DESC:
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority to and the benefit of Indian Patent Application No’s. 202421017746 filed on March 12, 2024 and 202421047906 filed on June 21, 2024.

FIELD OF THE INVENTION:
The present invention relates to a pharmaceutical composition for oral administration containing a therapeutically effective amount of Zonisamide or a pharmaceutically acceptable salt thereof, and a method for the preparation thereof. The invention also relates to the use of said composition as adjunctive therapy for the treatment of partial-onset seizures. The compositions of the invention provide improved stability especially during the manufacturing process to ensure reproducibility and quantitative accuracy. Moreover, nitrosamine impurities are eliminated or reduced in such compositions.

BACKGROUND OF THE INVENTION:
Zonisamide is an antiepileptic drug and chemically classified as a sulfonamide having the chemical name 1,2-benzisoxazole-3-methanesulfonamide. The molecular formula of zonisamide is C8H8N2O3S and the molecular weight is 212.23. The structural formula is:

Zonisamide is a white powder, pKa = 10.2, and is moderately soluble in water (0.80 mg/mL) and 0.1 N HCl (0.50 mg/mL).
Currently Zonisamide formulation marketed under tradename ZONISADE® oral suspension and ZONEGRAN® oral capsule dosage forms, and used as adjunctive therapy in the treatment of partial seizures.
Zonisamide is a benzisoxazole derivative, originally synthesized in Japan in 1974 during exploratory research on psychiatric drugs, where it was subsequently identified as having anticonvulsant activity during screening. The precise mechanism of action of zonisamide is still unknown. It probably has more than one mechanism of action, such as blockage of voltage-gated sodium and T-type calcium channels, binding for gamma-aminobutyric acid (GABA)-benzodiazepine receptor complex leading to an increase in extracellular GABA, etc. A multitude of mechanisms of action may explain the efficacy of zonisamide in different types of seizures: generalized tonic-clonic seizures, simple and complex focal onset seizures, seizures within the framework of Lennox–Gastaut syndrome, myoclonic epilepsies, and infantile spasms.
US patent no. 4,172,896 discloses zonisamide product generically as well as specifically. Also discloses a pharmaceutical composition which contains zonisamide in admixture with a pharmaceutical carrier. The pharmaceutical composition may be in the dosage forms such as tablets, capsules, granules, fine granules, powders, syrups, suppositories, injections, or the like.
US patent no. 6,342,515 discloses a medicament for neurodegenerative diseases comprising zonisamide or an alkali metal salt thereof as an active ingredient. The present medicament can be used in the prevention and treatment of neurodegenerative diseases such as Parkinson's disease, Huntington's disease, choreic syndrome and dystonic syndrome in mammals (including human).
US patent no. 11,478,456 discloses the pharmaceutical field, and more precisely it relates to a pharmaceutical composition for the oral administration of Zonisamide and to the process for the preparation thereof. In particular, the present invention relates to the oral liquid composition comprising Zonisamide.
PCT publication no.2019186515 discloses the liquid pharmaceutical compositions of an active pharmaceutical ingredient. In particular, the present invention relates to the liquid compositions comprising antiepileptic/anticonvulsant/antiseizurc drugs.
Zonisamide is a compound with complete absorption, but not highly soluble according to the BCS criteria. Therefore, it requires enhancement in solubility and dissolution rate in order to become bioavailable.
Additionally, nitrosamine impurities are possible in the synthesis of zonisamide and its pharmaceutical salt thereof. The Nitrosamine impurities may originate from any or all of the active pharmaceutical ingredient, excipients, pharmaceutical packaging materials, and/or manufacturing process and equipment. Examples of Nitrosamine impurities include, but are not limited to, N-Nitroso zonisamide, N-Nitrosodimethyl amine (“NDMA”), N-Nitrosodiethyl amine (“NDEA”), N-Nitrosodiisopropylamine (“NDIPA”), N-Nitrosoethylisopropylamine (“NIPEA”), N-nitroso-N-methyl-4-aminobutyric acid (“NMBA”), N-Nitrosodibutylamine (“NDBA”), and N-Methyl-N-phenylnitrosamine (“NMPA”). Nitrosamines are generally formed when a secondary or tertiary amine reacts with a nitrosating agent. While the amounts of the Nitrosamine impurities in drugs is generally low, some levels have been above the U.S. Food and Drug Administration’s acceptable daily limit, potentially exposing many people to a slightly increased risk of cancer. Because of the aforementioned health-related effects, stringent limitations have been placed upon the permissible amounts of nitrosamine impurities in drug products. Because of the exceptionally low allowable limits for nitrosamine impurities in these products it become important to control the nitrosamine impurities during synthesis of active pharmaceutical ingredient or drug formulation.
Some patient particularly children and the seriously ill persons are not able to swallow solid dosage forms. Children, the elderly and people may have difficulty in swallowing solid dosage forms. Based on prior formulations, still there is a need to develop stable formulations of zonisamide which provides improved patient compliance, solubility, dissolution rate, stability and manufacturing process. Additionally, there is a need to develop pharmaceutically acceptable zonisamide compositions wherein the amount of nitrosamine impurity is less than the FDA acceptable intake limit of the nitrosamine impurity based on maximum daily dose of zonisamide.

