Pharmaceutical compositions comprising viloxazine

Abstract

The present disclosure provides pharmaceutical compositions and dosage forms including viloxazine, or a pharmaceutically acceptable salt thereof, processes for the preparation thereof, and their use in the treatment of central nervous system disorders, including Attention-Deficit Hyperactivity Disorder (ADHD).

Description

PHARMACEUTICAL COMPOSITIONS COMPRISING VILOXAZINETECHNICAL FIELD

[0001] The present disclosure is directed to pharmaceutical compositions and dosage forms comprising viloxazine and pharmaceutically acceptable salts thereof, processes for the preparation thereof, and their use in the treatment of a central nervous system (CNS) disorder.BACKGROUND

[0002] Viloxazine (1 ), or (±)-2-[(2-ethoxyphenoxy)methyl]morpholine is the active pharmaceutical ingredient (API) provided in the form of its hydrochloride salt (1 :1 ) in branded pharmaceutical QELBREE®, a drug indicated for the treatment of attentiondeficit hyperactivity disorder (ADHD) in adults and pediatric patients 6 years and older. QELBREE® is provided as extended-release capsules for oral administration, containing 115 mg, 173 mg, and 231 mg viloxazine HCI, equivalent to 100 mg, 150 mg, and 200 mg of viloxazine free base, respectively. According to the product label for QELBREE®, “the inactive ingredients are: Ammonium hydroxide, black iron oxide, butyl alcohol, com starch, ethylcellulose, FD&C Blue #1 , FD&C Red #28, FD&C Yellow #5, FD&C Yellow #6, FD&C Yellow #10, gelatin, hypromellose, isopropyl alcohol, lactose monohydrate, medium chain triglycerides, oleic acid, polyethylene glycol, potassium hydroxide, propylene glycol, shellac, strong ammonia solution, sucrose, talc, triacetin, titanium dioxide.”

[0003] Pharmaceutical compositions of viloxazine and / or salts thereof, including capsule and / or tablet dosage forms, are reported in, for example, WO 2013 / 119794 A1 , US 2024 / 0041893 A1 , and IN 20241031199.

[0004] The purity of active pharmaceutical ingredients (APIs) and associated drug products is of great importance, the subject being central to all major drug regulatory guidances. In recent years, several marketed drug products were found to contain unacceptable levels of / V-nitrosamine impurities. / V-nitrosamines are a class of compounds featuring a nitroso group attached to a nitrogen atom as shown below in Figure 1 . / V-nitrosamines can form as a result of an N-N bond-forming reaction between a compound bearing an -NH group, particularly a secondary amine such as viloxazine, and a nitrosating agent.Figure 1. / V-nitrosamine structure.

[0005] There exists a need to provide pharmaceutical compositions and dosage forms comprising viloxazine, and pharmaceutically acceptable salts thereof, that are compliant with regulatory guidances such as the control of / V-nitrosamine impurities in drugs, whilst maintaining the efficacy of the drug, and to feasible processes for their manufacture.SUMMARY

[0006] The present disclosure provides pharmaceutical compositions and dosage forms of viloxazine, or a pharmaceutically acceptable salt thereof, which possess a balance of desirable properties, and processes for the preparation thereof.

[0007] In one non-limiting aspect, the present disclosure provides pharmaceutical compositions of viloxazine, or a pharmaceutically acceptable salt thereof, comprising an immediate-release portion and an extended-release portion wherein the viloxazine, or salt thereof, is segregated from contact with reactive excipients such as a sugar-based core and a release rate controlling substance.

[0008] Further provided by the present disclosure are pharmaceutical compositions of viloxazine, or a pharmaceutically acceptable salt thereof, comprising the antioxidant cysteine, or an equivalent thereof.

[0009] Additionally provided are dosage forms comprising the viloxazine pharmaceutical compositions, processes for their preparation and methods of use thereof.

[0010] Accordingly, in a first non-limiting aspect of the present disclosure, there is provided a pharmaceutical composition comprising an immediate-release portion comprising viloxazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable core; and an extended-release portion comprising viloxazine, or a pharmaceutically acceptable salt thereof, and a release rate controlling substance, wherein the viloxazine, or salt thereof, is segregated from contact with the pharmaceutically acceptable core and the release rate controlling substance. In some embodiments of the first non-limiting aspect, the viloxazine or a salt thereof is segregated from contact with the pharmaceutically acceptable core and the release rate controlling substance by a seal coat layer. In some embodiments of the first non-limiting aspect, the immediate-release portion comprises a pellet comprising: the pharmaceutically acceptable core; a first seal coat layer surrounding the core; a drug coat layer comprising the viloxazine, or a salt thereof, surrounding the first seal coat layer; and a second seal coat layer surrounding the drug coat layer. In some embodiments of the first non-limiting aspect, the extended-release portion comprises the immediate-release pellet, further surrounded by an extended-release layer comprising the release rate controlling substance. In some embodiments of the first non-limiting aspect, at least one of the drug coat layer, the first seal coat layer, the second seal coat layer and the extended-release layer comprises an antioxidant. In some embodiments of the first non-limiting aspect, the antioxidant is cysteine and / or a cysteine equivalent. In some embodiments of the first non-limiting aspect, the composition comprises hydroxypropyl methylcellulose. In some embodiments of the first non-limiting aspect, the release rate controlling substance is a cellulose derivative. In some embodiments of the first non-limiting aspect, the cellulose derivative is ethylcellulose. In some embodiments of the first non-limiting aspect, thecellulose derivative is used in combination with a suitable pore forming agent. In some embodiments of the first non-limiting aspect, the pore forming agent is a polyvinyl alcohol. In some embodiments of the first non-limiting aspect, the pharmaceutically acceptable core is a sugar-based core. In some embodiments of the first non-limiting aspect, the viloxazine is in the form of viloxazine hydrochloride. In some embodiments of the first nonlimiting aspect, the composition comprises from about 10 wt% to about 40 wt% of the immediate-release portion and from about 60 wt% to about 90 wt% of the extended- release portion.

