DESC:F O R M 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“A STABLE PHARMACEUTICAL COMPOSITION OF VILOXAZINE AND PROCESS OF PREPARATION THEREOF”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India

The following specification particularly describes the invention and the manner in which it is to be performed:
TECHNICAL FIELD:
The present subject matter relates to a stable pharmaceutical composition comprising a therapeutically effective amount of Viloxazine or a pharmaceutically acceptable salt thereof, as an active ingredient, and at least one pharmaceutical acceptable excipient and a process of preparation thereof. The present subject matter further relates to a stable extended release pharmaceutical composition with reduced nitrosamine impurity and a process of preparation thereof.

BACK GROUND:
Viloxazine is a serotonin norepinephrine modulating agent (SNMA). Viloxazine hydrochloride is chemically designated as (±)-2-[(2-ethoxyphenoxy)methyl]morpholine hydrochloride. Viloxazine is a racemic compound with two stereo isomers (R-Viloxazine and S-Viloxazine).

Viloxazine hydrochloride in the form of 100 mg, 150 mg and 200 mg extended release capsule is approved in the US under the brand name Qelbree®. Qelbree ® is administered orally, once daily, with or without food for the treatment of Attention-Deficit Hyperactivity Disorder (ADHD) in adults and pediatric patients 6 years and older.

Viloxazine hydrochloride is a white to off-white powder that is soluble in water, 0.1N HCl and aqueous solutions at pH of 1.2 through 9.5 and is sparingly soluble in methanol, very slightly soluble in acetonitrile, acetic acid and isopropyl alcohol, and practically insoluble in ethyl acetate.

WO2013/119794 patent application discloses different pharmaceutical formulations of Viloxazine intended for oral administration such as bi-layer tablet formulation; osmotic release formulation; extended release Viloxazine formulation in the form of a gastro-retentive tablet. Furthermore, examples disclose formulations of Viloxazine, for instance, extended release matrix tablet formulation of Viloxazine; multiparticulate formulation of Viloxazine and extended release pellets formulation of Viloxazine, wherein the pellets were prepared by wet granulation process and immediate release pellets were coated with extended release layer consisting of release rate controlling compound such as ethyl cellulose and specific pore formers selected from hydroxypropyl methylcellulose, povidone, hydroxyethyl cellulose, hydroxypropyl cellulose, and organic acids to demonstrate the range of extended release profiles that can be achieved with the pellet compositions.

There is a need in the art for alternative stable pharmaceutical compositions of Viloxazine or a pharmaceutically acceptable salt thereof. Moreover, there is a need in the art for stable pharmaceutical composition of Viloxazine or a pharmaceutically acceptable salt thereof, wherin the nitrosamine impurities remain under the established Acceptable Daily Intake (ADI) level, even during shelf life storage period.

The present subject matter relates to a stable extended release oral pharmaceutical composition comprising Viloxazine hydrochloride as an active ingredient and at least one pharmaceutically acceptable excipient and a process of preparation thereof.

The term N-nitrosamine, describes a class of compounds that has a chemical structure, R1N(-R2–N=O). N-nitrosamines can be formed by nitrosating reaction between amines (such as secondary, tertiary or quaternary amines) and nitrous acid. Nitrosamines are common in water and foods, including cured and grilled meats, dairy products and vegetables. Everyone is exposed to some level of nitrosamines. These impurities may increase the risk of cancer if people are exposed to them above acceptable levels over long periods of time.

FDA has identified seven nitrosamine impurities, that theoretically could be present in drug products: N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitroso-N-methyl-4-aminobutanoic acid (NMBA), N-nitrosoisopropylethyl amine (NIPEA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethylphenylamine (NMPA).

Furthermore, Viloxazine contains secondary/tertiary amines which might be the reason for the formation of nitrosamine impurities, specifically, Viloxazine N-nitrosamine during synthesis of Viloxazine or manufacturing of pharmaceutical compositions of Viloxazine. The structure of Viloxazine N-nitrosamine is as represented below:

It was unexpectedly found that use of certain excipients can possibly attain a stable pharmaceutical composition of Viloxazine with low level of nitrosamine impurities. After rigorous experimentations, a stable pharmaceutical composition of Viloxazine hydrochloride was developed with impurity level of Viloxazine N-nitrosamine under the established Acceptable Daily Intake (ADI) level, particularly, during the manufacturing process and the storage period; and these stable compositions can be prepared by simple, non-tedious and cost-effective process.

OBJECT OF THE SUBJECT MATTER:
The object of the present subject matter is to provide a stable extended release pharmaceutical composition of Viloxazine or pharmaceutically acceptable salt(s) thereof and at least one pharmaceutical acceptable excipient.

Another object of the present subject matter is to provide a stable extended release pharmaceutical composition of Viloxazine or pharmaceutically acceptable salt(s) thereof with a low level of Viloxazine N-nitrosamine impurities with acceptable dissolution profile.