SUMMARY OF THE INVENTION:
The present invention provides a pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, the pharmaceutical composition comprises zonisamide or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from but not limited to buffering agents, preservatives, suspending agents, anti-caking agents, sweetening agents, stabilizers, solvents, co-solvents, flavouring agents, and colouring agents.
Another aspect of the present invention provides a pharmaceutical composition comprising zonisamide or a pharmaceutically acceptable salt thereof, and suspending agents, anti-caking agents, buffering agents, preservatives, sweetening agents, and flavouring agents.
In another aspect of the invention, an oral pharmaceutical composition comprising about 0.5 to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In yet another aspect, there is provided a pharmaceutical composition comprising a) about 0.5 to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof;
b) about 90 to about 99.5% w/v of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of suspension.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of suspending agents; c) about 0.1 % w/v to about 10 % w/v of anti-caking agent; d) about 0.05 % w/v to about 5 % w/v of preservative; e) about 0.1 % w/v to about 5 % w/v of buffering agents; f) about 0.1 % w/v to about 5 % w/v of sweetening agent; g) about 0.01 % w/v to about 1 % w/v of flavouring agent; and h) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of suspending agents selected from but not limited to xanthan gum, sorbitol, guar gum, carrageenan, tragacanth, alginate, carbomers, combination of microcrystalline cellulose and sodium carboxymethylcellulose alone or combinations thereof; c) about 0.1 % w/v to about 10 % w/v of anti-caking agent selected from but not limited to silicified microcrystalline cellulose, magnesium silicate, silicon dioxide alone or combinations thereof; d) about 0.05 % w/v to about 5 % w/v of preservative selected from but not limited to benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, methyl paraben, propyl paraben, butyl paraben alone or combinations thereof; e) about 0.1 % w/v to about 5 % w/v of buffering agents selected from but not limited to citric acid, sodium citrate, acetic acid, sodium acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate alone or combinations thereof; f) sweetening agent; g) flavouring agent; and h) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of xanthan gum; c) about 0.1 % w/v to about 10 % w/v of silicified microcrystalline cellulose; d) about 0.05 % w/v to about 5 % w/v of sodium benzoate; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 5 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.35 % w/v to about 0.8 % w/v of xanthan gum; c) about 0.1% w/v to about 1 % w/v of silicified microcrystalline cellulose; d) about 1% w/v to about 2 % w/v of combination of sodium carboxymethylcellulose and microcrystalline cellulose; e) about 0.05 % w/v to about 1 % w/v of sodium benzoate; f) about 0.1 % w/v to about 1 % w/v of citric acid monohydrate; g) about 0.1 % w/v to about 1 % w/v of sodium citrate dihydrate; h) about 0.1 % w/v to about 1 % w/v of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients; wherein said dosage form is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.35 % w/v to about 0.8 % w/v of xanthan gum, preferably about 0.4 % w/v to about 0.6 % w/v, more preferably 0.4 % w/v, 0.45% w/v, 0.5 % w/v, 0.55% w/v, or 0.6 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.1% % w/v to about 1 % w/v of silicified microcrystalline cellulose, preferably about 0.2 % w/v to about 0.8 % w/v, more preferably 0.2 % w/v, 0.3 % w/v, 0.35% w/v, 0.4 % w/v, 0.45% w/v, 0.5% w/v, 0.55% w/v, 0.6 % w/v, or 0.7 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1% % w/v to about 2 % w/v of combination of sodium carboxymethylcellulose and microcrystalline cellulose, preferably about 1.2 % w/v to about 1.8 % w/v, more preferably 1.2 % w/v, 1.25 %w/v, 1.3 % w/v, 1.35 %w/v, 1.4 % w/v, 1.5 % w/v, 1.6 % w/v or 1.7 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.05 % w/v to about 0.2 % w/v of sodium carboxymethylcellulose, preferably about 0.08 % w/v to about 0.18 % w/v, more preferably 0.10 % w/v, 0.12 % w/v, 0.14 % w/v, 0.16 % w/v or 0.18 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1 % w/v to about 2 % w/v of microcrystalline cellulose, preferably about 1.2 % w/v to about 1.8 % w/v, more preferably 1.4 % w/v, 1.5 % w/v, 1.55 % w/v. 1.6 % w/v, 1.65 % w/v or 1.7 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.1 % w/v to about 2 % w/v of citric acid monohydrate, and sodium citrate dihydrate, preferably about 0.3 % w/v to about 1.5 % w/v, more preferably 0.3 % w/v, 0.4 % w/v, 0.5 % w/v, 0.6 % w/v, 0.7 % w/v, 0.8 % w/v, 0.9 % w/v, 1 % w/v, or 1.2 % w/v.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 2 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.5 % w/v of xanthan gum; c) about 0.4 % w/v of silicified microcrystalline cellulose; d) about 1.3 % w/v of combination of microcrystalline cellulose and sodium carboxymethylcellulose; e) about 0.1 % w/v of sodium benzoate; f) about 0.39 % w/v of citric acid monohydrate; g) about 0.39 % w/v of sodium citrate dihydrate; h) about 0.3 % w/v of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients.
In one of the further preferred embodiments, the pharmaceutical composition has a particle size distribution of Zonisamide of D10 not more than 30 µm, D50 not more than 60 µm and D90 not more than 100 µm.
In one of the further preferred embodiments, the pharmaceutical composition has a particle size distribution of Zonisamide of D90 ranges from about 30 to about 100 µm, preferably from about 40 to about 70 µm, more preferably about 45 µm, 55 µm, 60 µm, 63 µm, 65 µm, or 68 µm.
In one of the further preferred embodiments, the pharmaceutical composition of zonisamide has a particle size distribution of D90 ranges from about 30 to about 100 µm, preferably from about 40 to about 70 µm, more preferably about 45 µm, 55 µm, 60 µm, 63 µm, 65 µm, or 68 µm.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Zonisamide or pharmaceutically acceptable salts thereof which is substantially free of impurity i.e. total impurity present in the composition in an amount of less than or equal to 0.5 % w/w.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Zonisamide or pharmaceutically acceptable salts thereof contains not more than 0.5% w/w of Zonisamide related compound-A, Methyl Zonisamide, Any Unspecified degradation product.
In yet another aspect, the present invention further relates to stable pharmaceutical composition of zonisamide which is substantially free of nitrosamine impurity i.e. total nitrosamine impurity present in the composition in an amount of less than 1000 parts per billion (ppb), preferably less than 700 ppb, more preferably less than 400 ppb.