[0011] In a second non-limiting aspect of the present disclosure, there is provided a pharmaceutical composition comprising from about 20 wt% to about 40 wt% of a pharmaceutically acceptable core; a first seal coat layer surrounding the core comprising from about 2 wt% to about 15 wt% of a first sealant; a drug coat layer surrounding the first seal coat layer comprising from about 30 wt% to about 60 wt% viloxazine, or a pharmaceutically acceptable salt thereof and from about 2 wt% to about 10 wt% of a binder; a second seal coat layer surrounding the drug coat layer comprising from about 2 wt% to about 15 wt% of a second sealant. In some embodiments of the second nonlimiting aspect, the pharmaceutical composition comprises from about 0.5 wt% to about 5 wt% of an antioxidant. In some embodiments of the second non-limiting aspect, the antioxidant is present in a seal coat layer and the drug coat layer. In some embodiments of the second non-limiting aspect, the antioxidant is present in the drug coat layer and the second seal coat layer. In some embodiments of the second non-limiting aspect, the antioxidant is cysteine and / or a cysteine equivalent. In some embodiments of the second non-limiting aspect, the pharmaceutical composition is in the form of an immediate- release pellet. In some embodiments of the second non-limiting aspect, the composition comprises an extended-release layer surrounding the second seal coat layer comprising from about 2 wt% to about 10 wt% of a release rate controlling substance, from about 2 wt% to about 10 wt% of a pore forming agent and from about 0.2 wt% to about 2 wt% of a lubricant. In some embodiments of the second non-limiting aspect, the first and second sealant are hypromellose. In some embodiments of the second non-limiting aspect, the release rate controlling substance is ethylcellulose. In some embodiments of the second non-limiting aspect, the pore forming agent is polyvinyl alcohol. In some embodiments ofthe second non-limiting aspect, the lubricant is talc. In some embodiments of the second non-limiting aspect, the pharmaceutical composition is in the form of an extended-release pellet.

[0012] In a third non-limiting aspect of the present disclosure, there is provided a pharmaceutical composition comprising viloxazine, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient(s), and cysteine, and / or a cysteine equivalent. In some embodiments of the third non-limiting aspect, the composition comprises from about 0.5 wt% to about 5 wt% cysteine and / or a cysteine equivalent. In some embodiments of the third non-limiting aspect, the cysteine is in the form of L- cysteine hydrochloride. In some embodiments of the third non-limiting aspect, the weight ratio of cysteine and / or cysteine equivalent: viloxazine, or a pharmaceutically acceptable salt thereof, is from about 1 :40 to about 1 :10.

[0013] In a fourth non-limiting aspect of the present disclosure, there is provided a pharmaceutical composition of the first, second or third non-limiting aspects, wherein the composition comprises no more than about 1 ppm of N-nitrosoviloxazine with respect to viloxazine free base after storage for 1 month at 40 °C, 75% relative humidity. In some embodiments of the fourth non-limiting aspect, the composition comprises no more than about 0.25 ppm of / V-nitrosoviloxazine with respect to viloxazine free base after storage for 1 month at 40 °C, 75% relative humidity.

[0014] In a fifth non-limiting aspect of the present disclosure, there is provided a capsule comprising the pharmaceutical composition of the first, second, third or fourth non-limiting aspects. In some embodiments of the fifth non-limiting aspect, the capsule comprises an amount of viloxazine, or a pharmaceutically acceptable salt thereof, of from about 100 mg to about 200 mg viloxazine, or an equivalent amount of salt thereof.

[0015] In a sixth non-limiting aspect of the present disclosure, there is provided a method for the treatment of a central nervous system (CNS) disorder comprising the administration of the pharmaceutical composition of the first, second, third or fourth nonlimiting aspects, or the capsule of the fifth non-limiting aspect, to a human subject in a therapeutically effective amount for the treatment a central nervous system (CNS)disorder. In some embodiments of the sixth non-limiting aspect, the CNS disorder is Attention-Deficit Hyperactivity Disorder (ADHD).

[0016] In a seventh non-limiting aspect of the present disclosure, there is provided a solid pharmaceutical composition comprising viloxazine, or a pharmaceutically acceptable salt thereof, / V-nitrosoviloxazine, and a pharmaceutically acceptable excipient, wherein the composition comprises no more than about 1 ppm of / V-nitrosoviloxazine with respect to viloxazine free base. In some embodiments of the seventh non-limiting aspect, the / V-nitrosoviloxazine is present in a concentration that is no more than about 0.5 ppm with respect to viloxazine free base. In some embodiments of the seventh non-limiting aspect, the / V-nitrosoviloxazine is present in a concentration that is no more than about 0.17 ppm with respect to viloxazine free base. In some embodiments of the seventh nonlimiting aspect, the viloxazine is in the form of the hydrochloride salt.

[0017] Other non-limiting aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments of the disclosure in conjunction with the accompanying figures.DETAILED DESCRIPTION

[0018] As a secondary amine, viloxazine has the potential to undergo / V-nitrosation to generate (‘ / V-nitrosoviloxazine’) of formula VIO-NO:

[0019] It has been discovered by the present inventors that / V-nitrosation of viloxazine can be limited in the presence of an antioxidant. In some non-limiting embodiments, pharmaceutical compositions of viloxazine, or a pharmaceutically acceptable salt thereof, comprising the antioxidant cysteine, or its equivalent, exhibit lower levels of VIO-NO compared to the same compositions without an antioxidant.

[0020] In some embodiments are pharmaceutical compositions of viloxazine, or a pharmaceutically acceptable salt thereof, which are formed in a manner to reduce contact between viloxazine, or a salt thereof, and reactive exipicients, particularly in relation to the formation of the / V-nitrosamine impurity VIO-NO.

[0021] Additionally, dosage forms, including capsules comprising the pharmaceutical composition are provided.

[0022] As used herein, “immediate-release” (IR) refers to a composition or portion which, when taken orally, substantially provides the API in a more immediate time period, such as within about one hour. The term also refers to a composition or portion in which no deliberate effort has been made to modify the API release rate (wherein a disintegrant is not considered a modification in the context of capsules and tablets). For example, the pharmaceutical compositions of the present disclosure preferably comprise a portion intended for immediate-release. In some embodiments, “immediate-release” refers to release of greater than or equal to 80% by weight, or greater than or equal to 85% by weight, or greater than or equal to 90% by weight, or greater than or equal to 95% by weight, of the API from the immediate-release portion of less than or equal to one hour.

[0023] As used herein, “extended-release” (ER) refers to a composition or portion which, when taken orally, substantially provides the API over a longer time period, such as within about two hours or more. For example, the pharmaceutical compositions of the present disclosure preferably comprise a portion intended for extended-release. In some embodiments, “extended-release” refers to release of greater than or equal to 80% by weight, or greater than or equal to 85% by weight, or greater than or equal to 90% by weight, or greater than or equal to 95% by weight, of the API from the extended-release portion over a time period of at least two hours.

[0024] As used herein, the term “wt%” (weight %) refers to the ratio of the weight of a subject component to the weight of the subject mixture, using the same weight unit, expressed as a percentage. For example, with respect to a composition comprising a mixture of components, wt% refers to the ratio of the weight of a component (in mg) to the weight of the composition (in mg), expressed as a percentage.

[0025] As used herein, the term “ppm” (parts per million) refers to the ratio of the weight of a subject component to the weight of another component, using the same weight unit, multiplied by one million. For example, with respect to the amount of / V- nitrosoviloxazine (VIO-NO) in the pharmaceutical compositions of the present disclosure, ppm refers to: (weight VIO-NO in mg / weight viloxazine free base in mg) x 1 ,000,000. When the viloxazine is present as the hydrochloride salt, the weight of viloxazine free base equivalent to the amount of hydrochloride salt is used unless otherwise noted.