SUMMARY OF THE SUBJECT MATTER:
In one embodiment, the present subject matter provides a stable extended release pharmaceutical composition comprising,
(a) Viloxazine or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable excipient, wherein, at least one pharmaceutically acceptable excipient is selected from drug carriers/inert cores, diluent/fillers, binders, disintegrants, antioxidants, adsorbents, film forming agent, antistatic agents, lubricants or glidants, pore formers, coloring or flavoring agent or combination thereof.

In one embodiment, the present subject matter provides a stable extended release pharmaceutical composition comprising,
(a) Viloxazine or a pharmaceutically acceptable salt thereof,
(b) at least one pharmaceutically acceptable excipient, wherein at least 80% of said active ingredient is released from said composition after 12 hours, as measured in 900 mL of pH of 6.8 phosphate buffer at paddle rotation speed of 50 rpm.

While not wishing to be bound by theory, it is believed that one of the reasons for the build-up of the nitrosamine impurities in the pharmaceutical drug products is due to the interaction between nitrites and certain secondary, tertiary or quaternary amines during the manufacturing process or shelf life storage period. Such formation of nitrosamine impurities can be minimized with the use of antioxidants in the pharmaceutical drug products, resulting in nitrosamine impurities to be under the established Acceptable Daily Intake (ADI) level. Further, it has been found that nitrosamine impurities specifically can be significantly reduced and controlled in pharmaceutical drug products by introducing one or more antioxidants into the pharmaceutical formulations.

In an embodiment, the present subject matter provides a pharmaceutical composition comprising Viloxazine hydrochloride as active pharmaceutical ingredient and at least one pharmaceutical acceptable excipient and, wherein at least one pharmaceutical acceptable excipient is antioxidant (s) in the concentration from about 0.1 to about 10 % w/w, preferably from about 0.5 to about 5 % w/w, typically from about 0.1 to about 2 % w/w, for example from about 0.2 to about 1 % w/w, based on the total weight of composition.

DETAILED DESCRIPTION OF THE SUBJECT MATTER:
As used herein, "a" or "an" means one or more unless otherwise specified.

The term "composition" and “compositions” is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term "stable" and "stability" as used herein refers to both the physical form and the chemical purity of the active pharmaceutical ingredient or the pharmaceutical active dosage form including non-limiting examples of tablet, capsules. Stable compositions refers to compositions which contain acceptable levels of nitrosamine impurities, which is not more than 0.166 ppm, when stored at 40°C ± 2°C and 75% ± 5% relative humidity (40°C/75%RH) for at least 1 month, or at least 2 months, or at least 3 months, or at least 6 months, or at least 12 months, or at least 24 months, or at least 36 months, or when stored at 25°C ± 2°C and 60% ± 5% relative humidity (25°C/60%RH) for at least 1 month, or at least 2 months, or at least 3 months, or at least 6 months, or at least 12 months, or at least 24 months, or at least 36 months. Further, stable compositions refers to compositions which contain about 0.4 % w/w/ or less of the total impurities and/or about 0.2% w/w or less of individual impurities during the shelf life of the composition.

In this specification, the word “comprising” describes components that must be present, but leaves open the possibility that other unspecified components may also be present within the scope of the relevant term.

In one embodiment, Viloxazine present in pharmaceutical composition is in the form of pharmaceutically acceptable salt of Viloxazine.

In one embodiment, Viloxazine present in pharmaceutical composition is in the form of hydrochloride salt of Viloxazine.

In another embodiment, Viloxazine hydrochloride in the pharmaceutical composition of present subject matter is in the concentration of about 25 % to about 60 % w/w, preferably in the concentration of about 30 % to about 55 % w/w of based on the total weight of the composition.

One aspect of the present subject matter provides a stable pharmaceutical composition of Viloxazine hydrochloride comprising,
(a) an inert core such as carrier/pellets/spheres,
(b) active pharmaceutical ingredient,
(c) one or more pharmaceutically acceptable excipients, selected from, but not limited to, binder (s), film forming agent (s), anti-tacking agent (s), polymer (s), sugar (s), diluent (s), plasticizer (s), pore former (s), lubricant (s), or combinations thereof.

Another aspect of the present subject matter provides a stable pharmaceutical composition of Viloxazine hydrochloride comprising,
(a) an inert core such as carrier/pellets/spheres,
(b) active pharmaceutical ingredient,
(c) one or more pharmaceutically acceptable antioxidant (s),
(d) one or more pharmaceutically acceptable excipients, selected from, but not limited to, binder (s), film forming agent (s), anti-tacking agent (s), polymer (s), sugar (s), diluent (s), plasticizer (s), pore former (s), lubricant (s), or combinations thereof.

Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) inert spheres,
(b) Viloxazine hydrochloride as the active pharmaceutical ingredient,
(c) one or more pharmaceutically acceptable film forming agent (s),
(d) one or more pharmaceutically acceptable anti-tacking agent (s),
(e) one or more pharmaceutically acceptable lubricant (s).
(f) one or more pharmaceutically acceptable hydrophobic polymer (s),
(g) one or more pharmaceutically acceptable diluent (s),
(h) one or more pharmaceutically acceptable plasticizer (s),
(i) optionally one or more pharmaceutically acceptable pore former (s).

