plasma concentration (Cmax) of sepiapterin of at least 0.5 ng / ml in the plasma of a subject within one hour after administration of sepiapterin or a pharmaceutically acceptable salt thereof with food.

4. The composition for use according to any one of claims 1 to 3, wherein the effective amount is 2.5 mg / kg to 100 mg / kg per administration.

5. The composition for use according to claim 4, wherein the administration to the subject is performed more than 30 minutes before or more than 4 hours after the intake of food.

6. A composition for use according to any one of claims 1 to 5, wherein the effective amount results in an increase in the maximum plasma, CSF, and / or cerebral concentration (Cmax) of sepiapterin or a pharmaceutically acceptable salt thereof compared to administration with food.

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