[0026] As used herein, the singular form "a", "an", and "the" include plural references. For example, "an" excipient includes one or more excipients. As used herein, the term “about” means “close to” and that variation from the exact value that follows the term is within amounts that a person of skill in the art would understand to be reasonable. For example, when the term “about” is used with respect to a numerical value, the value may vary within a reasonable range, such as within + / -10%, + / -5%, or + / -1 % of the stated value. Any numerical range recited herein is intended to include all sub-ranges subsumed therein. For example, a range of “90 to 95” is intended to include any and all sub-ranges between and including the recited minimum value of 90 and the recited maximum value of 95, that is, all subranges beginning with a minimum value equal to or greater than 90 and ending with a maximum value equal to or less than 95, and all subranges in between, e.g., 90 to 94.3, or 92.5 to 95, or 91 to 94.

[0027] As used herein, “cysteine”, refers to the compound 2-amino-3- sulfhydrylpropanoic acid, which may be in the form of a pharmaceutically acceptable salt thereof, an R (i.e. L) or S (i.e. D) isomer, or a mixture thereof. The natural L-cysteine isomer is preferred.

[0028] A pharmaceutical composition, as used herein, refers to a mixture of viloxazine or a pharmaceutically acceptable salt thereof, optionally a second active ingredient, and pharmaceutically acceptable excipient(s). The pharmaceutical composition facilitates administration of an active ingredient to a human subject. The pharmaceutical composition is preferably administered orally, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. For example,the pharmaceutical composition is preferably administered orally in a solid dosage form for oral administration, such as a tablet or a capsule. Solid dosage forms include, but are not limited to, tablets, capsules, beads, granules, powders, caplets, troches, sachets, cachets, pouches, gums, sprinkles, etc. Preferably, the solid dosage forms of the present disclosure are in the form of a capsule.

[0029] As used herein, the phrase “therapeutically effective amount” means that amount of viloxazine, or a pharmaceutically acceptable salt thereof, that will elicit a biological or medical response of a tissue, system, or patient that is being sought by the administrator (such as a researcher, doctor, or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing, or halting of progression of the condition or disease, including but not limited to attentiondeficit hyperactivity disorder (ADHD) .

[0030] Unless otherwise specified, when it is said that a composition has no more than X ppm / V-nitrosoviloxazine, the amount of / V-nitrosoviloxazine is determined by the Analytical Method described herein in Paragraph

[0062] ,

[0031] In some embodiments of the present disclosure, there is provided a pharmaceutical composition comprising an immediate-release portion comprising viloxazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable core; and an extended-release portion comprising viloxazine, or a pharmaceutically acceptable salt thereof, and a release rate controlling substance, wherein the viloxazine, or salt thereof, is segregated from contact with the pharmaceutically acceptable core and the release rate controlling substance. Preferably, the composition comprises from about 10 wt% to about 40 wt% of the immediate-release portion and from about 60 wt% to about 90 wt% of the extended-release portion. For example, the composition may comprise about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt% or about 40 wt% of the immediate-release portion together with the respective balance of about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt% or about 60 wt% of extended-releaseportion. Preferably, the composition comprises about 28 wt% of the immediate-release portion and about 72 wt% of the extended-release portion.

[0032] It has been discovered by the present inventors that / V-nitrosation of viloxazine can occur when viloxazine is in direct contact with a reactive excipient in a composition, for example excipients such as a sugar-based core and / or a release rate controlling substance, such as a cellulose-based release rate controlling substance. In some embodiments, the present inventors have developed compositions which segregate viloxazine from direct contact with a reactive expicient(s).

[0033] The immediate-release portion of the composition and the extended-release portion of the composition may comprise different units or pellets. For example, the immediate-release pellet may be a layered pellet wherein a drug coat layer comprising viloxazine, or a salt thereof, is layered between a first seal coat layer surrounding the core and a second seal coat layer surrounding the drug coat layer. In this example, the extended-release pellet comprises the immediate-release pellet further layered with an extended-release layer.

[0034] The pharmaceutically acceptable core is inactive (i.e., contains no active substance) and forms the internal foundation of a composition portion. Examples of pharmaceutically acceptable cores comprise excipients found in a pharmacopeia, such as sucrose, microcrystalline cellulose (MCC), isomalt, anhydrous dibasic calcium phosphate base, lactose, tartaric acid, and silica. Preferably, the pharmaceutically acceptable core is sugar-based and comprises sucrose (e.g., sugar spheres). Preferably, the pharmaceutical composition comprises from about 20 wt% to about 40 wt% of a sugar-based core. For example, the composition may comprise about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt% or about 40 wt% of the sugar-based core.

[0035] The seal coat layer provides a physical barrier between the active substance viloxazine, or a salt thereof, and a reactive excipient, such as an excipient having nitrosating potential. The seal coat layer comprises a suitable inert sealant, preferably a hydrophilic film forming polymer such as hydroxypropyl methylcellulose (hypromellose) or hydroxypropyl cellulose. Preferably, the sealant comprises hypromellose (e.g.,PHARMACOAT® hypromellose available from Shin-Etsu). Preferably, the pharmaceutical composition comprises from about 2 wt% to about 15 wt% of a sealant in each seal coat layer. For example, the composition may comprise about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt% of a sealant in each seal coat layer.

[0036] The drug coat layer comprises viloxazine, or a salt thereof, and a pharmaceutically acceptable excipient. Preferably, excipients are minimized in the drug coat layer. The drug coat layer may comprise a suitable inert binder, preferably a hydrophilic polymer such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose or polyvinylpyrrolidone (povidone). Preferably, viloxazine is in the form of viloxazine hydrochloride. Preferably, the pharmaceutical composition comprises from about 30 wt% to about 60 wt% viloxazine, or a pharmaceutically acceptable salt. For example, the composition may comprise about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt% or about 60 wt% of viloxazine, or a pharmaceutically acceptable salt thereof.

[0037] The extended-release layer comprises a suitable release rate controlling substance. The release rate controlling substance may be a hydrophilic compound such as, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene oxide, acacia, acrylic acid derivatives, alginic acid, its salts and derivatives thereof, hydroxyethyl cellulose, povidone, carrageenan, carboxymethylcellulose, tragacanth, polyvinyl alcohol, xanthan gum, and / or combinations thereof. Preferably, the release rate controlling substance is a hydrophobic compound such as, for example, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, waxes, hydrogenated vegetable oils, glyceryl behenate, glyceryl palmitostearate, PEG glyceryl esters, poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer, poly (ethyl acrylate-co-methyl methacrylate- cotrimethylammonioethyl methacrylate chloride), polyvinyl acetate, cellulose acetate propionate, and / or combinations thereof. Most preferably, the release rate controlling substance is ethyl cellulose. The release rate controlling substance is preferably used in combination witha pore forming agent which modifies the permeability of the rate controlling substance such as, for example, polyvinyl alcohol, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, organic acids and / or salts. Preferably, the pore forming substance is polyvinyl alcohol. Preferably, the pharmaceutical composition comprises from about 2 wt% to about 10 wt% of a release rate controlling substance. For example, the composition may comprise about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt% of a release rate controlling substance. Preferably, the pharmaceutical composition comprises from about 2 wt% to about 10 wt% of a pore forming agent. For example, the composition may comprise about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt% of a pore forming agent.