Another aspect of the present subject matter provides a stable pharmaceutical composition comprising,
(a) inert spheres,
(b) Viloxazine hydrochloride as the active pharmaceutical ingredient,
(c) one or more pharmaceutically acceptable film forming agent (s),
(d) one or more pharmaceutically acceptable anti-tacking agent (s),
(e) one or more pharmaceutically acceptable antioxidant (s),
(f) one or more pharmaceutically acceptable lubricant (s).
(g) one or more pharmaceutically acceptable hydrophobic polymer (s),
(h) one or more pharmaceutically acceptable diluent (s),
(i) one or more pharmaceutically acceptable plasticizer (s).
(j) optionally one or more pharmaceutically acceptable pore former (s).

Another aspect of the present subject matter provides a stable extended release pharmaceutical composition of a pharmaceutically acceptable salt of Viloxazine and at least one pharmaceutically acceptable excipient selected from, but not limited to,
(a) 10 - 50 % w/w of inert spheres,
(b) 25 - 60 % w/w of Viloxazine hydrochloride,
(c) 1 - 25 % w/w of film forming agent (s),
(d) 0.5 - 20 % w/w of anti-tacking agent (s),
(e) 0 - 10 % w/w of antioxidants (s),
(f) 0.01 - 5 % w/w of lubricant (s),
(g) 1 - 20 % w/w of hydrophobic polymer (s),
(h) 0 - 5 % w/w of diluent (s),
(i) 0.05 - 10 % w/w of plasticizer (s),
(j) 0 - 30 % w/w of binder (s),
(k) 0 - 15 % w/w of pore former (s) or combinations thereof.

Another aspect of the present subject matter provides a process to prepare a stable extended release pharmaceutical composition of Viloxazine or a pharmaceutically acceptable salt thereof comprising,
(a) coating of inert spheres with Viloxazine hydrochloride, one or more pharmaceutically acceptable film forming agent (s) and/or one or more pharmaceutically acceptable anti-tacking agent (s) to form drug coated spheres,
(b) the drug coated spheres of step (a) are further coated with one or more pharmaceutically acceptable film forming agent (s) and/or one or more pharmaceutically acceptable anti-tacking agent (s),
(c) 20% of the coated spheres of step (b) are further blended with one or more pharmaceutically acceptable lubricant (s),
(d) 80% of the coated spheres of step (b) are further coated with extended release coating using hydro-alcoholic solvent system with one or more pharmaceutically acceptable hydrophobic polymer (s), one or more pharmaceutically acceptable diluent (s), one or more pharmaceutically acceptable plasticizer (s), one or more pharmaceutically acceptable anti-tacking agent (s), and/or one or more pharmaceutically acceptable film forming agent (s) and optionally, further seal coating the extended release coated spheres with one or more pharmaceutically acceptable film forming agent (s) and/or one or more pharmaceutically acceptable anti-tacking agent (s),
(e) the coated spheres of step (d) are further blended with one or more pharmaceutically acceptable lubricant (s),
(f) finally, the lubricated spheres of step (c) and (e) are filled into the capsules.

Another aspect of the present subject matter provides a process to prepare a stable pharmaceutical composition of Viloxazine or a pharmaceutically acceptable salt thereof comprising,
(a) inert spheres,
(b) coating the spheres of step (a) with Viloxazine hydrochloride, one or more pharmaceutically acceptable film forming agent (s), one or more pharmaceutically acceptable antioxidant (s) and/or one or more pharmaceutically acceptable anti-tacking agent (s),
(c) drug coated spheres of step (b) are further coated with one or more pharmaceutically acceptable film forming agent (s) and/or one or more pharmaceutically acceptable anti-tacking agent (s),
(d) 20% of the coated spheres of step (c) are further blended with one or more pharmaceutically acceptable lubricant (s),
(e) 80% of the coated spheres of step(c) are further coated with extended release coating using hydro-alcoholic solvent system with one or more pharmaceutically acceptable hydrophobic polymer (s), one or more pharmaceutically acceptable diluent (s), one or more pharmaceutically acceptable plasticizer (s), one or more pharmaceutically acceptable anti-tacking agent (s), and/or one or more pharmaceutically acceptable film forming agent (s) and optionally, further seal coating the extended release coated spheres with one or more pharmaceutically acceptable film forming agent (s) and one or more pharmaceutically acceptable anti-tacking agent (s),
(f) the coated spheres of step (e) are further blended with one or more pharmaceutically acceptable lubricant (s),
(g) finally, the lubricated spheres of step (d) and (f) are filled into the capsules.