In yet another aspect, the present invention further relates to stable pharmaceutical composition of zonisamide contains less than 100 ppb of NDMA and NDEA impurities.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of xanthan gum; c) about 0.1 % w/v to about 10 % w/v of silicified microcrystalline cellulose; d) about 0.05 % w/v to about 5 % w/v of sodium benzoate; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients; wherein said dosage form is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension dosage form comprising: a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 1 mg/mL to about 10 mg/mL of xanthan gum; c) about 1 mg/mL to about 40 mg/mL of silicified microcrystalline cellulose; d) about 0.5 mg/mL to about 5 mg/mL of sodium benzoate; e) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate, and sodium citrate dihydrate; f) about 1 mg/mL to about 5 mg/mL of sucralose; g) about 1 mg/mL to about 5 mg/mL of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 5 mg/mL to about 50 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 3.5 mg/mL to about 8 mg/mL of xanthan gum; c) about 1 mg/mL to about 10 mg/mL of silicified microcrystalline cellulose; d) about 10 mg/mL to about 20 mg/mL of combination of sodium carboxymethylcellulose and microcrystalline cellulose; e) about 0.5 mg/mL to about 10 mg/mL of sodium benzoate; f) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate; g) about 1 mg/mL to about 10 mg/mL of sodium citrate dihydrate; h) about 1 mg/mL to about 10 mg/mL of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients; wherein said dosage form is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 3.5 mg/mL to about 8 mg/mL of xanthan gum, preferably about 4 mg/mL to about 6 mg/mL, more preferably 4 mg/mL, 4.5 mg/mL, 5 mg/mL, 5.5 mg/mL, or 6 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1 mg/mL to about 10 mg/mL of silicified microcrystalline cellulose, preferably about 2 mg/mL to about 8 mg/mL, more preferably 2 mg/mL, 3 mg/mL, 3.5 mg/mL, 4 mg/mL, 4.5 mg/mL, 5 mg/mL, 5.5 mg/mL, 6 mg/mL or 7 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 10 mg/mL to about 20 mg/mL of combination of sodium carboxymethylcellulose and microcrystalline cellulose, preferably about 12 mg/mL to about 18 mg/mL, more preferably 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL or 17 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.5 mg/mL to about 2 mg/mL of sodium carboxymethylcellulose, preferably about 0.8 mg/mL to about 1.8 mg/mL, more preferably 1 mg/mL, 1.2 mg/mL, 1.4 mg/mL, 1.6 mg/mL or 1.7 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 10 mg/mL to about 20 mg/mL of microcrystalline cellulose, preferably about 12 mg/mL to about 18 mg/mL, more preferably 14 mg/mL, 14.5 mg/mL, 15 mg/mL, 15.5 mg/mL, 16 mg/mL, 16.5 mg/mL or 17 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1 mg/mL to about 20 mg/mL of citric acid monohydrate, and sodium citrate dihydrate, preferably about 3 mg/mL to about 15 mg/mL, more preferably 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL or 12 mg/mL.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 5 mg/mL of xanthan gum; c) about 4 mg/mL of silicified microcrystalline cellulose; d) about 13 mg/mL of combination of microcrystalline cellulose and sodium carboxymethylcellulose; e) about 1 mg/mL of sodium benzoate; f) about 3.9 mg/mL of citric acid monohydrate; g) about 3.9 mg/mL of sodium citrate dihydrate; h) about 3 mg/mL of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of suspending agents selected from but not limited to xanthan gum, sorbitol, guar gum, carrageenan, tragacanth, alginate, carbomers, combination of microcrystalline cellulose and sodium carboxymethylcellulose alone or combinations thereof; c) about 0.05 % w/v to about 5 % w/v of preservative selected from but not limited to benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, methyl paraben, propyl paraben, butyl paraben alone or combinations thereof; d) about 0.1 % w/v to about 5 % w/v of buffering agents selected from but not limited to citric acid, sodium citrate, acetic acid, sodium acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate alone or combinations thereof; e) about 0.1 % w/v to about 5 % w/v of stabilizers selected from but not limited to silicon dioxide, povidone, sulfites, bisulfites, pyrosulfites, cysteines, methionines, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, alone or combinations thereof; f) about 0.1 % w/v to about 5 % w/v of co-solvents selected from but not limited to propylene glycol, benzyl alcohol, ethanol, isopropyl alcohol, polyethylene glycol, glycerin alone or combinations thereof; g) sweetening agent; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 5 % w/v of carrageenan; c) about 0.1 % w/v to about 5 % w/v of guar gum; d) about 0.05 % w/v to about 5 % w/v of methyl paraben and propyl paraben; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) about 0.1 % w/v to about 5 % w/v of silicon dioxide; i) about 0.1 % w/v to about 5 % w/v of propylene glycol; j) flavouring agent; and k) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 5 % w/v of carrageenan; c) about 0.1 % w/v to about 5 % w/v of guar gum; d) about 0.05 % w/v to about 5 % w/v of methyl paraben and propyl paraben; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) about 0.1 % w/v to about 5 % w/v of silicon dioxide; i) about 0.1 % w/v to about 5 % w/v of propylene glycol; j) flavouring agent; and k) optionally other pharmaceutically acceptable excipients; wherein said composition is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 1 mg/mL to about 15 mg/mL of carrageenan; c) about 1 mg/mL to about 10 mg/mL of guar gum; d) about 0.1 mg/mL to about 5 mg/mL of methyl paraben and propyl paraben; e) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate, and sodium citrate dihydrate; f) about 1 mg/mL to about 5 mg/mL of sucralose; g) about 1 mg/mL to about 5 mg/mL of sorbitol; h) about 1 mg/mL to about 10 mg/mL of silicon dioxide; i) about 1 mg/mL to about 10 mg/mL of propylene glycol; j) flavouring agent; and k) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides a stable pharmaceutical composition comprising zonisamide, wherein the amount of nitrosamine impurity after exposure of the pharmaceutical composition to 40°C/75% RH is less than the FDA acceptable limit based on maximum daily dose of zonisamide.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt used as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older.
In yet another aspect, the present invention relates to a method of treating partial-onset seizures in adults and pediatric patients 16 years of age and older by pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt.
In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older.