[0038] It has also been discovered by the present inventors that / V-nitrosation of viloxazine can be minimized in the presence of a suitable antioxidant.

[0039] In some embodiments, the pharmaceutical composition may further comprise an antioxidant. The term antioxidant refers to a substance suitable for use in a pharmaceutical which inhibits oxidation. Antioxidants suitable for pharmaceutical use include those that are listed in the U.S. Food & Drug Administration’s (FDA’s) Inactive Ingredient Database (HD), for example. The HD list provides information on inactive ingredients present in FDA-approved drug products. Once an inactive ingredient has appeared in an approved drug product for a particular route of administration, the inactive ingredient is not considered new, and may require a less extensive review the next time it is included in a new drug product. Examples of an antioxidant that may be used in compositions of the present disclosure include ferulic acid, ascorbic acid, potassium metabisulfite, sodium metabisulfite, propyl gallate, ascorbyl palmitate, vitamin E (tocopherols), dihydroxybenzoic acid, citric acid (including hydrates thereof), sodium thiosulfate, caffeic acid, butylated hydroxyanisole, butylated hydroxytoluene, cysteine and its equivalents such as A / -acetyl cysteine, isomers and mixtures thereof. For purposes of the present disclosure, in the case of antioxidants bearing acidic or basic moieties, it will be understood that salts thereof are included.

[0040] Preferably, in some embodiments, the antioxidant is cysteine and / or a cysteine equivalent, most preferably, the antioxidant is L-cysteine hydrochloride.

[0041] The antioxidant can be included in any part of the pharmaceutical composition that is in contact with the active ingredient viloxazine, or a salt thereof. Preferably, in a layered pellet, the antioxidant may be included in the drug coat layer and at least one seal coat layer, preferably the second seal coat layer.

[0042] The pharmaceutical composition may comprise any amount of antioxidant, preferably cysteine, and / or an equivalent thereof, for example from about 0.5 wt% to about 5 wt% of cysteine, and / or an equivalent thereof, for example L-cysteine hydrochloride. For example, the composition may comprise about 0.5 wt%, about 1 wt%, about 1 .5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt% or about 5 wt% of an antioxidant.

[0043] Other pharmaceutically acceptable excipients suitable for use in the pharmaceutical composition comprise, for example, a lubricant (antitacking agent) such as magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil, hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol, and / or talc, preferably talc. The composition may comprise from about 0.2 wt% to about 2 wt% of a lubricant(s). For example, the composition may comprise about 0.2 wt%, about 0.5 wt%, about 1 wt%, about 1 .5 wt%, about 2 wt% of a lubricant.

[0044] Other excipients suitable for use in oral solid dosage forms, including plasticizer(s), preservative(s), stabiliser(s), silica based flow enhancer anti-adherent(s), and / or glidant(s) as described generally, for example, in Remington The Science and Practice of Pharmacy 21 st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45) may be added as required.

[0045] In some embodiments of the present disclosure, there is provided a pharmaceutical composition comprising: i) from about 20 wt% to about 40 wt% of a pharmaceutically acceptable core;ii) a first seal coat layer surrounding the pharmaceutically acceptable core comprising from about 2 wt% to about 15 wt% of a first sealant; iii) a drug coat layer surrounding the first seal coat layer comprising from about 30 wt% to about 60 wt% viloxazine, or a pharmaceutically acceptable salt thereof and from about 2 wt% to about 10 wt% of a binder; and iv) a second seal coat layer surrounding the drug coat layer comprising from about 2 wt% to about 15 wt% of a second sealant.

[0046] The composition of this embodiment may be in the form of an immediate- release portion or pellet and / or an extended-release portion or pellet. For example, the immediate-release portion may be in the form of a layered pellet wherein a drug coat layer comprising viloxazine, or a salt thereof, is layered between a first seal coat layer surrounding the core and a second seal coat layer surrounding the drug coat layer. In this example, an extended-release pellet comprises the immediate-release pellet further layered with an extended-release layer. Preferably, the composition comprises a mixture of both an immediate-release portion and an extended-release portion to afford different release profiles. Preferably, the composition comprises from about 10 wt% to about 40 wt% of the immediate-release portion and from about 60 wt% to about 90 wt% of the extended-release portion. For example, the composition may comprise about 10 wt%, about 15 wt%, about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt% or about 40 wt% of the immediate-release portion together with the respective balance of about 90 wt%, about 85 wt%, about 80 wt%, about 75 wt%, about 70 wt%, about 65 wt% or about 60 wt% of extended-release portion. Preferably, the composition comprises about 28 wt% of the immediate-release portion and about 72 wt% of the extended-release portion.

[0047] The pharmaceutically acceptable core forms the internal foundation of a composition portion. Preferably, the core is sugar-based and comprises sucrose (e.g., sugar spheres) or isomalt. The composition may comprise about 20 wt%, about 25 wt%, about 30 wt%, about 35 wt% or about 40 wt% of the sugar-based core.

[0048] The seal coat layer provides a physical barrier between the active substance viloxazine, or a salt thereof, and a reactive excipient, such as an excipient having nitrosating potential. The seal coat layer comprises a suitable inert sealant, preferably a hydrophilic film forming polymer such as hydroxypropyl methylcellulose (Hypromellose or HPMC) or hydroxypropyl cellulose. Preferably, the sealant comprises hypromellose (e.g., PHARMACOAT®). The composition may comprise about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt%, about 10 wt%, about 11 wt%, about 12 wt%, about 13 wt%, about 14 wt%, or about 15 wt% of a sealant in each seal coat layer.

[0049] The drug coat layer comprises viloxazine, or a salt thereof, and a pharmaceutically acceptable excipient, preferably an inert binder such as hydroxypropyl methylcellulose (hypromellose). Preferably, excipients are minimized in the drug coat layer. The drug coat layer may comprise a suitable inert binder, preferably a hydrophilic polymer such as hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose or polyvinylpyrrolidone (povidone). Preferably, viloxazine is in the form of viloxazine hydrochloride. The composition may comprise about 30 wt%, about 35 wt%, about 40 wt%, about 45 wt%, about 50 wt%, about 55 wt% or about 60 wt% of viloxazine, or a pharmaceutically acceptable salt thereof.