In this specification, the terms “film forming agent” and “film forming agents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable film forming agents according to the present subject matter can be selected from, but not limited to hydroxypropylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), hydroxypropyl methylcellulose, hydroxypropyl cellulose SSL (HPC-SSL), hydroxypropyl cellulose SL (HPC-SL), hydroxypropyl cellulose L (HPC-L), hydroxyethyl cellulose, povidone, Kollidone K30 LP, Kollidone VA64, Plasdone, Copovidone, Plasdone S630, polyoxyethylene–polyoxypropylene copolymers (Poloxamers), polyvinylpyrrolidone vinyl acetate, polyvinylacetal diethylaminoacetate (AEA®), polyvinyl acetate phthalate, polysorbate 80, polyoxyethylene (40) stearate, polyethylene glycol monomethyl ether, polyethylene glycol, methylcellulose, methacrylic acid copolymer (Eudragit or Eudragit-EPO), and the like.

In another embodiment, suitable film forming agents used in the pharmaceutical composition of present subject matter, are in the concentration of about 1 % to about 25 % w/w, based on the total weight of the composition.

In this specification, the terms “lubricant”, “lubricants”, anti-tacking agent” and “anti-tacking agents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable pharmaceutical lubricants or anticaking agents according to the present subject matter can be selected from, but not limited to, talc, magnesium, aluminium, zinc or calcium stearate, glyceryl behenate, glyceryl dibehenate, glyceryl monostearate, glyceryl palmitostearate, a mixture of benenate esters of glycerine (e.g. a mixture of glyceryl bihenehate, tribehenin and glyceryl behenate), magnesium stearate, myristic acid, palmitic acid, stearic acid, tribehenin, sodium stearyl fumarate (SSF), and the like.

In another embodiment, suitable lubricants used in the pharmaceutical composition of present subject matter, are in the concentration of about 0.01 % to about 5 % w/w, preferably in the concentration of about 0.05 to about 2 % w/w, based on the total weight of the composition.

In this specification, the terms “hydrophobic polymer” and “hydrophobic polymers” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable hydrophobic polymers according to the present subject matter can be selected from, but not limited to, ethyl cellulose, polyvinyl acetate, cellulose acetate, eudragit® RS and eudragit® RL (poly (ethyl acrylate-co-methyl methacrylate- cotrimethylammonioethyl methacrylate chloride)), eudragit® NE 30 D or eudragit® NM 30 D (poly(ethyl acrylate-co-methyl methacrylate)), ethyl acrylate methyl methacrylate copolymer, cellulose acetate butyrate, cellulose esters, cellulose acetate propionate, waxes, hydrogenated vegetable oils, glyceryl behenate; glyceryl palmitostearate; PEG glyceryl esters, and the like.

In another embodiment, suitable hydrophobic polymers used in the pharmaceutical composition of present subject matter, are in concentration of about 1 to about 20 % w/w, preferably in the concentration of about 1 to about 10 % w/w, based on the total weight of the composition.

In this specification the terms “diluent” and “diluents” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable diluents according to the present subject matter can be selected from, but not limited to, sugar and sugar alcohol such as mannitol, lactose, fructose, isomalt, lactitol, maltitol, sorbitol, erythritol, erythritol, maltose, polydextrose, sucrose, trehalose and xylitol; calcium carbonate; dicalcium phosphate; pregelatinized starch; corn starch; calcium sulfate; cellulose acetate; ethylcellulose; inulin; magnesium carbonate; magnesium oxide; maltodextrin; sodium bicarbonate; sodium carbonate; sodium chloride, microcrystalline cellulose, polyethylene glycol, and the like.

In another embodiment, suitable diluents used in the pharmaceutical composition of present subject matter, are in the concentration of 0 to 5 % w/w, preferably in the concentration of about 0.05 to about 3 % w/w, based on the total weight of the composition.

In this specification, the terms “plasticizer” and “plasticizers” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable plasticizers according to the present subject matter can be selected form the group of, but not limited to glycerol, xylitol, sorbitol, polyglycerol, glucose, fructose, triethyl citrate, polyethylene glycol, castor oil, diethyl phthalate, polysorbate, propylene glycol, triacetin and the like.

In another embodiment, suitable plasticizers used in the pharmaceutical composition of present subject matter, are in the concentration of about 0.05 to about 10 % w/w, preferably in the concentration of about 0.2 to about 5 % w/w, based on the total weight of the composition.

In this specification, the terms “binder” and “binders” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable binders according to the present subject matter can be selected from, but not limited to, povidone, copovidone, pregelatinized starch, cellulose, methyl cellulose, ethyl cellulose, cellulose derivatives (e.g., hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC)), polyethylene glycol, and the like.

In this specification, the terms “sugar” and “sugars” are intended to be interpreted in the context of pharmaceutical formulation science. Suitable sugars according to the present subject matter can be selected from, but not limited to, sucrose, glucose, fructose, lactose, maltose, dextrose, and the like.