DESCRIPTION OF THE INVENTION:
The present invention can be more readily understood by reading the following description of the invention and study of the included examples.
The use of the word "a" or "an" when used in conjunction with the term "comprising" in the claims and/or the specification may mean "one," but it is also consistent with the meaning of "one or more," "at least one," and "one or more than one."
The term "about" as used herein means a deviation within 10%, more preferably within 5%, and even more preferably, within 2% of the numbers reported.
The term ‘‘stable’’ refers to formulations that substantially retain the labelled amount of the therapeutically active ingredient during storage for commercially relevant times, and the drug-related impurity contents in the formulations remain within acceptable limits.
“Bioequivalence” means the absence of a significant difference in the rate and extent to which the active agent or surrogate marker for the active agent in pharmaceutical equivalents or pharmaceutical alternatives becomes available at the site of action when administered in an appropriately designed study.
The term “impurity” refers to undesired contents present or produced in a pharmaceutical composition.
As used herein, the term “substantially free of any impurity” means total impurity present in the composition in an amount of less than or equal to 0.5% w/w.
The term “therapeutically effective amount” is defined to mean the amount or quantity of the active drug is sufficient to elicit an appreciable pharmacological response, when administered to the patient.
As used herein, the term "bioavailability" denotes the degree to which a drug or other substance becomes available to the target tissue after administration.
“Pharmaceutically acceptable excipient(s)” are components that are added to the pharmaceutical composition other than the active ingredient. Pharmaceutically acceptable excipient(s) includes, but not limited to, buffering agents, preservatives, suspending agents, anti-caking agents, sweetening agents, stabilizers, solvents, co-solvents, flavouring agents, colouring agents and any other excipient known to the art for making oral liquid pharmaceutical composition. The excipients that are useful in preparing a pharmaceutical composition are generally safe, inert, non-toxic and are acceptable for human use.
The "w/v" refers "weight by volume," and it is commonly used to describe the concentration of a substance in a liquid composition.
By the term “pharmaceutical composition” or “solid oral pharmaceutical composition" or "composition" or "formulation" as used herein refers to a solid dosage form comprising zonisamide suitable for administration such as a granule, hard or soft gelatin capsule, tablet, caplet, mini-tablets, pellets, pills, granules or powder for suspension, suspension and the like.
The term “active ingredient” or “active agent” or “drug” used interchangeably, is defined to mean active drug i.e. zonisamide and its salt, solvate, esters, isomers, polymorphs that induce a desired pharmacological or physiological effect.
The term “zonisamide” includes all pharmaceutically acceptable salts, esters, isomers, stereo isomers, crystalline and amorphous forms. Pharmaceutically acceptable salts of zonisamide include but not limited to oxalate, phosphate or acid phosphate, hydrochloride, hydrobromide, sulphate, mesylate, acetate, maleate, fumarate, lactate, tartrate, citrate, methanesulfonate, pamoate, palmitate, and gluconate salts.
The present invention provides a zonisamide or pharmaceutically acceptable salt thereof may be present in an amount of about 0.5 to about 10 % w/v, preferably about 1 to about 5 % w/v, more preferably about 1.5 to 2.5 % w/v of the composition. The present invention also provides a pharmaceutical composition comprising zonisamide in an amount of about 10 to 20 mg/mL, preferably about 20 mg/mL.
The present invention provides a zonisamide or pharmaceutically acceptable salt thereof having particle size distribution of Zonisamide of D10 in the range of 5 to 30 µm, D50 in the range of 15 to 60 µm and D90 in the range of 30 to 100 µm.
The present invention provides a pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
Another aspect of the invention, the pharmaceutical composition comprises zonisamide or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients selected from but not limited to buffering agents, preservatives, suspending agents, anti-caking agents, sweetening agents, stabilizers, solvents, co-solvents, flavouring agents, and colouring agents.
Another aspect of the present invention provides a pharmaceutical composition comprising zonisamide or a pharmaceutically acceptable salt thereof, and suspending agents, anti-caking agents, buffering agents, preservatives, sweetening agents, and flavouring agents.
Buffering agents according to the present invention are selected from, but not limited to, sodium bicarbonate, citric acid, maleic acid, phosphoric acid, sodium citrate, tartrate, acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate and the like used either alone or in combinations thereof. Buffering agent may be present in an amount of about 0.1 % w/v to about 5 % w/v, preferably about 0.2 % w/v to about 3% w/v of the composition, more preferably 0.3 % w/v, 0.4 % w/v, 0.5 % w/v, 0.6 % w/v, 0.7 % w/v, 0.8 % w/v, 0.9 % w/v, 1 % w/v, or 1.2 % w/v.
In some embodiments, the buffering agent is present to maintain a pH of about 3.5 to 5.5.
The term “preservative,” as used herein, refers to an agent or mixture of agents that is used to protect a composition against antimicrobial (e.g., yeast, mold, bacteria) activity. Preservatives include, but are not limited to, benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, sorbic acid, benzalkonium chloride, butyl paraben, methyl paraben, ethylparaben, propyl paraben, sodium propionate, and the like used either alone or in combinations thereof. Preservative may be present in an amount of about 0.05 % w/v to about 5 % w/v, preferably about 0.05 % w/v to about 3 % w/v of the composition.
The term “suspending agent or viscosity enhancer,” as used herein, refers to an agent or a mixture of agents that increases the thickness of a liquid thereby keeping the active ingredient suspended to allow accurate dosing. Suspending agent include, but are not limited to, xantham gum, guar gum, acacia, alginic acid, sodium alginate, alginate, carbomer, salts of carboxymethylcellulose, methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, bentonite, carrageenan, sucrose, sucralose, sorbitol, xylitol, dextrose, fructose, maltitol, gelatin, tragacanth, a polyvinyl alcohol, cetearyl alcohol, combination of microcrystalline cellulose and carboxymethylcellulose sodium/ Co-processed Microcrystalline cellulose & Sodium carboxymethylcellulose (Avicel CL 611, Avicel RC-591), and the like used either alone or in combinations thereof. Suspending agents may be present in an amount of about 0.1 % w/v to about 10 % w/v, preferably about 0.1 % w/v to about 5 % w/v of the composition.
Anti-caking agents according to the present invention are selected from, but not limited to silicified microcrystalline cellulose (PROSOLV® namely PROSOLV® SMCC 50 LD; PROSOLV® SMCC 50; PROSOLV® SMCC 90; PROSOLV® SMCC HD 90; PROSOLV® SMCC 90 LM, AVICEL® SMCC, COMPRECEL® SMCC), magnesium silicate, silicon dioxide alone or combinations thereof. Anti-caking agents may be present in an amount of about 0.1 % w/v to about 10 % w/v, preferably about 0.1 % w/v to about 5 % w/v of the composition.
Suitable sweetening agents include, but are not limited to, natural sweeteners such as sugars e.g. fructose, glucose, sucrose, sorbitol or mixtures thereof and artificial sweeteners such as sodium saccharine, sucralose, sodium cyclamate, aspartame and the like used either alone or in combinations thereof. Sweetening agents may be present in an amount of about 0.1 % w/v to about 5 % w/v, preferably about 0.1 % w/v to about 3 % w/v of the composition.
