A low-dose, sustained-release formulation for the relief of symptoms caused by elevated levels of dopamine and norepinephrine

Abstract

Formulations for alleviating symptoms of autism spectrum disorder as well as other indications are described herein. In at least one embodiment, a low-dose sustained-release formulation comprising alpha-methyl-L-tyrosine (AMT or AMPT) is described. Such low-dose sustained-release formulations provide a less uniform treatment regimen and minimize potential adverse side effects.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Application No. 63 / 407,207, filed September 16, 2022, the entire disclosure of which is incorporated herein by reference.

[0002] The field of embodiments of the present application relates to formulations for alleviating symptoms associated with anxiety, post-traumatic stress disorder (PTSD), hypertension, cytochrome storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging through inhibition of dopamine and / or norepinephrine in patients in need thereof. In particular, described herein are low-dose sustained-release formulations comprising alpha-methyl-L-tyrosine (AMT or AMPT) useful for alleviating symptoms of ASD. [Background technology]

[0003] Autism and post-traumatic stress disorder (PTSD) are characterized by either too many neurons and synapses or overly sensitive neurons and synapses, respectively. Characteristics of these conditions include excessive dopamine and norepinephrine activity. Sensory input, memories, and thoughts can be too intense and harmful, thereby causing or promoting these conditions.

[0004] Autism spectrum disorder ("autism" or "ASD") is a neurological and developmental disorder that affects how individuals interact, learn, behave, and communicate with others. ASD is known as a "spectrum" disorder because individuals with ASD vary greatly in the type and severity of symptoms they exhibit. While ASD can be diagnosed at any age, symptoms typically appear within the first two years of life, and therefore it is commonly described as a "developmental disorder."

[0005] Currently, there are 5.5 million adults and 2 million children in the United States (80 million adults and 20 million children worldwide) who fall somewhere on the autism spectrum. One in 36 8-year-olds is diagnosed with autism, with males outnumbering females by a ratio of 4:1. Thirty percent of children diagnosed with autism remain nonverbal into adolescence. Autistic people have a higher mortality rate (especially by suicide), and many end their lives through violent means. Incidence rates are highest in Massachusetts, California, Connecticut, and New Jersey in the United States, and globally in the United Kingdom, Sweden, Qatar, and the United Arab Emirates. According to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5), people with ASD often have difficulty communicating and interacting with others, restricted interests and repetitive behaviors, and a variety of symptoms that affect their ability to function socially and in other aspects of life.

[0006] People of all genders, races, ethnicities, and economic backgrounds can be diagnosed with ASD. Although ASD can be a lifelong disorder, treatments and services can improve a person's symptoms and daily functioning. However, there is currently no single standard treatment for ASD.

[0007] Due to the wide range of symptoms experienced by the ASD population, the most effective treatments and procedures often vary from person to person. However, many individuals with ASD respond most favorably to highly structured, specialized programs. Research has shown that early diagnosis and treatment, such as during or before school age, is most likely to have a significant positive effect on symptoms. Common treatments for aspects of ASD may include, but are not limited to, behavioral management therapy, cognitive behavioral therapy, early intervention, educational and school-based therapy, joint attention therapy, medication, nutritional therapy, occupational therapy, parent-mediated therapy, physical therapy, social skills training, and speech therapy.

[0008] In some cases, treatment can significantly reduce symptoms and help people with autism with their daily activities. The present application and its embodiments aim to alleviate the symptoms of ASD while minimizing treatment regimens and adverse side effects.

[0009] PTSD also significantly impacts populations in the United States and worldwide. Estimates of the number of individuals in the United States with some degree of PTSD at any given time include 10 million women and 5 million men. Approximately 6% of the general population will experience PTSD in their lifetime, and 11% of American women will experience PTSD at some point in their lives. 8% of adolescent females will develop some level of PTSD, and 75% of women who have been sexually assaulted will experience some level of PTSD. Additionally, 10–30% of veterans of the Gulf War and Iraq War experience some degree of PTSD. Tragically, 15% of veterans who experience PTSD attempt suicide.