In this specification, terms “antioxidant'' and “antioxidants'', as used herein, refers to a group of substances that are capable of inhibiting, preventing or reducing oxidative reactions. Preferred antioxidants are, examples of which include, but not limited to, butylated hydroxy anisole (BHA), butylated hydroxy toulene (BHT), ascorbic acid, sodium ascorbate, alpha-tocopherol, sulfamic acid, caffeic acid, acetyl cysteine, cysteine, thiourea, 1-thiosorbitol, sulphites (eg sodium sulphite), bisulphites (eg sodium bisulphite), metabisulphites (eg sodium metabisulphite), thiosulphates (eg sodium thiosulfate), citric acid, tartaric acid, phosphoric acid, malic acid, lactic acid, methanesulfonic acid, ethanesulfonic acid, ?-toluenesulfonic acid, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, gluconic acid, glucuronic acid, glutamic acid, fumaric acid, maleic acid, and the like.

In another embodiment, suitable antioxidants used in the pharmaceutical composition of present subject matter, are in the concentration of about 0.1 to about 10 % w/w, preferably from about 0.5 to about 5 % w/w, typically from about 0.1 to about 2 % w/w, for example from about 0.2 to about 1 % w/w, based on the total weight of composition.

In one embodiment, the pharmaceutical composition of the present subject matter may be in the form of capsules, tablets, syrups, lozenges. The pharmaceutical composition includes tablets, coated tablets, layered tablets, granules, powders, microparticles, caplets, sachets, pellets, spheroids, mini-tablets, beads, capsules which may be hard gelatin or soft gelatin capsules, delayed-release capsules, extended release capsule, gastro-resistant capsules, microcapsules and pills.

In one embodiment, pharmaceutical composition of the present subject matter may be in the form of extended release capsule, which are suitable for oral administration to a human.

In one embodiment, the pharmaceutical composition of the present subject matter is a extended release capsule composition suitable for oral administration to a human subject for the treatment of attention deficit hyperactivity disorder.

In one embodiment, the pharmaceutical composition comprises 100 mg, 150 mg and 200 mg Viloxazine free base, equivalent to 115 mg, 173 mg and 231 mg of Viloxazine hydrochloride respectively.

In a further aspect of the present subject matter there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament.

In one embodiment, there is provided the use of a pharmaceutical composition, as defined herein, for the manufacture of a medicament for the treatment of neurodevelopmental disorders.

In one aspect of the present subject matter there is provided a pharmaceutical composition, as defined herein, for use as a medicament.

In one embodiment, the neurodevelopmental disorder is attention deficit hyperactivity disorder.

According to one embodiment, the process for preparation of Viloxazine hydrochloride capsule can be selected form, but not limited to wet granulation process, dry granulation process and direct compression process.

In another embodiment, the present subject matter relates to a process for the preparation of a stable pharmaceutical composition, comprising the steps of:
a) dispersing an active ingredient in a solution with film forming agent (s) and mixing anti-tacking agent (s) to form a dispersion,
b) spraying the dispersion of step a) on to the spheres to form a drug layer coating,
c) preparing a barrier coating solution with film forming agent (s) and/or anti-tacking agent (s) to form a dispersion,
d) spraying the dispersion of step c) onto the drug layered pellets to form barrier coated pellets, followed by drying of the pellets,
e) lubricating the 20% of the pellets of step d) with an anti-tacking agent (s),
f) coating the 80% of the pellets of step d) with extended release dispersion of hydrophobic polymer (s), diluent (s), plasticizer (s) and/or anti-tacking agent (s), followed by drying the extended release coated pellets, further optionally seal coating the extended release coated pellets with dispersion of film forming agent (s) and/or anti-tacking agent (s) to prevent dose dumping,
g) lubricating the coated pellets of step f) with an anti-tacking agent (s),
f) finally, filling the lubricated pellets of step e) and g) into the capsules.

In another embodiment, the present subject matter relates to a process for the preparation of a stable pharmaceutical composition, comprising the steps of:
a) dispersing an active ingredient in solution with antioxidant (s), then to it, film forming agent (s) and mixing anti-tacking agent (s) to form a dispersion,
b) spraying the drug dispersion of step a) on to the spheres to form a drug layer coating,
c) preparing a barrier coating solution with film forming agent (s) and/or anti-tacking agent (s) to form a dispersion,
d) spraying the dispersion of step c) onto the drug layered pellets to form barrier coated pellets, followed by drying of the pellets,
e) lubricating the 20% of the pellets of step d) with an anti-tacking agent (s),
f) coating the 80% of the pellets of step d) with extended release coating comprising hydrophobic polymer (s), diluent (s), plasticizer (s) and/or anti-tacking agent (s), followed by drying of the extended release coated pellets, and further optionally seal coating the extended release coated pellets pellets with dispersion of film forming agent (s) and/or anti-tacking agent (s) to prevent dose dumping,
g) lubricating the coated pellets of step f) with an anti-tacking agent (s),
f) finally, filling the lubricated pellets of step e) and g) into the capsules.

Accordingly, the stable pharmaceutical compositions prepared by the method given according to the subject matter and stored under the conditions, such as, but not limited to, room temperature, accelerated condition, with or without using nitrogen purging, at high temperature, etc.; complies the regulatory requirement with respect to genotoxic impurities as prescribed by various regulatory bodies like USFDA, PMDA, EMCA, TGA etc. throughout their stability period.