Stabilizers according to the present invention are selected from, but not limited to silicon dioxide, povidone, sulfites, bisulfites, pyrosulfites, cysteines, silicified microcrystalline cellulose, methionines, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, alone or combinations thereof. Stabilizers may be present in an amount of about 0.1 % w/v to about 5 % w/v, preferably about 0.1 % w/v to about 3 % w/v of the composition.
The term “flavoring agent,” as used herein, refers to an agent or a mixture of agents that adds flavor to a mixture. Flavoring agents include, but are not limited to, artificial strawberry flavor, banana flavor, vanilla, artificial cream flavor and the like used either alone or in combinations thereof.
Antioxidants are used to prevent oxidation, thereby preventing the deterioration of the preparation. Suitable antioxidants for use in the present invention include but not limited to propyl gallate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), and combinations thereof.
A ‘‘Solvent/vehicle’’ is a substance that dissolves a solute (a chemically distinct liquid, solid or gas), resulting in a suspension or solution. Examples include but not limited to purified water, alcoholic solvents methanol, ethanol; ketones such as acetone, propanone; esters such as ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate and the like; ethers such as dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, and dioxane.
Co-solvents according to the present invention are selected from, but not limited to Glycerin, dimethylsulfoxide, N-methylpyrrolidone, dimethyl acetamide (DMA), dimethylsulfoxide (DMSO), dimethyl formamide, glycerol formal, ethoxy diglycol, triethylene glycol dimethyl ether, triacetin, diacetin, corn oil, acetyl triethyl citrate (ATC), ethyl lactate, polyglycolated capryl glycerides, butyrolactone, dimethyl isosorbide, benzyl alcohol, ethanol, isopropyl alcohol, propylene glycol, polyethylene glycol, purified water.
In some embodiments, coloring agents may be used to introduce a uniformity of appearance to the product and/or to protect any light-sensitive ingredients. Suitable coloring agents include all pigments, dyes and lakes approved by the U.S. Food and Drug Administration (e.g., FD&C colorants), including but not limited to FD&C Yellow #6, FD&C Blue #1, FD&C Red #3, black iron oxide, red iron oxide, iron oxide yellow, tartrazine, erythrosine, amaranth lake, titanium dioxide, opadry systems, or any combination thereof.
In another aspect of the invention, an oral pharmaceutical composition comprising about 0.5 to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.
In yet another aspect, there is provided a pharmaceutical composition comprising a) about 0.5 to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 90 to about 99.5% w/v of pharmaceutically acceptable excipients; wherein, said pharmaceutical composition is in the form of suspension.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of suspending agents; c) about 0.1 % w/v to about 10 % w/v of anti-caking agent; d) about 0.05 % w/v to about 5 % w/v of preservative; e) about 0.1 % w/v to about 5 % w/v of buffering agents; f) about 0.1 % w/v to about 5 % w/v of sweetening agent; g) about 0.01 % w/v to about 1 % w/v of flavouring agent; and h) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of suspending agents selected from but not limited to xanthan gum, sorbitol, guar gum, carrageenan, tragacanth, alginate, carbomers, combination of microcrystalline cellulose and sodium carboxymethylcellulose alone or combinations thereof; c) about 0.1% w/v to about 10 % w/v of anti-caking agent selected from but not limited to silicified microcrystalline cellulose, magnesium silicate, silicon dioxide alone or combinations thereof; d) about 0.05 % w/v to about 5 % w/v of preservative selected from but not limited to benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, methyl paraben, propyl paraben, butyl paraben alone or combinations thereof; e) about 0.1 % w/v to about 5 % w/v of buffering agents selected from but not limited to citric acid, sodium citrate, acetic acid, sodium acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate alone or combinations thereof; f) sweetening agent; g) flavouring agent; and h) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of xanthan gum; c) about 0.1 % w/v to about 10 % w/v of silicified microcrystalline cellulose; d) about 0.05 % w/v to about 5 % w/v of sodium benzoate; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 5 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.35 % w/v to about 0.8 % w/v of xanthan gum; c) about 0.1% w/v to about 1 % w/v of silicified microcrystalline cellulose; d) about 1% w/v to about 2 % w/v of combination of sodium carboxymethylcellulose and microcrystalline cellulose; e) about 0.05 % w/v to about 1 % w/v of sodium benzoate; f) about 0.1 % w/v to about 1 % w/v of citric acid monohydrate; g) about 0.1 % w/v to about 1 % w/v of sodium citrate dihydrate; h) about 0.1 % w/v to about 1 % w/v of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients; wherein said dosage form is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.35 % w/v to about 0.8 % w/v of xanthan gum, preferably about 0.4 % w/v to about 0.6 % w/v, more preferably 0.4 % w/v, 0.45% w/v, 0.5 % w/v, 0.55% w/v, or 0.6 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.1% % w/v to about 1 % w/v of silicified microcrystalline cellulose, preferably about 0.2 % w/v to about 0.8 % w/v, more preferably 0.2 % w/v, 0.3 % w/v, 0.35% w/v, 0.4 % w/v, 0.45% w/v, 0.5% w/v, 0.55% w/v, 0.6 % w/v, or 0.7 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1% % w/v to about 2 % w/v of combination of sodium carboxymethylcellulose and microcrystalline cellulose, preferably about 1.2 % w/v to about 1.8 % w/v, more preferably 1.2 % w/v, 1.25 %w/v, 1.3 % w/v, 1.35 %w/v, 1.4 % w/v, 1.5 % w/v, 1.6 % w/v, or 1.7 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.05 % w/v to about 0.2 % w/v of sodium carboxymethylcellulose, preferably about 0.08 % w/v to about 0.18 % w/v, more preferably 0.10 % w/v, 0.12 % w/v, 0.14 % w/v, 0.16 % w/v, or 0.18 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1 % w/v to about 2% w/v of microcrystalline cellulose, preferably about 1.2 % w/v to about 1.8 % w/v, more preferably 1.4 % w/v, 1.5 % w/v, 1.55 % w/v. 1.6 % w/v, 1.65 % w/v, or 1.7 % w/v.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.1 % w/v to about 2 % w/v of citric acid monohydrate, and sodium citrate dihydrate, preferably about 0.3 % w/v to about 1.5 % w/v, more preferably 0.3 % w/v, 0.4 % w/v, 0.5 % w/v, 0.6 % w/v, 0.7 % w/v, 0.8 % w/v, 0.9 % w/v, 1 % w/v, or 1.2 % w/v.
In In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 2 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.5 % w/v of xanthan gum; c) about 0.4 % w/v of silicified microcrystalline cellulose; d) about 1.3 % w/v of combination of microcrystalline cellulose and sodium carboxymethylcellulose; e) about 0.1 % w/v of sodium benzoate; f) about 0.39 % w/v of citric acid monohydrate; g) about 0.39 % w/v of sodium citrate dihydrate; h) about 0.3 % w/v of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients.
In one of the further preferred embodiments, the pharmaceutical composition has a particle size distribution of Zonisamide of D10 not more than 30 µm, D50 not more than 60 µm and D90 not more than 100 µm.
In one of the further preferred embodiments, the pharmaceutical composition has a particle size distribution of Zonisamide of D90 ranges from about 30 to about 100 µm, preferably from about 40 to about 70 µm, more preferably about 45 µm, 55 µm, 60 µm, 63 µm, 65 µm, or 68 µm.
In one of the further preferred embodiments, the pharmaceutical composition of zonisamide has a particle size distribution of D90 ranges from about 30 to about 100 µm, preferably from about 40 to about 70 µm, more preferably about 45 µm, 55 µm, 60 µm, 63 µm, 65 µm, or 68 µm.