[0050] An extended-release layer comprises a suitable release rate controlling substance. The release rate controlling substance may be a hydrophilic compound such as, for example, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, polyethylene oxide, acacia, acrylic acid derivatives, alginic acid, its salts and derivatives thereof, hydroxyethyl cellulose, povidone, carrageenan, carboxymethylcellulose, tragacanth, polyvinyl alcohol, xanthan gum, and / or combinations thereof. Preferably, the release rate controlling substance is a hydrophobic compound such as, for example, ethyl cellulose, cellulose acetate, cellulose acetate butyrate, waxes, hydrogenated vegetable oils, glyceryl behenate, glyceryl palmitostearate, PEG glyceryl esters, poly(ethyl acrylate-co-methyl methacrylate) ethyl acrylate methyl methacrylate copolymer, poly (ethyl acrylate-co-methyl methacrylate- cotrimethylammonioethyl methacrylate chloride), polyvinyl acetate, cellulose acetate propionate, and / orcombinations thereof. Most preferably, the release rate controlling substance is ethyl cellulose. The release rate controlling substance is preferably used in combination with a pore forming agent which modifies the permeability of the rate controlling substance such as, for example, polyvinyl alcohol, hypromellose, hydroxyethyl cellulose, hydroxypropyl cellulose, organic acids and / or salts. Preferably, the pore forming substance is polyvinyl alcohol. Preferably, the pharmaceutical composition comprises from about 2 wt% to about 10 wt% of a release rate controlling substance. For example, the composition may comprise about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt% of a release rate controlling substance. Preferably, the pharmaceutical composition comprises from about 2 wt% to about 10 wt% of a pore forming agent. For example, the composition may comprise about 2 wt%, about 3 wt%, about 4 wt%, about 5 wt%, about 6 wt%, about 7 wt%, about 8 wt%, about 9 wt% or about 10 wt% of a pore forming agent.

[0051] The pharmaceutical composition of this embodiment may further comprise an antioxidant. Preferably, the antioxidant is cysteine and / or a cysteine equivalent, most preferably, the antioxidant is L-cysteine hydrochloride.

[0052] The antioxidant can be included in any part of the pharmaceutical composition that is in contact with the active ingredient viloxazine, or a salt thereof. Preferably, in a layered pellet, the antioxidant may be included in the drug coat layer and at least one seal coat layer, preferably the second seal coat layer.

[0053] The pharmaceutical composition may comprise any amount of antioxidant, preferably cysteine, and / or an equivalent thereof, for example from about 0.5 wt% to about 5 wt% of L-cysteine hydrochloride. For example, the composition may comprise about 0.5 wt%, about 1 wt%, about 1.5 wt%, about 2 wt%, about 2.5 wt%, about 3 wt%, about 3.5 wt%, about 4 wt%, about 4.5 wt% or about 5 wt% of an antioxidant.

[0054] Other pharmaceutically acceptable excipients suitable for use in the pharmaceutical composition comprise, for example, a lubricant (antitacking agent) such as magnesium stearate, sodium stearyl fumarate, stearic acid, calcium stearate, zinc stearate, potassium benzoate, sodium benzoate, myristic acid, palmitic acid, mineral oil,hydrogenated castor oil, medium-chain triglycerides, poloxamer, polyethylene glycol, and / or talc, preferably talc. The composition may comprise from about 0.2 wt% to about 2 wt% of a lubricant(s) of a lubricant(s). For example, the composition may comprise about 0.2 wt%, about 0.5 wt%, about 1 wt%, about 1 .5 wt%, about 2 wt% of a lubricant.

[0055] Other excipients suitable for use in oral solid dosage forms, including plasticizer(s), preservative(s), stabiliser(s), silica based flow enhancer anti-adherent(s), and / or glidant(s) as described generally, for example, in Remington The Science and Practice of Pharmacy 21 st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 45) may be added as required.

[0056] In some embodiments of the present disclosure, the pharmaceutical composition is provided as a solid dosage form suitable for oral administration, such as a capsule or tablet. In such form, the composition is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose. For convenience, the total daily dosage may be divided and administered in portions during the day as required. In some examples, the dosage can range from about 0.01 mg / kg to about 10 mg / kg of body weight / day of viloxazine, or a pharmaceutically acceptable salt thereof.

[0057] Preferably, the solid dosage form is a hard-gelatin capsule, comprising a mixed composition of both immediate-release and extended-release portions comprising viloxazine hydrochloride and pharmaceutically acceptable excipients. Preferably, the amount of viloxazine, or salt thereof, present in the dosage form is equivalent to from about 10 mg to about 800 mg of viloxazine, or a pharmaceutically acceptable salt thereof. Preferably, the solid dosage form comprises 115 mg, 173 mg, or 231 mg of viloxazine hydrochloride, equivalent to 100 mg, 150 mg, or 200 mg of viloxazine free base respectively, and is considered bioequivalent to the respective branded 100 mg, 150 mg, or 200 mg QELBREE® drug products. Preferably, the 100 mg solid dosage form comprises an immediate-release portion or pellet providing from about 10 mg to about 40 mg viloxazine free base equivalent and an extended-release portion or pellet providing a respective amount of from about 90 mg to about 60 mg viloxazine free base equivalent.Preferably, the 150 mg dosage form comprises an immediate-release portion or pellet providing from about 15 mg to about 60 mg viloxazine free base equivalent and an extended-release portion or pellet providing a respective amount of from about 135 mg to about 90 mg viloxazine free base equivalent. Preferably, the 200 mg dosage form comprises an immediate-release portion or pellet providing from about 20 mg to about 80 mg viloxazine free base equivalent and an extended-release portion or pellet providing a respective amount of from about 180 mg to about 120 mg viloxazine free base equivalent. Preferably, the solid dosage form is characterized by a maximum plasma concentration (Cmax) of viloxazine in the range of 80% to 125% as compared to that produced by the comparable strength of a QELBREE® drug product. The pharmaceutical composition may be in the form of a powder / particle, pellet, minitablet, and / or granule. Preferably, the pharmaceutical composition provides a dose of viloxazine hydrochloride that is equivalent to the 115 mg, 173 mg, or 231 mg of viloxazine hydrochloride found in the respective dosages of the QELBREE® drug products.

[0058] Optionally, when the pharmaceutical composition is a solid dosage form, the solid dosage form may be prepared with coatings, such as enteric coatings and extended release coatings, using standard pharmaceutical coatings. Such coatings, and their application, are well known to persons skilled in the art, and are described, for example, in Remington The Science and Practice of Pharmacy 21 st Edition (Lippincott Williams & Wilkins: Philadelphia; 2006; Chapter 46).