Stability testing is carried out to provide evidence of how the quality of the manufactured capsules (especially nitrosamine impurities) may change with time under the influence of environmental factors such as temperature and humidity coupled with presence and absence of antioxidants.

Embodiments provided herein may be more fully understood by reference to the following examples. These examples are meant to be illustrative of pharmaceutical compositions and dosage forms provided herein, but are not in any way limiting.

EXAMPLES
Example 1:
Table 1 - Stable pharmaceutical compositions of Viloxazine and at least one pharmaceutically acceptable excipient
Sr. No. Ingredients % w/w of core tablet
1 Viloxazine or a pharmaceutically acceptable salt thereof 25 – 60 % w/w
2 Inert core such as sugar spheres, organic acid pellets, microcrystalline cellulose sphere, corn starch pellets, etc. 10 – 50 % w/w
3 Film forming agents (e.g. Hydroxy propyl methyl cellulose, hydroxypropyl cellulose, copovidone, etc.) 1 – 25 % w/w
4 Anti-tacking agents or Lubricants (e.g. Talc, Magnesium stearate, Stearic acid, sodium stearyl fumarate) 0.01 – 20 % w/w
5 Antioxidants (e.g. sodium ascorbate, ascorbic acid, alpha-tocopherol, sulfamic acid, caffeic acid, etc.) 0 – 10 % w/w
6 Hydrophobic polymers (e.g. ethyl cellulose, polyvinyl acetate, cellulose acetate, eudragit, etc.) 1 – 20 % w/w
7 Diluents (e.g. lactose, sucrose, mannitol, maltodextrin, polyethylene glycol, etc.) 0 – 5 % w/w
8 Plasticizers (e.g. glycerol, triethyl citrate, polyethylene glycol, triacetin, etc.) 0.05 – 10 % w/w
9 Binders 0 – 30 % w/w
10 Pore formers 0 – 15 % w/w

Example 2:
Table 2 - Stable extended release pharmaceutical compositions of Viloxazine
Sr. no Composition Batches 2A 2B 2C 2D 2E
Ingredients %w/w
Drug layering stage
1 Sugar spheres 39.68 37.03 28.13 26.90 31.90
2 Viloxazine HCl 41.11 41.11 33.98 33.98 40.61
3 Hydroxypropyl methyl cellulose 2.19 2.19 2.65 2.65 3.17
4 Talc 8.20 8.20 8.83 8.83 10.56
5 Ascorbic acid - - 0.74 0.74 0.88
Barrier Coating stage of Drug layered pellets
6 Hydroxypropyl methylcellulose 1.82 1.82 1.69 1.66 1.98
7 Talc 0.91 0.91 0.56 0.55 0.66
Lubrication of Barrier Coated (For Immediate release)
8 Talc 0.18 0.18 0.15 0.15 0.18
Functional coating of Barrier Coated pellets (For Extended release)
9 Ethyl cellulose 3.33 4.86 5.12 5.97 -
10 Polyvinyl acetate - - - - 6.32
11 Sucrose 1.17 1.71 1.09 1.27 -
12 Polyethylene glycol - - - - 1.58
13 Triethyl citrate 0.33 0.49 0.51 0.60 -
14 Talc 0.90 1.32 1.24 1.18 1.98
Seal Coating stage of Extended release pellets
15 Hydroxypropyl methylcellulose - - 11.71 11.82 -
16 Talc - - 3.45 3.55 -
Lubrication of Extended release pellets
17 Talc 0.18 0.18 0.15 0.15 0.18

Example 3:
Table 3 - Stable extended release pharmaceutical compositions of Viloxazine
Sr. no Composition Batches 3A 3B 3C 3D 3E
Ingredients %w/w
Drug layering stage
1 Sugar spheres 33.14 31.90 33.14 31.96 30.56
2 Viloxazine HCl 39.90 40.61 39.90 40.69 38.80
3 Hydroxypropyl methylcellulose 3.11 3.17 3.11 3.17 3.03
4 Talc 10.38 10.56 10.38 10.58 10.09
5 Ascorbic acid 0.86 0.88 0.86 0.88 0.84
Barrier Coating stage of Drug layered pellets
6 Hydroxypropyl methylcellulose 1.95 1.98 1.95 1.98 1.89
7 Talc 0.65 0.66 0.65 0.66 0.56
Lubrication of Barrier Coated (For Immediate release)
8 Talc 0.17 0.18 0.17 0.18 0.17
Functional coating of Barrier Coated pellets (For Extended release)
10 Polyvinyl acetate 7.34 - - - -
11 Cellulose acetate - 6.32 7.34 - -
12 Eudragit RLPO - - - 5.76 8.23
13 Eudragit RSPO - - - 1.44 2.06
15 Polyethylene glycol 1.09 1.58 1.09 - -
16 Triethyl citrate - - - 0.72 1.03
17 Talc 1.24 1.98 1.24 1.80 2.57
Lubrication of Extended release pellets
20 Talc 0.17 0.18 0.17 0.18 0.17