In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Zonisamide or pharmaceutically acceptable salts thereof which is substantially free of impurity i.e. total impurity present in the composition in an amount of less than or equal to 0.5 % w/w.
In yet another aspect, the present invention further relates to stable solid pharmaceutical composition of Zonisamide or pharmaceutically acceptable salts thereof contains not more than 0.5% w/w of Zonisamide related compound-A, Methyl Zonisamide, Any Unspecified degradation product.
In yet another aspect, the present invention further relates to stable pharmaceutical composition of zonisamide which is substantially free of nitrosamine impurity i.e. total nitrosamine impurity present in the composition in an amount of less than 1000 parts per billion (ppb), preferably less than 700 ppb, more preferably less than 400 ppb.
In yet another aspect, the present invention further relates to stable pharmaceutical composition of zonisamide contains less than 100 ppb of NDMA and NDEA impurities.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of xanthan gum; c) about 0.1 % w/v to about 10 % w/v of silicified microcrystalline cellulose; d) about 0.05 % w/v to about 5 % w/v of sodium benzoate; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients; wherein said composition is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of xanthan gum; c) about 1 % w/v to about 10 % w/v of combination of microcrystalline cellulose and sodium carboxymethylcellulose; d) about 0.05 % w/v to about 5 % w/v of sodium benzoate; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 1 mg/mL to about 10 mg/mL of xanthan gum; c) about 1 mg/mL to about 40 mg/mL of silicified microcrystalline cellulose; d) about 0.5 mg/mL to about 5 mg/mL of sodium benzoate; e) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate, and sodium citrate dihydrate; f) about 1 mg/mL to about 5 mg/mL of sucralose; g) about 1 mg/mL to about 5 mg/mL of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 1 mg/mL to about 10 mg/mL of xanthan gum; c) about 10 mg/mL to about 40 mg/mL of combination of microcrystalline cellulose and sodium carboxymethylcellulose; d) about 0.5 mg/mL to about 5 mg/mL of sodium benzoate; e) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate, and sodium citrate dihydrate; f) about 1 mg/mL to about 5 mg/mL of sucralose; g) about 1 mg/mL to about 5 mg/mL of sorbitol; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 5 mg/mL to about 50 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 3.5 mg/mL to about 8 mg/mL of xanthan gum; c) about 1 mg/mL to about 10 mg/mL of silicified microcrystalline cellulose; d) about 10 mg/mL to about 20 mg/mL of combination of sodium carboxymethylcellulose and microcrystalline cellulose; e) about 0.5 mg/mL to about 10 mg/mL of sodium benzoate; f) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate; g) about 1 mg/mL to about 10 mg/mL of sodium citrate dihydrate; h) about 1 mg/mL to about 10 mg/mL of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients; wherein said dosage form is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 3.5 mg/mL to about 8 mg/mL of xanthan gum, preferably about 4 mg/mL to about 6 mg/mL, more preferably 4 mg/mL, 4.5 mg/mL, 5 mg/mL, or 6 mg/mL .
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1 mg/mL to about 10 mg/mL of silicified microcrystalline cellulose, preferably about 2 mg/mL to about 8 mg/mL, more preferably 2 mg/mL, 3 mg/mL, 3.5 mg/mL, 4 mg/mL, 4.5 mg/mL, 5 mg/mL, 5.5 mg/mL, 6 mg/mL, or 7 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 10 mg/mL to about 20 mg/mL of combination of sodium carboxymethylcellulose and microcrystalline cellulose, preferably about 12 mg/mL to about 18 mg/mL, more preferably 12 mg/mL, 12.5 mg/mL, 13 mg/mL, 13.5 mg/mL, 14 mg/mL, 15 mg/mL, 16 mg/mL or 17 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 0.5 mg/mL to about 2 mg/mL of sodium carboxymethylcellulose, preferably about 0.8 mg/mL to about 1.8 mg/mL, more preferably 1 mg/mL, 1.2 mg/mL, 1.4 mg/mL, 1.6 mg/mL, or 1.8 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 10 mg/mL to about 20 mg/mL of microcrystalline cellulose, preferably about 12 mg/mL to about 18 mg/mL, more preferably 14 mg/mL, 14.5 mg/mL, 15 mg/mL, 15.5 mg/mL, 16 mg/mL, 16.5 mg/mL, or 17 mg/mL.
In yet another aspect of the present invention provides oral suspension of zonisamide comprising about 1 mg/mL to about 20 mg/mL of citric acid monohydrate, and sodium citrate dihydrate, preferably about 3 mg/mL to about 15 mg/mL, more preferably 3 mg/mL, 4 mg/mL, 5 mg/mL, 6 mg/mL, 7 mg/mL, 8 mg/mL, 9 mg/mL, 10 mg/mL, or 12 mg/mL.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 5 mg/mL of xanthan gum; c) about 4 mg/mL of silicified microcrystalline cellulose; d) about 13 mg/mL of combination of microcrystalline cellulose and sodium carboxymethylcellulose; e) about 1 mg/mL of sodium benzoate; f) about 3.9 mg/mL of citric acid monohydrate; g) about 3.9 mg/mL of sodium citrate dihydrate; h) about 3 mg/mL of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 10 % w/v of suspending agents selected from but not limited to xanthan gum, sorbitol, guar gum, carrageenan, tragacanth, alginate, carbomers, combination of microcrystalline cellulose and sodium carboxymethylcellulose alone or combinations thereof; c) about 0.05 % w/v to about 5 % w/v of preservative selected from but not limited to benzoic acid, sodium benzoate, ethylenediaminetetraacetic acid, methyl paraben, propyl paraben, butyl paraben alone or combinations thereof; d) about 0.1 % w/v to about 5 % w/v of buffering agents selected from but not limited to citric acid, sodium citrate, acetic acid, sodium acetate, carbonate, phosphate, metaphosphate, glycerophosphate, polyphosphate, pyrophosphate alone or combinations thereof; e) about 0.1 % w/v to about 5 % w/v of stabilizers selected from but not limited to silicon dioxide, povidone, sulfites, bisulfites, pyrosulfites, cysteines, methionines, polyethylene glycol, polyoxyethylene polyoxypropylene glycol, alone or combinations thereof; f) about 0.1 % w/v to about 5 % w/v of co-solvents selected from but not limited to propylene glycol, benzyl alcohol, ethanol, isopropyl alcohol, polyethylene glycol, glycerin alone or combinations thereof; g) sweetening agent; h) flavouring agent; and i) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 5 % w/v of carrageenan; c) about 0.1 % w/v to about 5 % w/v of guar gum; d) about 0.05 % w/v to about 5 % w/v of methyl paraben and propyl paraben; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) about 0.1 % w/v to about 5 % w/v of silicon dioxide; i) about 0.1 % w/v to about 5 % w/v of propylene glycol; j) flavouring agent; and k) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 0.5 % w/v to about 10 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.1 % w/v to about 5 % w/v of carrageenan; c) about 0.1 % w/v to about 5 % w/v of guar gum; d) about 0.05 % w/v to about 5 % w/v of methyl paraben and propyl paraben; e) about 0.1 % w/v to about 5 % w/v of citric acid monohydrate, and sodium citrate dihydrate; f) about 0.1 % w/v to about 5 % w/v of sucralose; g) about 0.1 % w/v to about 5 % w/v of sorbitol; h) about 0.1 % w/v to about 5 % w/v of silicon dioxide; i) about 0.1 % w/v to about 5 % w/v of propylene glycol; j) flavouring agent; and k) optionally other pharmaceutically acceptable excipients; wherein said composition is stable for at least 3 months of storage at 25° C. and 60% relative humidity (RH) or stable for at least 1 month of storage at 40° C. and 75% relative humidity (RH).
In yet another aspect of the present invention provides oral suspension dosage form comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 1 mg/mL to about 15 mg/mL of carrageenan; c) about 1 mg/mL to about 10 mg/mL of guar gum; d) about 0.1 mg/mL to about 5 mg/mL of methyl paraben and propyl paraben; e) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate, and sodium citrate dihydrate; f) about 1 mg/mL to about 5 mg/mL of sucralose; g) about 1 mg/mL to about 5 mg/mL of sorbitol; h) about 1 mg/mL to about 10 mg/mL of silicon dioxide; i) about 1 mg/mL to about 10 mg/mL of propylene glycol; j) flavouring agent; and k) optionally other pharmaceutically acceptable excipients.
In yet another aspect of the present invention provides zonisamide oral suspension characterization by tests such as description, identification, assay, dissolution, uniformity of dosage units (UOD), microbial enumeration test, residual solvents, degradation products, elemental impurities, pH, viscosity, sedimentation volume, wt./ml, nitrosamine impurities, re-dispersibility test, photo stability study, particle size distribution study, preservative efficacy test etc or any other tests known in the art for characterization of oral suspension product.
In yet another aspect, the present invention relates to the process for preparation of a suspension, wherein process comprises steps of: 1. Dissolving of sweetener, preservative in purified water under stirring to get clear solution; 2. Addition of suspending agent and anti-caking agent in step 1 under stirring and homogenise to get homogeneous gel mass; 3. Addition of zonisamide and flavor, in step 1 under continuous stirring; 4. Dissolving of buffering agent in purified water, to prepare buffer solution; 5. Addition of buffer solution in step 1 to maintain pH around 4.5 and allowing to final mixing for 30 minutes; 6. Making up final volume using purified water & filling in bottle.
In yet another aspect, the present invention relates to the process for preparation of a suspension, wherein process comprises steps of: 1. Dissolving of sweetener in purified water under stirring to get clear solution; 2. Addition of suspending agents in step 1 under stirring and homogenise to get homogeneous gel mass; 3. Dissolving of preservatives in co-solvent under stirring to get clear solution and addition into the step 1 & mix well; 4. Addition of Zonisamide, stabilizer and flavor, in step 1 under continuous stirring; 5. Dissolving of buffering agent in purified water, to prepare buffer solution; 6. Addition of buffer solution in step 1 to maintain pH around 4.5 and allowing to final mixing for 30 minutes; 7. Making up final volume using purified water & filling in bottle.
In yet another aspect, the present invention provides a pharmaceutical composition of zonisamide, which is bioequivalent to the marketed zonisamide product.
In yet another aspect, the present invention provides a process for preparation of a stable, reproducible and bioequivalent pharmaceutical composition of zonisamide.
In yet another aspect, the present invention relates to a pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt used as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older.
In yet another aspect, the present invention relates to a method of treating partial-onset seizures in adults and pediatric patients 16 years of age and older by pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt.
In yet another aspect, the present invention relates to a use of pharmaceutical composition comprising zonisamide or pharmaceutically acceptable salt as adjunctive therapy for the treatment of partial-onset seizures in adults and pediatric patients 16 years of age and older.
The composition of the invention can be packed into suitable packaging system e. g. bottles such as glass and plastic bottles with or without child resistant caps, etc.