[0059] In some embodiments of the present disclosure, there is provided a pharmaceutical composition comprising viloxazine, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient(s), and cysteine, and / or a cysteine equivalent. Preferably, the composition is a mixed composition of both immediate-release and extended-release portions comprising viloxazine hydrochloride and pharmaceutically acceptable excipients. Preferably, the composition comprises from about 0.5 wt% to about 5 wt% cysteine and / or a cysteine equivalent, preferably L-cysteine hydrochloride. Preferably, in the pharmaceutical composition, the weight ratio of cysteine and / or cysteine equivalent to viloxazine, or a pharmaceutically acceptable salt thereof, is from about 1 :40 to about 1 :10. For example, the weight ratio of cysteine and / or cysteine equivalent toviloxazine may be from about 1 :40, about 1 :35, about 1 :30, about 1 :25, about 1 :20, about 1 :15 or about 1 :10.

[0060] In some embodiments of the present disclosure, there is provided a pharmaceutical composition or dosage form comprising no more than about 1 ppm, no more than about 0.5 ppm, no more than about 0.25 ppm and preferably no more than about 0.17 ppm of / V-nitrosoviloxazine with respect to viloxazine free base at the time of preparation (t=0 or time zero), for example. In some embodiments of the present disclosure, there is provided a pharmaceutical composition or dosage form comprising no more than about 0.1 ppm and preferably no more than about 0.05 ppm of / V- nitrosoviloxazine with respect to viloxazine free base at the time of preparation (t=0 or time zero), for example. Based on the FDA guidance document Recommended Al Limits for Certain Hypothetical NDSRIs (3 / 5 / 2024), the recommended allowable intake (Al) limit for N-nitrosoviloxazine is 100 ng / day. Since the maximum recommended human dose of viloxazine is 600 mg / day, a limit of 0.167 ppm of / V-nitrosoviloxazine would limit exposure to within the allowable intake of this nitrosam ine as per the FDA guidance. Preferably, the levels of / V-nitrosoviloxazine are no more than about 1 ppm, no more than about 0.5 ppm, no more than about 0.25 ppm, no more than about 0.17 ppm, no more than about 0.1 ppm, or no more than about 0.05 ppm with respect to viloxazine free base after storage for 1 month at 40 °C, 75% relative humidity, for 2 months at 40 °C, 75% relative humidity, for 3 months at 40 °C, 75% relative humidity, for 4 months at 40 °C, 75% relative humidity, for 5 months at 40 °C, 75% relative humidity, and / or for 6 months at 40 °C, 75% relative humidity.EXAMPLES

[0061] The following non-limiting examples are illustrative of some of the non-limiting aspects and embodiments of the disclosure described herein. The viloxazine hydrochloride used in the following examples was crystalline and contained about 0.1 ppm VIO-NO impurity with respect to viloxazine free base, unless otherwise indicated.Analytical Method for Determining Impurity / V-Nitrosoviloxazine in Viloxazine Capsules

[0062] The analytical method (“Analytical Method”) shown in Table 1 was used to quantify the amount of impurity / V-nitrosoviloxazine (VIO-NO) in viloxazine drug substance.* These parameters can be adjusted to achieve the adequate sensitivity to meet the criteria of system suitability.Example 1 : Capsules (200 mg) Composition without First Seal Coat Layer

[0063] Extended-release capsules containing a mixture of immediate-release pellets and extended-release pellets comprising viloxazine hydrochloride without a seal coat layer on the core, with and without propyl gallate, were prepared having the components shown in Tables 2 and 3. The composition of the capsules is shown in Table 4.

[0064] The capsules were manufactured using the components shown in Tables 2 and3, according to the following steps:Immediate-Release PelletsDrug Coating1 . Sugar spheres were pass through # 24 / 40 mesh. Sugar spheres which passed through the #24 mesh and were retained on the #40 mesh were used for the drug coating.2. Hypromellose was mixed in purified water using an overhead stirrer. Viloxazine hydrochloride was added and the mixture stirred until a uniform dispersion formed. For composition B-IR, propyl gallate and talc were also added in the drug coating dispersion.3. After completing the drug coating, the pellets were passed through a # 20 / 35 mesh. The drug coated pellets which passed through the #20 mesh and were retained on the #35 mesh were used for further seal coating.Seal Coating1. Hypromellose, lactose monohydrate, polyethylene glycol, triacetin and titanium dioxide were mixed in purified water using an overhead stirrer to afford a dispersion.2. The drug coated pellets were loaded in a Wurster coater (GPCG) and coated using the dispersion in 1 ).3. After completing the seal coating, the pellets were passed through # 20 / 40 mesh. The resulting immediate-release pellets which passed through the #20 mesh and were retained on #40 mesh were used further.Extended-Release PelletsExtended-Release Coating1. HPMC and talc were mixed with purified water. For composition B-IR, polyvinyl alcohol was used instead of HPMC.2. Surelease® E-7-19040 was slowly added into the mixture of step 1 ) and stirred until a uniform extended-release dispersion formed.3. A portion (80%) of the above immediate-release pellets were loaded into a Wurster coater (GPCG) and coated with the extended-release dispersion.4. After completing the extended-release coating, the pellets were passed through a# 20 / 40 mesh. The resulting extended-release pellets which passed through the #20 mesh and were retained on the #40 mesh were used for encapsulation.Encapsulation:1. Capsules were filled with the distribution of immediate-release and extended- release pellets as shown in Table 4.Amg / cap weight is after Potency adjustment * Viloxazine Immediate-Release Pellets Contains 40 mg Of Viloxazine free base.$ Viloxazine Extended-Release Pellets Contains 160mg Of Viloxazine free base.Example 2: Levels of / V-Nitrosoviloxazine in Capsule Compositions A and B

[0065] The capsules prepared in Example 1 were packaged and analysed for the presence of VIO-NO (ppm) with respect to viloxazine free base initially and following storage under accelerated (40 °C / 75% RH) and ambient (25 °C Z60% RH) conditions for3 and 6 months. The results are reported in Table 5.Table 5: Levels of VIO-NO in Packaged Capsules of Viloxazine HCIExample 3: Capsules (200 mg) Composition with First Seal Coat Layer

[0066] Extended-release capsules containing a mixture of immediate-release pellets and extended-release pellets comprising viloxazine hydrochloride with a seal coat layer on the core, and with L-cysteine hydrochloride antioxidant, were prepared having the components shown in Tables 6 and 7. The composition of the capsules is shown in Table 8.★Evaporate during process$ Each 46. 15 mg of Viloxazine Hydrochloride is equivalent to 40 mg of Viloxazine free base.'Evaporate during process$Each 160 mg of Viloxazine free base is equivalent to 184.58 mg of Viloxazine Hydrochloride.