Example 4:
Table 4 – Extended release pharmaceutical compositions of Viloxazine HCl with or without antioxidant (s)
Sr. No. Composition Batches 4A 4B 4C 4D 4E
Ingredients %w/w
Drug layering stage
1 Sugar spheres 32.72 32.52 32.00 26.88 28.07
2 Viloxazine HCl 39.16 37.75 39.87 34.23 35.39
3 Hydroxypropyl methylcellulose 2.54 2.45 2.59 2.67 3.22
4 Talc 3.38 3.27 8.62 8.90 9.20
5 Ascorbic acid -- 0.41 0.52 0.74 1.53
Barrier Coating stage of Drug layered pellets
6 Hydroxypropyl methylcellulose 1.87 2.19 2.51 1.67 1.98
7 Talc 0.47 -- 0.33 0.55 0.63
Lubrication of Barrier Coated (For Immediate release)
8 Talc 0.17 0.17 0.17 0.17 0.15
Functional coating of Barrier Coated pellets (For Extended release)
10 Ethyl cellulose 3.80 3.57 4.15 5.53 2.91
11 Sucrose 1.33 1.25 1.38 1.17 0.62
12 Triethyl citrate 0.38 0.36 0.42 0.55 0.29
13 Talc 1.02 0.96 1.11 1.34 0.71
Seal Coating of Extended release pellets
14 Hydroxypropyl methylcellulose 11.30 11.95 4.93 11.87 11.53
15 Talc 1.69 2.99 1.23 3.56 3.50
Lubrication of Extended release pellets
16 Talc 0.17 0.16 0.17 0.17 0.21

Example 5:
Manufacturing Process:
Examples 1 – 4 can be prepared using wet granulation process, dry granulation process or direct compression process. Preferably, compositions can be prepared using wet granulation process.
The process for the preparation of stable pharmaceutical compositions disclosed herein may typically involve:
• Raw materials were dispensed as per the formula;
• Desired fraction of sugar sphere were sifted;
• Drug dispersion with Viloxazine Hydrochloride, film forming agent (s), anti-tacking agent (s) and/or antioxidant (s) was prepared, and sprayed onto the spheres;
• Barrier coating solution with film forming agent (s) and/or anti-tacking agent (s) was prepared, and sprayed onto the drug layered pellets;
• The above barrier coated pellets were divided into 2 components;
• 1st component, i.e, 20% of the pellets were lubricated with anti-tacking agent (s);
• 2nd component i.e, 80% of the pellets were coated with extended release layer having hydrophobic polymer (s), diluent (s), plasticizer (s) and/or anti-tacking agent (s), further, extended release pellets were dried; optionally extended release pellets were further seal coated with dispersion of film forming agent (s) and/or anti-tacking agent (s); and lastly lubricating the pellets with anti-tacking agent (s);
• Finally, lubricated pellets, i.e, both 1st component and 2nd component were filled into the capsules.

Example 6:
Table 6 – In Vitro Dissolution data of extended release pharmaceutical compositions of Viloxazine HCl
Time points (Hr) Reference Product - Qelbree® Composition Batches (% drug release)
2A 2B 2C 2D 4E
0.25 19 17 18 12 14 -
0.5 19 18 19 16 17 -
1 21 22 21 19 19 20
2 31 32 28 26 23 25
4 52 54 42 49 47 43
6 66 70 56 69 68 60
8 78 81 68 79 80 74
10 86 88 78 83 87 84
12 92 92 85 85 91 89
14 95 94 91 87 94 93
16 97 95 94 88 96 95

Example 7:
Table 7 – Stability data of extended release pharmaceutical compositions of Viloxazine HCl
Condition Initial
3M– 40°C/75%RH 6M– 40°C/75%RH 6M– 25°C/60%RH
Composition Batch – 2A
% Assay 101.7 100.5 103.6 104.9
Any individual unspecified organic impurity (% w/w) 0.005 0.021 0.026 0.003
Total organic impurities (% w/w) 0.010 0.00 0.00 0.00
Composition Batch – 2B
% Assay 100.4 100.5 100.6 100.1
Any individual unspecified organic impurity (% w/w) 0.005 0.017 0.022 Not detected
Total organic impurities (% w/w) 0.009 0.00 0.00 Not detected
Composition Batch – 4E
% Assay 97.5 - 103.2 102.4
Any individual unspecified organic impurity (% w/w) 0.05 - 0.041 0.033
Total organic impurities (% w/w) 0.08 - 0.104 0.082

Example 8:
Table 8 – Stability data of extended release pharmaceutical compositions of Viloxazine HCl with or without antioxidant (s)
Composition Batches Condition Impurity level of N-Nitrosamine (ppm)
Viloxazine HCl - API Initial (RT) 0.405
4A Initial (RT) 0.510
6M 40°C/75%RH (ACC) 2.889
6M 25°C/60%RH 1.439
4B Initial (RT) 0.422
15 days 60°C (open exposure) 0.399
30 days 60°C (open exposure) 0.127
45 days 40°C/75%RH (ACC) 0.113
4E Initial (RT) 0.0093
3M 40°C/75% RH (ACC) 0.033
RT – Room temperature; ACC – accelerated condition; API – Active pharmaceutical ingredient

It is evident from above table that compositions without antioxidant(s) has propensity to have increased nitrosamine impurities and it is difficult to control it during the shelf life stage. However, compositions with antioxidant(s) not only have less nitrosamine impurities, they are better controlled. The antioxidant (s) such as ascorbic acid in the formulation has the potential to reduce the nitrosamine impurities to a greater extent (batch 4B and 4E) compared to formulation without antioxidants (batch 4A) and API Viloxazine HCl.