[0010] The annual economic burden of ASD and PTSD is estimated to be approximately $450 billion and $300 billion per year in the United States, meaning that these two dopamine-related disorders have a combined economic impact of three-quarters of a trillion dollars per year. Taking into account the global population, the economic impact is substantial.

[0011] Review of related technologies: U.S. Pat. No. 9,962,336 relates to a method for preparing a stable extended-release suspension composition comprising a multiply coated active ingredient core by using a suspension base that ensures a substantially similar in vitro dissolution release profile of the active ingredient when the suspension composition is stored for at least 7 days.

[0012] U.S. Pat. No. 8,841,486 relates to compositions comprising diastereomers in substantially diastereomerically pure form and enantiomers in substantially enantiomerically pure form, as well as processes for preparing them and converting them to metyrosine.

[0013] US Patent Application Publication No. 2021 / 0283083 relates to the use of compounds capable of inhibiting tyrosine hydroxylase, such as alpha-methyl-p-tyrosine (AMPT), for the prevention or treatment of aortic aneurysms, preferably abdominal aortic aneurysms.

[0014] Therefore, various treatments for ASD are generally known in the art.However, these formulations and treatment methods are significantly different from the present application.Known formulations and methods cannot address the problems taught herein by the present disclosure.At least one embodiment of the present invention will be described in more detail herein. Summary of the Invention

[0015] In general, the present application and its embodiments provide formulations for low-dose sustained-release compositions effective in alleviating symptoms associated with, but not limited to, anxiety, post-traumatic stress disorder (PTSD), hypertension, cytokine storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging through inhibition of dopamine and / or norepinephrine in patients in need thereof.

[0016] One aspect of the present invention is a composition for alleviating symptoms of autism spectrum disorder (ASD), comprising a therapeutically effective amount of a tyrosine hydroxylase inhibitor, wherein the therapeutically effective amount is in the range of 0.1 mg to 300 mg. Alternatively, the therapeutically effective amount may depend on the patient's weight, such that heavier patients receive higher doses. For example, a patient may receive a therapeutically effective amount of the composition in the range of 0.1 to 5.0 mg of compound / kg of patient mass. In one embodiment of the present application, the tyrosine hydroxylase inhibitor is metyrosine.

[0017] In one embodiment of the present application, the therapeutically effective amount is in the range of 50 mg to 100 mg.

[0018] In one embodiment of the present application, the therapeutically effective amount is 100 mg.

[0019] In one embodiment of the present application, the metyrosine is α-methyl-L-tyrosine.

[0020] In one embodiment of the present application, the composition is an extended release composition.

[0021] In one embodiment of the present application, the composition is a tablet or a transdermal patch.

[0022] In another aspect of the application, there is a composition for inhibiting dopamine and / or norepinephrine, the composition comprising a therapeutically effective amount of a tyrosine hydroxylase inhibitor.

[0023] In one embodiment of the present application, the composition is effective in alleviating symptoms associated with anxiety, post-traumatic stress disorder (PTSD), hypertension, cytochrome storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging.

[0024] In yet another aspect of the present application, there is provided a method for alleviating symptoms of autism spectrum disorder (ASD), comprising administering a therapeutically effective amount of a tyrosine hydroxylase inhibitor to a patient in need thereof, wherein the therapeutically effective amount is in the range of 0.1 mg to 300 mg.

[0025] In one embodiment of the present application, the therapeutically effective amount is administered four times every 24 hours.

[0026] In one embodiment of the present application, the tyrosine hydroxylase inhibitor is metyrosine.

[0027] In one embodiment of the present application, the therapeutically effective amount is in the range of 50 mg to 100 mg.

[0028] In one embodiment of the present application, the therapeutically effective amount is 100 mg.

[0029] In one embodiment of the present application, the metyrosine is α-methyl-L-tyrosine.

[0030] In one embodiment of the present application, the composition is administered orally.

[0031] In one embodiment of the present application, the composition is administered transdermally. DETAILED DESCRIPTION OF THE INVENTION

[0032] Reference will now be made in detail to various embodiments of the present invention. Such embodiments are provided by way of illustration of the present invention and are not intended to be limiting. Indeed, those skilled in the art will recognize that various modifications and variations can be made upon reading this specification.