[0067] The capsules were manufactured using the components shown in Tables 6 and 7, according to the following steps: Immediate-Release PelletsFirst Seal Coating1 . Sugar spheres were passed through a # 24 / 35 mesh. Sugar spheres which passed through the #24 mesh and were retained on the #35 mesh were used for the drug coating.2. Hypromellose USP (PHARMACOAT® 603) was added in purified water and mixed to afford a uniform solution.3. The sugar spheres were loaded into a Wurster coater (CPCG) and coated with the hypromellose solution.4. After completing the seal coating, the pellets were passed through a # 24 / 35 mesh. The seal coated pellets which passed through the #24 mesh and were retained on the #35 mesh were used for further drug coating.Drug Coat Layering1. L-cysteine hydrochloride and hypromellose were mixed with purified water and viloxazine hydrochloride was added to afford a dispersion.2. The above seal coated pellets were loaded in a Wurster coater (GPCG) and coated using the dispersion in 1 ).3. After completing drug coating, the pellets were passed through a # 20 / 35 mesh. The drug coated pellets which passed through the #20 mesh and were retained on the #35 mesh were used for further seal coating.Second Seal Coating1. L-cysteine hydrochloride and hypromellose were dissolved in purified water to afford a solution.2. The drug coated pellets were loaded into a Wurster coater (GPCG) and coated using the solution in 1 ).3. The resulting seal coated pellets were passed through a # 18 / 35 mesh. The pellets which passed through the #18 mesh and were retained on #35 mesh were used further.Extended-Release PelletsExtended-Release Coating1. Dibutyl sebacate was mixed with ethanol and purified water (90:10) to afford a uniform solution. Polyvinyl alcohol was added with mixing.2. Ethyl cellulose and talc were mixed with the solution in 1 ) to afford a uniform dispersion.3. A portion (90%) of the immediate-release pellets were loaded into a Wurster coater (GPCG) and coated using the dispersion in 2).4. After completing extended-release coating, the pellets were passed through a # 16 mesh and a # 35 mesh. The resulting extended-release pellets which passed through the #16 mesh and were retained on the #35 mesh were used for encapsulation.Encapsulation:1 . Capsules were filled with the immediate-release and extended-release pellets as shown in Table 8.Example 4: Levels of / V-Nitrosoviloxazine in Capsule Composition C

[0068] The capsules prepared in Example 3 were packaged and analysed for the presence of VIO-NO (ppm) with respect to viloxazine free base initially and followingstorage under accelerated conditions (40 °C / 75% RH) for 1 and 3 months. The results are reported in Table 9.Example 5: Composition of Viloxazine ER Capsules 100 mg, 150 mg, 200 mg

[0069] An extended-release formulation consisting of a mixture of immediate-release pellets and extended-release pellets filled in hard gelatin capsules comprising viloxazine hydrochloride was prepared. The components and guantitative composition along with the function and grade of each excipient is listed in Table 10. The viloxazine hydrochloride active ingredient contained about 0.03 to 0.05 ppm VIO-NO impurity with respect to viloxazine free base.*115.365 mg Viloxazine Hydrochloride is equivalent to 100 mg Viloxazine**173.05 mg Viloxazine Hydrochloride is equivalent to 150 mg Viloxazine***230. 73 mg Viloxazine Hydrochloride is equivalent to 200 mg Viloxazine''Does not contribute to the weight of the product, evaporates during coating process$92.96% drug film coated pellets are divided into 68.7 mg for IR part and 160.3 mg for ER part$$343.5 mg of drug film coated pellets are divided into 103.3 mg for IR part and 240.4 mg for ER part$$$458 mg of drug film coated pellets are divided into 137.4 mg for IR part and 320.6 mg for ER part

[0070] The capsules were manufactured using the components shown in Table 10, according to the following steps: Immediate-Release PelletsFirst Seal Coating1 . Sugar spheres were sifted using a #30 mesh on top and a #35 mesh on bottom.2. Hypromellose USP (PHARMACOAT® 603) was added in purified water and mixed to afford a uniform solution.3. The sugar spheres were loaded into a Glatt® 32” fluid bed processor with Wurster coater (GPCG) and coated with the hypromellose solution.4. After completing the seal coating, the pellets were screened using a #24 mesh on top and a #35 mesh on bottom and were used for further drug coating.Drug Coat Layering and Second Seal Coating5. L-cysteine hydrochloride monohydrate and hypromellose were mixed with purified water and viloxazine hydrochloride was added to afford a dispersion.6. L-cysteine hydrochloride and hypromellose were dissolved in purified water to afford a solution.7. The above seal coated pellets were loaded into the Glatt® 32” processor with Wurster coater (GPCG) and coated using the dispersion from step 5) followed by the second seal coating using the solution from step 6).Blending of Pellets and Segregation8. Two batches of pellets from step 7) were blended for 3 minutes at 10 rpm.9. The blended pellets were separated into an IR portion (30%) for lubrication and an IR portion (70%) to form the ER portion.IR Pellets Lubrication10. The 30% IR portion from step 9) was blended with Talc (hand screened through a #40 mesh) in a blender for 3 minutes at 10 rpm.Extended-Release PelletsExtended-Release Coating and Lubrication11. Dibutyl sebacate was mixed with ethanol and purified water to afford a uniform solution. Polyvinyl alcohol was added with mixing.12. Ethyl cellulose and talc were mixed with the solution from step 11 ) to afford a uniform dispersion.13. The 70% IR portion from step 9) was loaded into the Glatt® 32” processor with Wurster coater (GPCG) and coated using the dispersion from 12).14. After completing extended-release coating, the pellets were passed through a #18 mesh on top and a #30 mesh on bottom.15. The ER coated pellets from step 14) were blended with Talc (sifted through a #40 mesh) in a blender for 3 minutes at 10 rpm.Encapsulation and Packaging16. The IR lubricated Pellets from step 10) and the ER lubricated Pellets from step 15) were encapsulated into different strengths as per weight and appropriate capsule sizes and packaged into bottles.

[0071] Thirty capsules of three batches of the highest and lowest strengths and one batch of the intermediate strength were packaged in HDPE bottles fitted with a screw cap with tri-seal liner, a lift and peel induction seal and 1 or 2 gram silica gel dessicant and placed on stability under the following conditions:• Accelerated (40°C + / - 2°C / 75% RH + / -5% RH) with testing at 0, 1 , 3 and 6 months• Intermediate (30°C + / - 2°C / 65% RH + / -5% RH) with testing at 0, 3 and 6 months• Long-term (25°C + / - 2°C / 60% RH + / -5% RH) with testing at 0, 3 and 6 months

[0072] Testing at the initial and subsequent stability time points was performed and the levels of VIO-NO (ppm) with respect to viloxazine free base ranged from Below Quantitation Limit (BQL - 0.03 ppm) to 0.06 ppm at accelerated and intermediate conditions and BQL to 0.05 ppm at long-term conditions. The results are reported in Table 11.BQL is below quantitation limit (QL = 0.03 ppm); N / A is not applicable

Claims

What is claimed is:

1. A pharmaceutical composition comprising: i) an immediate-release portion comprising viloxazine, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable core; and ii) an extended-release portion comprising viloxazine, or a pharmaceutically acceptable salt thereof, and a release rate controlling substance, wherein the viloxazine, or salt thereof, is segregated from contact with the pharmaceutically acceptable core and the release rate controlling substance.