EXAMPLES
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that the specific methods and results discussed are merely illustrative of the invention, and not to be construed as limiting the invention, as many variations thereof are possible without departing from the spirit and scope of the invention.

Example - 1: Zonisamide oral suspension
Sr. Ingredients mg/mL % w/v
1 Zonisamide 20 0.5-10
2 Xanthan gum 1-10 0.1-10
3 Silicified microcrystalline cellulose (SMCC) 1-40 0.1-10
4 Sorbitol 1-5 0.1-5
5 Sucralose 1-5 0.1-5
6 Sodium benzoate 0.5-5 0.05-5
7 Citric acid monohydrate 1-5 0.1-2
8 Sodium citrate dihydrate 1-5 0.1-2
9 Strawberry flavour 0.5-2 0.01-1
10 Purified water q. s. q. s.

Manufacturing process for example 1:
1. Dissolving of sorbitol, sucralose, and sodium benzoate in purified water under stirring to get clear solution.
2. Addition of xanthan gum and SMCC in step 1 under stirring and homogenized to get homogeneous gel mass.
3. Addition of zonisamide and strawberry flavor, in step 1 under continuous stirring.
4. Dissolving of sodium citrate dihydrate and citric acid monohydrate in purified water, to prepare buffer solution.
5. Addition of buffer solution in step 1 to maintain pH around 4.5 and allowing for final mixing for 30 minutes.
6. Making up the final volume by using purified water & filled in bottle.