[0033] While the invention and embodiments thereof have been described with a certain degree of particularity, it is to be understood that the disclosure has been made by way of example only, and that many changes may be made in the details of construction and arrangement of parts without departing from the spirit and scope of the invention.

[0034] As referred to herein, unless otherwise stated, all compositional amounts or percentages are by weight of the total composition unless otherwise specified.

[0035] It will be further understood that the terms "comprise," "comprising," "include," and / or "including," as used herein, specify the presence of stated features, integers, steps, operations, elements, and / or components, but do not exclude the presence or addition of one or more other features, integers, steps, operations, elements, components, and / or groups thereof.

[0036] In certain embodiments, when the terms "about" or "approximately" are used in conjunction with a numerical range, they modify that range by extending the boundaries above and below those numerical values. Generally, the term "about" is used herein to modify a numerical value above and below a stated value by a variance of 20%, 10%, 5%, or 1%. In certain embodiments, the term "about" is used to modify a numerical value above and below a stated value by a variance of 10%. In certain embodiments, the term "about" is used to modify a numerical value above and below a stated value by a variance of 5%. In certain embodiments, the term "about" is used to modify a numerical value above and below a stated value by a variance of 1%. In certain embodiments, the term "about" is used to modify a numerical value above and below a stated value by a variance of 0.1%.

[0037] As used herein, the word "include" and variations thereof are intended to be non-limiting, such that the recitation of items in a list does not exclude other similar items that may also be useful in the compositions and methods of the present technology.

[0038] The phrase "and / or," as used in the specification and claims, should be understood to mean "either or both" of the elements so conjoined, i.e., elements that are present conjunctively in some cases and disjunctively in other cases. Thus, as a non-limiting example, a reference to "A and / or B," when used in conjunction with open-ended language such as "comprising," can refer, in one embodiment, to A only (optionally including elements other than B); in another embodiment, to B only (optionally including elements other than A); in yet another embodiment, to both A and B (optionally including other elements); and so forth.

[0039] Similarly, the terms "can" and "may" and variations thereof are intended to be non-limiting, so a statement that an embodiment can or may include certain elements or features does not exclude other embodiments of the technology that do not contain those elements or features.

[0040] As used herein, unless otherwise specified, the term patient refers to a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate such as a monkey, chimpanzee, or baboon. The terms "subject" and "patient" are used interchangeably. In certain embodiments, the patient is a human. In certain embodiments, the human is a pediatric human. In certain embodiments, the subject is an adult human.

[0041] The terms "effective amount" or "therapeutically effective amount," as used herein, unless otherwise specified, refer to a sufficient amount of at least one administered agent to achieve a desired result, e.g., alleviating to some extent one or more symptoms of the disease or condition being treated. In certain instances, the result is reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. In some embodiments, an effective amount is a dose generally effective in alleviating, reducing, significantly reducing, or eliminating symptoms associated with ASD. In certain instances, an "effective amount" for therapeutic use is the amount of a composition comprising an agent described herein required to produce a clinically significant reduction in the disease. An appropriate "effective" amount in any individual case will be determined using any suitable technique, such as a dose escalation study.

[0042] Metyrosine is commonly used to treat high blood pressure in people with certain adrenal tumors (e.g., pheochromocytoma). It is useful for preventing high blood pressure before and immediately after surgery to remove the tumor. It is also used long-term in people who cannot undergo surgery. However, metyrosine is not used for other types of high blood pressure.

[0043] Metyrosine belongs to a class of compounds known as tyrosine hydroxylase inhibitors, or THIs. THIs are a class of drugs that inhibit the production of catecholamines, such as adrenaline, noradrenaline, and dopamine, which help the body respond to stress or fear and act primarily by inhibiting an enzyme known as tyrosine hydroxylase.

[0044] By inhibiting tyrosine hydroxylase, THI prevents the production of the aforementioned neurotransmitters.Thus, THI is recognized to be beneficial in conditions involving excessive release of adrenaline and noradrenaline.However, the present application and its embodiments identify that THI, particularly metyrosine, is useful for alleviating symptoms related to anxiety, post-traumatic stress disorder (PTSD), hypertension, cytochrome storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging.Each of the aforementioned indications is related to an increase in dopamine and / or norepinephrine.