Example 9
Bioequivalence study:
An open label, balanced, randomized, single oral dose, crossover, bioequivalence study of Viloxazine hydrochloride stable extended release compositions in comparison with Qelbree® (Viloxazine hydrochloride) 200 mg extended release capsules (Marketed by Supernus Pharmaceuticals Inc) was performed in healthy, adult, human subjects under fasting and fed conditions.
The outcome of the bioequivalence study for Viloxazine hydrochloride stable extended release compositions of the present subject matter under fasting and fed conditions complies with pre-defined bioequivalence criteria for Cmax, AUC0-t and AUC0-8.

,CLAIMS:We Claim:

1. A stable extended release pharmaceutical composition comprising viloxazine or a pharmaceutically acceptable salt thereof, an inert core, one or more pharmaceutically acceptable antioxidants and one or more pharmaceutically acceptable excipients.

2. The stable extended release pharmaceutical composition as claimed in claim 1, comprising:
(a) 10 - 50 % w/w of inert core,
(b) 25 - 60 % w/w of Viloxazine hydrochloride,
(c) 1 - 25 % w/w of film forming agent (s),
(d) 0.5 - 20 % w/w of anti-tacking agent (s),
(e) 0 - 10 % w/w of antioxidants (s),
(f) 0.01 - 5 % w/w of lubricant (s),
(g) 1 - 20 % w/w of hydrophobic polymer (s),
(h) 0 - 5 % w/w of diluent (s),
(i) 0.05 - 10 % w/w of plasticizer (s),
(j) 0 - 30 % w/w of binder (s),
(k) 0 - 15 % w/w of pore former (s),
and/or combinations thereof.

3. The stable extended release pharmaceutical composition as claimed in claim 2, wherein the content of Viloxazine hydrochloride is about 30 to about 55 % w/w, based on the total weight of the composition.

4. The stable extended release pharmaceutical composition as claimed in claim 2, wherein the pharmaceutically acceptable antioxidants are selected from sodium ascorbate, ascorbic acid, alpha-tocopherol, sulfanic acid, caffeic acid, or combinations thereof, and wherein the content of pharmaceutically acceptable antioxidant is about 0.1 to about 10 % w/w, preferably about 0.1 to about 2 % w/w, based on the total weight of the composition.

5. The stable extended release pharmaceutical composition as claimed in claim 1, wherein the inert core is selected from sugar spheres, organic acid pellets, microcrystalline cellulose spheres, or corn starch pellets.

6. The stable extended release pharmaceutical composition as claims in claim 1 or 2, wherein the process for preparation of said composition comprises,
a) dispersing an active ingredient in solution with antioxidant (s), adding, film forming agent (s) and mixing anti-tacking agent (s) to form a dispersion,
b) spraying the drug dispersion of step a) on to the spheres to form a drug layer coating,
c) preparing barrier coating solution with film forming agent (s) and/or anti-tacking agent (s) to form a dispersion,
d) spraying the dispersion of step c) onto the drug layered pellets to form barrier coated pellets, followed by drying of the pellets,
e) lubricating 20% of the pellets of step d) with an anti-tacking agent (s),
f) coating the 80% of the pellets of step d) with extended release coating comprising hydrophobic polymer (s), diluent (s), plasticizer (s) and/or anti-tacking agent (s), followed by drying of the extended release coated pellets, and further optionally seal coating the extended release coated pellets with dispersion of film forming agent (s) and/or anti-tacking agent (s) to prevent dose dumping,
g) lubricating the coated pellets of step f) with an anti-tacking agent (s),
f) filling the lubricated pellets of step e) and g) into the capsules.

7. The stable extended release pharmaceutical composition as claimed in any precedent claim, wherein the process for the preparation of said composition comprises dry granulation, wet granulation or direct mixing with excipients.

8. The stable extended release pharmaceutical composition as claimed in any precedent claim, wherein said composition is in the form of a capsules tablet, coated tablet, layered tablet, granules, powder, microparticle, caplet, sachet, pellet, spheroid, mini-tablet, bead and/or combination thereof.

9. The stable extended release pharmaceutical composition as claimed in any precedent claim, wherein said composition is for use as a medicament in the treatment of attention deficit hyperactivity disorder.

Dated this 10th Jan, 2025
________________
(Sonal Ben Parimal Patel)
For Alembic Pharmaceuticals Limited