2. The pharmaceutical composition of claim 1 , wherein the viloxazine or a salt thereof is segregated from contact with the pharmaceutically acceptable core and the release rate controlling substance by a seal coat layer.

3. The pharmaceutical composition of claim 2, wherein the immediate-release portion comprises a pellet comprising: i) the pharmaceutically acceptable core; ii) a first seal coat layer surrounding the core; iii) a drug coat layer comprising the viloxazine, or a salt thereof, surrounding the first seal coat layer; and iv) a second seal coat layer surrounding the drug coat layer.

4. The pharmaceutical composition of claim 3, wherein the extended-release portion comprises the immediate-release pellet, further surrounded by an extended-release layer comprising the release rate controlling substance.

5. The pharmaceutical composition of claim 3 or 4, wherein at least one of the drug coat layer, the first seal coat layer, the second seal coat layer and the extended-release layer comprises an antioxidant.

6. The pharmaceutical composition of claim 5, wherein the antioxidant is cysteine and / or a cysteine equivalent.

7. The pharmaceutical composition of any one of claims 1 to 6, comprising hydroxypropyl methylcellulose.

8. The pharmaceutical composition of any one of claims 1 to 7, wherein the release rate controlling substance is a cellulose derivative.

9. The pharmaceutical composition of claim 8, wherein the cellulose derivative is ethylcellulose.

10. The pharmaceutical composition of any one of claims 8 or 9, wherein the cellulose derivative is used in combination with a suitable pore forming agent.

11. The pharmaceutical composition of claim 10, wherein the pore forming agent is polyvinyl alcohol.

12. The pharmaceutical composition of any one of claims 1 to 11 , wherein the pharmaceutically acceptable core is a sugar-based core.

13. The pharmaceutical composition of any one of claims 1 to 12, wherein the viloxazine is in the form of viloxazine hydrochloride.

14. The pharmaceutical composition of any one of claims 1 to 13, comprising from about 10 wt% to about 40 wt% of the immediate-release portion and from about 60 wt% to about 90 wt% of the extended-release portion.

15. A pharmaceutical composition comprising: i) from about 20 wt% to about 40 wt% of a pharmaceutically acceptable core; ii) a first seal coat layer surrounding the pharmaceutically acceptable core comprising from about 2 wt% to about 15 wt% of a first sealant;iii) a drug coat layer surrounding the first seal coat layer comprising from about 30 wt% to about 60 wt% viloxazine, or a pharmaceutically acceptable salt thereof and from about 2 wt% to about 10 wt% of a binder; and iv) a second seal coat layer surrounding the drug coat layer comprising from about 2 wt% to about 15 wt% of a second sealant.

16. The pharmaceutical composition of claim 15, comprising from about 0.5 wt% to about 5 wt% of an antioxidant.

17. The pharmaceutical composition of claim 16, wherein the antioxidant is present in a seal coat layer and the drug coat layer.

18. The pharmaceutical composition of claim 17, wherein the antioxidant is present in the drug coat layer and the second seal coat layer.

19. The pharmaceutical composition of any one of claims 16 to 18, wherein the antioxidant is cysteine and / or a cysteine equivalent.

20. The pharmaceutical composition of any one of claims 16 to 19, wherein the antioxidant is L-cysteine hydrochloride.

21. The pharmaceutical composition of any one of claims 15 to 20, wherein the pharmaceutical composition is in the form of an immediate-release pellet.

22. The pharmaceutical composition of any one of claims 16 to 21 , further comprising an extended-release layer surrounding the second seal coat layer comprising from about 2 wt% to about 10 wt% of a release rate controlling substance and from about 2 wt% to about 10 wt% of a pore forming agent.

23. The pharmaceutical composition of claim 22, wherein the first and second sealant are hypromellose.

24. The pharmaceutical composition of claim 22 or 23, wherein the release rate controlling substance is ethylcellulose.

25. The pharmaceutical composition of any one of claims 22 to 24, wherein the pore forming agent is polyvinyl alcohol.

26. The pharmaceutical composition of any one of claims 22 to 25, wherein the lubricant is talc.

27. The pharmaceutical composition of any one of claims 22 to 26, wherein the pharmaceutical composition is in the form of an extended-release pellet.

28. A pharmaceutical composition comprising viloxazine, or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable excipient(s), and cysteine, and / or a cysteine equivalent.

29. The pharmaceutical composition of claim 28, wherein the composition comprises from about 0.5 wt% to about 5 wt% cysteine and / or a cysteine equivalent.

30. The pharmaceutical composition of claim 29, wherein the cysteine is in the form of L-cysteine hydrochloride.31 . The pharmaceutical composition of any one of claims 28 to 30, wherein the weight ratio of cysteine and / or cysteine equivalent: viloxazine, or a pharmaceutically acceptable salt thereof, is from about 1 :40 to about 1 :10.

32. The pharmaceutical composition of any one of claims 1 to 31 , wherein the composition comprises no more than about 1 ppm of / V-nitrosoviloxazine with respect to viloxazine free base after storage for 1 month at 40 °C, 75% relative humidity.

33. The pharmaceutical composition of any one of claims 1 to 32, wherein the composition comprises no more than about 0.25 ppm of / V-nitrosoviloxazine with respect to viloxazine free base after storage for 1 month at 40 °C, 75% relative humidity.

34. A capsule comprising the pharmaceutical composition of any one of claims 1 to 33.

35. The capsule of claim 34, wherein the capsule comprises an amount of viloxazine, or a pharmaceutically acceptable salt thereof, of from about 100 mg to about 200 mg viloxazine, or an equivalent amount of salt thereof.

36. A method for the treatment of a central nervous system (CNS) disorder comprising the administration of the pharmaceutical composition of any one of claims 1 to 33, or the capsule of claims 34 or 35, to a human subject in a therapeutically effective amount for the treatment a central nervous system (CNS) disorder.

37. The method of claim 36, wherein the CNS disorder is Attention-Deficit Hyperactivity Disorder (ADHD).

38. A solid pharmaceutical composition comprising viloxazine, or a pharmaceutically acceptable salt thereof, / V-nitrosoviloxazine, and a pharmaceutically acceptable excipient, wherein the composition comprises no more than about 1 ppm of / V-nitrosoviloxazine with respect to viloxazine free base.

39. The pharmaceutical composition of claim 38, wherein / V-nitrosoviloxazine is present in a concentration that is no more than about 0.5 ppm with respect to viloxazine free base.

40. The pharmaceutical composition of claim 38, wherein / V-nitrosoviloxazine is present in a concentration that is no more than about 0.17 ppm with respect to viloxazine free base.

41. The pharmaceutical composition of any one of claims 39 to 40, wherein the viloxazine is in the form of the hydrochloride salt.

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