[0045] Accordingly, embodiments of the present application are directed to compositions and methods for inhibiting dopamine and / or norepinephrine production. Inhibition of such neurotransmitters is useful for alleviating symptoms of the above-mentioned indications, particularly symptoms of autism spectrum disorder (ASD), as described herein. For any composition within the scope of the present application, the active pharmaceutical ingredient (API) is metyrosine, particularly α-methyl-L-tyrosine. The amount of metyrosine present in the composition may vary depending on various factors, including, but not limited to, the patient's gender and age, the indication being treated, whether the formulation is extended-release or immediate-release, and the frequency of administration of the composition.

[0046] Preferably, the therapeutically effective amount is in the range of 0.1 mg to 300 mg per administration of the composition. However, any amount between 0.1 mg and 300 mg (inclusive) is acceptable. For example, 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 2 mg, 3 mg, 4 mg, ..., 300 mg. The amount of API may be a whole number (e.g., 10 mg) or a fraction (e.g., 10.5 mg), depending on the patient's needs and other factors discussed herein. In at least one embodiment, the composition more preferably contains a therapeutically effective amount of metyrosine in the range of 50 mg to 100 mg, and more specifically, 100 mg.

[0047] The administration of the composition can be achieved by traditional means, including but not limited to oral, subcutaneous, intradermal, intramuscular, including but not limited to intramuscular depot, intraperitoneal, intravenous, intranasal, epidural, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectal, by inhalation, or topically, particularly to the ear, nose, eye, or skin.The mode of administration can be left to the discretion of the practitioner.In most cases, administration releases the compound described herein or its pharmaceutically acceptable salt into the bloodstream.Preferred administration mechanisms are either oral or by transdermal patch.When administered orally, such compositions are preferably administered via tablets or capsules containing additional ingredients, based in part on the desired release profile. However, additional delivery mechanisms within the scope of this application may include a wide variety of dosage forms, which may include tablets, lozenges, aqueous or oily suspensions, solutions, granules, capsules, powders, pills, pellets, capsules containing liquids, emulsions, syrups or elixirs, suppositories, sustained release formulations, or any other form suitable for use.

[0048] A preferred method for alleviating symptoms of autism spectrum disorder (ASD) comprises administering to a patient in need thereof a therapeutically effective amount of a tyrosine hydroxylase inhibitor, wherein the therapeutically effective amount is in the range of 0.1 mg to 300 mg, and the therapeutically effective amount is administered at least four times per 24-hour period, the number of 24-hour periods comprising the treatment protocol varying as needed.

[0049] In addition to the API described herein, the composition embodiments can optionally contain a suitable amount of pharmaceutically acceptable excipients to provide a form for proper administration to a patient. Such pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil, etc. Pharmaceutical excipients can be saline, acacia gum, gelatin, starch paste, talc, keratin, colloidal silica, urea, etc. Additionally, auxiliary agents, stabilizers, thickeners, lubricants, and coloring agents can be used. In one embodiment, the pharmaceutically acceptable excipients are sterile at the time of administration to a subject. Water is a useful excipient when the compound of the present invention or a pharmaceutically acceptable salt thereof is administered intravenously. Saline and aqueous dextrose and glycerol solutions can also be used as liquid excipients, particularly for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol, etc. The composition can also contain a small amount of wetting or emulsifying agent, or pH buffering agent, if necessary. Other examples of suitable pharmaceutical excipients are listed in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro, ed., 19th ed., 1995), the entire contents of which are incorporated herein by reference.

[0050] In embodiments, the compositions of the invention may be administered as prodrugs to overcome barriers in patients such as lack of solubility, permeability, stability, metabolism prior to systemic circulation, or limited targeting in the systemic circulation.

[0051] In embodiments, the compositions of the present invention may be administered in combination with risperidone and / or aripiprazole.

[0052] In one embodiment, the compositions and therapeutically effective agents of the present invention may be administered in polymorphic and / or crystalline forms. Alternatively, the therapeutically effective agents may be administered as solvates. Alternatively, the therapeutically effective agents may be administered in enantiomerically pure or partially pure forms. Alternatively, the therapeutically effective agents may be administered as racemic mixtures.

[0053] Orally administered compositions can contain one or more agents, such as sweeteners such as fructose, aspartame, or saccharin; flavoring agents such as peppermint, wintergreen oil, or cherry; coloring agents; and preservatives, to provide a pharmaceutically palatable preparation. Furthermore, in tablet or pill form, the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract, thereby providing a sustained action over an extended period of time. Selectively permeable membranes surrounding the osmotically active compounds of the present invention are also suitable for oral administration. In these latter platforms, the driving compound absorbs fluid from the environment surrounding the capsule, swelling and displacing the drug or drug composition through an opening. These delivery platforms can provide an essentially zero-order delivery profile, as opposed to the spiked profiles of immediate-release formulations. Time-delay materials such as glycerol monostearate or glycerol stearate can also be useful. Oral compositions can contain standard excipients such as mannitol, lactose, starch, magnesium stearate, sodium saccharin, cellulose, and magnesium carbonate. In one embodiment, the excipients are of pharmaceutical grade.

[0054] The compound described herein or its pharmaceutically acceptable salt can be administered by controlled release or sustained release means or by delivery device known to those skilled in the art.This dosage form can be useful for providing controlled release or sustained release of one or more active ingredients, for example, by using hydropropylmethylcellulose, other polymer matrix, gel, permeable membrane, osmotic system, multi-layer coating, microparticle, liposome, microsphere or their combination, to provide desired release profile of various ratios.

[0055] Suitable controlled- or sustained-release formulations known to those skilled in the art, including those described herein, can be readily selected for use with metyrosine or a pharmaceutically acceptable salt thereof. Thus, in certain embodiments, embodiments provide single-unit dosage forms suitable for oral administration, such as, but not limited to, tablets, capsules, gelcaps, and caplets adapted for controlled or sustained release.

[0056] In certain embodiments, the ingredients of a single unit dose are supplied either separately or mixed together, for example, as a dry lyophilized powder or water-free concentrate in a hermetically sealed container, such as an ampoule or sachet indicating the quantity of active agent. When the compounds described herein or pharmaceutically acceptable salts thereof are to be administered by injection, they can be dispensed, for example, in an infusion bottle containing sterile pharmaceutical-grade water or saline. When the compounds described herein or pharmaceutically acceptable salts thereof are administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.

[0057] As used herein, "controlled release" is meant to encompass release of an API (e.g., metyrosine) at a selected or otherwise controllable rate, interval, and / or amount that is substantially unaffected by the environment of use. Thus, "controlled release" encompasses, but is not necessarily limited to, substantially continuous delivery and patterned delivery (e.g., intermittent delivery over a period of time interrupted by regular or irregular time intervals).

[0058] In certain embodiments, by way of example only, the composition optionally contains vitamin B2 (riboflavin), glucosamine HCl, chlorogenic acid, lipoic acid, catechin hydrate, creatine, acetyl-L-carnitine HCl, vitamin B6, pyridoxine, caffeic acid, naringenin, vitamin B1 (thiamine HCl), baicalein, luteolin, hesperidin, rosmarinic acid, epicatechin gallate, epigallocatechin, vitamin B9 (folic acid), genistein, methylvanillin, ethylvanillin, silibinin, daidzein, melatonin, rutin hydrate, vitamin A, retinol , vitamin D2 (ergocalciferol), vitamin E (tocopherol), diosmin, menadione (K3), vitamin D3 (cholecalciferol), phloretin, indole-3-carbinol, fisetin, glycitein, chrysin, gallocatechin, vitamin B4 (adenine), vitamin B5 (pantothenic acid), vitamin B7 (biotin), theobromine, resveratrol, epigallocatechin-3-gallate (EGCG), quercetin, ferulic acid, ellagic acid, hesperidin, and protocatechuic acid.

[0059] In embodiments, the present invention relates to treating patients with dopamine and / or norepinephrine-related disorders, such as ASD and PTSD.Treatment parameters are as described herein.During treatment, patients should be given a certain dose, and by monitoring patients and obtaining findings of the relevant changes that may occur in treated patients, the dose can be adjusted to an appropriate level. Among the changes to be monitored are any changes in the patient's appearance that may occur, evidence of any physical changes in the patient, evidence of pertinent chemical changes (such as dopamine and / or norepinephrine levels), evidence of changes in the patient's appearance, evidence of metabolic changes, evidence of the delivery mechanism and whether or not there are transport changes, identification of any changes in efficacy associated with the therapeutically active agent, evidence of any stability or permeability changes that may occur, evidence of any clearance changes to see how the body processes associated metabolites and removes them from the system, or possible compositional changes. In a variant, the present invention relates, to some extent, to methods of monitoring changes in individuals treated with the therapeutically active agents discussed herein, and monitoring patients for the changes listed above. Dosage should be adjusted to obtain a more optimal condition as indicated by these changing parameters.

[0060] In embodiments, the present invention provides a composition for alleviating symptoms of autism spectrum disorder (ASD), comprising: a therapeutically effective amount of a tyrosine hydroxylase inhibitor; The therapeutically effective amount is in the range of 0.1 mg to 300 mg.

[0061] In a variation, the tyrosine hydroxylase inhibitor is metyrosine. In a variation, the therapeutically effective amount is in the range of 50 mg to 100 mg. In a variation, the therapeutically effective amount is about 100 mg. In an embodiment, the metyrosine is α-methyl-L-tyrosine. In a variation, the composition is an extended-release composition. In a variation, the composition is a tablet or a transdermal patch.

[0062] Alternatively, the present invention relates to a method for alleviating symptoms of ASD by administering the compositions described above. The method further includes using α-methyl-L-typrosine and / or an extended-release composition. The method further includes having the composition as a tablet or transdermal patch.

[0063] In one embodiment, the present invention relates to a method for inhibiting dopamine or norepinephrine, comprising administering a therapeutically effective amount of a tyrosine hydroxylase inhibitor to an individual in need thereof. The tyrosine hydroxylase inhibitor includes α-methyl-L-tyrosine. In a variant, the method comprises administering the therapeutically effective amount as an extended-release composition. In a variant, the method allows for its use as a tablet or transdermal patch. The method comprises alleviating symptoms / conditions of diseases including anxiety, post-traumatic stress disorder (PTSD), hypertension, cytokine storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging.

[0064] In embodiments, the present invention relates to a composition for inhibiting dopamine and / or norepinephrine, comprising a therapeutically effective amount of a tyrosine hydroxylase inhibitor. In variants, the composition is effective in alleviating symptoms associated with anxiety, post-traumatic stress disorder (PTSD), hypertension, cytokine storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging.

[0065] In one embodiment, the compositions and methods include administering the compositions together with other pharmaceutical agents. In a variation, the compositions and methods include compositions further comprising risperidone and / or aripiprazole. In a variation, the compositions and methods of using the compositions include compositions further comprising one or more of an excipient, an adjuvant, and / or a surfactant.

[0066] In embodiments, the present invention provides a method for alleviating a symptom of autism spectrum disorder (ASD), comprising: administering a therapeutically effective amount of a tyrosine hydroxylase inhibitor to a patient in need thereof; The therapeutically effective amount is in the range of 0.1 mg to 300 mg.

[0067] In a variation, the therapeutically effective amount is administered four times every 24 hours. In a variation, the therapeutically effective amount is administered once daily, twice daily, or three times daily. In a variation, the tyrosine hydroxylase inhibitor is metyrosine.

[0068] In a variation, the therapeutically effective amount is in the range of 50 mg to 100 mg.

[0069] In a variation, the therapeutically effective amount is 100 mg. In a variation, the metyrosine is α-methyl-L-tyrosine. In a variation of this method, the composition is administered orally. In a variation, the composition is administered transdermally. In a variation, the metyrosine is administered in conjunction with an adjuvant, excipient, and / or surfactant.

[0070] Alternatively, the compositions and methods of the present invention allow for the administration of therapeutically effective amounts of compounds of the present invention as racemates or alternatively as pure isomers (or as mixtures in which one of the isomers is present in enantiomeric excess). It should be understood that lower dosages may be achieved when therapeutically effective amounts of compounds of the present invention are administered as pure isomers. Furthermore, any adverse conditions caused by inactive isomers may be reduced and / or eliminated. Alternatively, the biologically active isomer may be administered at half the dose of the racemic mixture, achieving the same or potentially better effects (as side effects may be reduced or eliminated). Alternatively, racemic mixtures or pure isomers of compounds of the present invention (e.g., metrilosin) may be administered as delayed-release and / or sustained-release compositions. Racemic mixtures or pure isomers may be used for any of ASD, PTSD, anxiety, cytokine storm, hypertension, insulin resistance, mania, and / or inflammation.

[0071] While the invention has been described with a certain degree of particularity, it is to be understood that the disclosure has been made by way of example only, and that many changes may be made in the details of construction and arrangement of parts without departing from the spirit and scope of the invention.

[0072] Any patents, patent applications, publications, or other disclosure materials identified herein are incorporated herein by reference in their entirety. Any material, or portion thereof, that is said to be incorporated herein by reference but that conflicts with existing definitions, descriptions, or other disclosure materials explicitly set forth herein is incorporated only to the extent that no conflict arises between the incorporated material and the present disclosure material. In the event of a conflict between this express disclosure and a document incorporated by reference, this express disclosure shall be the operative disclosure.

Claims

1. A composition for alleviating symptoms of autism spectrum disorder (ASD), comprising: a therapeutically effective amount of a tyrosine hydroxylase inhibitor; The composition, wherein the therapeutically effective amount is in the range of 0.1 mg to 300 mg.

2. 2. The composition of claim 1, wherein the tyrosine hydroxylase inhibitor is metyrosine.

3. 10. The composition of claim 1, wherein the therapeutically effective amount is in the range of 50 mg to 100 mg.

4. 4. The composition of claim 3, wherein the therapeutically effective amount is about 100 mg.

5. 3. The composition of claim 2, wherein the metyrosine is α-methyl-L-tyrosine.

6. The composition of claim 1, which is an extended release composition.

7. 10. The composition of claim 1, which is a tablet or a transdermal patch.

8. 1. A method of inhibiting dopamine and / or norepinephrine in an individual in need thereof, comprising administering to said individual a therapeutically effective amount of a tyrosine hydroxylase inhibitor.

9. 10. The method of claim 8, wherein the therapeutically effective amount of a tyrosine hydroxylase inhibitor is administered as a composition, and the composition is effective in alleviating symptoms associated with anxiety, post-traumatic stress disorder (PTSD), hypertension, cytokine storm, insulin resistance, inflammation, mania, autism spectrum disorder (ASD), and aging.

10. 6. The composition of claim 5, further comprising risperidone and / or aripiprazole.

11. The composition of claim 10, further comprising one or more of an excipient, an adjuvant, and / or a surfactant.

12. 1. A method for alleviating symptoms of autism spectrum disorder (ASD), comprising: administering a therapeutically effective amount of a tyrosine hydroxylase inhibitor to a patient in need thereof; wherein said therapeutically effective amount is in the range of 0.1 mg to 300 mg.

13. 13. The method of claim 12, wherein the therapeutically effective amount is administered four times every 24 hours.

14. 13. The method of claim 12, wherein the tyrosine hydroxylase inhibitor is metyrosine.

15. 13. The method of claim 12, wherein the therapeutically effective amount is in the range of 50 mg to 100 mg.

16. 16. The method of claim 15, wherein the therapeutically effective amount is 100 mg.

17. 15. The method of claim 14, wherein the metyrosine is α-methyl-L-tyrosine.

18. 13. The method of claim 12, wherein the composition is administered orally.

19. The method of claim 12, wherein the composition is administered transdermally.

20. 15. The method of claim 14, wherein the metyrosine is administered in conjunction with an adjuvant, excipient, and / or surfactant.

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