Suspension obtained in example 1 was subjected for various testing and viscosity of the example 1 was not comparable with RLD product.

Example - 2: Zonisamide oral suspension
Sr. Ingredients mg/ mL % w/v
1 Zonisamide (D90: More than 200 µm) 20 2
2 Sodium benzoate 1 0.1
3 Sucralose 2 0.2
4 Sorbitol 2 0.2
5 Xanthan gum 5 0.5
6 Silicified microcrystalline cellulose 25 2.5
7 Citric acid monohydrate 0.80 0.08
8 Sodium citrate dihydrate 0.80 0.08
9 Strawberry flavour 0.10 0.01
10 Purified water q. s. to 1 mL q. s.

Manufacturing process for example 2: same as example 1.
Suspension obtained in example 2 was subjected for various testing and it was observed that complete dissolution of test product was not achieved which may be due to higher particle size of zonisamide and also viscosity of test product was found to be too low compared to reference listed drug (RLD) product.

Example - 3: Zonisamide oral suspension
S. No. Name of Ingredients Qty. (mg/mL) % w/v
1 Zonisamide (D90: Less than 40 µm) 20 2
2 Sodium Benzoate 1 0.1
3 Sucralose 2 0.2
4 Sorbitol 2 0.2
5 Xanthan Gum 5 0.5
6 Silicified Microcrystalline Cellulose 18 1.8
7 Citric acid monohydrate 0.40 0.04
8 Sodium citrate dihydrate 0.40 0.04
9 Strawberry Flavour 0.10 0.02
10 Purified Water q. s. to 1 mL q. s.

Manufacturing process for example 3: same as example 1.
Suspension obtained in example 3 was subjected for various testing and it was observed that complete dissolution of test product was achieved which may be due to reduction in particle size of zonisamide, however viscosity of test product was found to be too low compared to reference listed drug (RLD) product.

Example - 4: Zonisamide oral suspension
S. No. Name of Ingredients Qty. (mg/mL) % w/v
1 Zonisamide (D90: Less than 7 µm) 20 2
2 Sodium Benzoate 1 0.1
3 Sucralose 2 0.2
4 Xanthan Gum 5 0.5
5 Microcrystalline cellulose & Sodium carboxymethylcellulose 13 1.3
6 Silicified Microcrystalline Cellulose 8 0.8
7 Citric acid monohydrate 0.40 0.04
8 Sodium citrate dihydrate 0.40 0.04
9 Strawberry Flavour 0.10 0.02
10 Purified Water q. s. to 1 mL q. s.

Manufacturing process for example 4: same as example 1.
Suspension obtained in example 4 was subjected for various testing and it was observed that viscosity of test product was comparable with RLD product, however there was increase in dissolution rate of the test product due to reduction in particle size of zonisamide.

Example - 5: Zonisamide oral suspension
S. No. Name of Ingredients 5A
(mg/mL) 5B (mg/mL) 5C (mg/mL) % w/v
1 Zonisamide 20 20 20 2
2 Sodium Benzoate 0.9 1 1.1 0.09-0.11
3 Sucralose 2.8 3 3.2 0.28-0.32
4 Xanthan Gum 4.5 5 4.8 0.45-0.5
5 Microcrystalline cellulose & Sodium carboxymethylcellulose 12 13 14 1.2-1.4
6 Silicified microcrystalline cellulose 3.5 4 4.5 0.35-0.45
7 Citric acid monohydrate 3.5 3.90 4.1 0.35-0.41
8 Sodium citrate dihydrate 3.5 3.90 4.1 0.35-0.41
9 Strawberry Flavour 0.30 0.30 0.30 0.03
10 Purified Water q. s. to
1 mL q. s. to
1 mL q. s. to
1 mL q. s.

Manufacturing process for example 5:
1. Dissolving of sucralose, and sodium benzoate in purified water under stirring to get clear solution.
2. Addition of Microcrystalline cellulose & Sodium carboxymethylcellulose, xanthan gum, and Silicified microcrystalline cellulose in step 1 under stirring and homogenized to get homogeneous gel mass.
3. Addition of zonisamide and strawberry flavor, in step 1 under continuous stirring.
4. Dissolving of sodium citrate dihydrate and citric acid monohydrate in purified water, to prepare buffer solution.
5. Addition of buffer solution in step 1 to maintain pH around 4.5 and allowing for final mixing for 30 minutes.
6. Making up the final volume by using purified water & filled in bottle.

Zonisamide oral suspension obtained in example 5 was subjected to testing and results obtained as below @ 25º C & 60 RH:

Test Specification Test- Initial Test- 3M Test- 6M RLD- Zonisade-Initial
Description White to off white liquid suspension
having strawberry flavor Complies Complies Complies Complies
pH 3.5 - 5.5 4.3 4.2 4.3 4.41
Viscosity (cP) 800 ± 300
(Between 600 to 1200) 824 873 935 982
wt/mL (g/mL) Between 1.016 ± 0.15 1.002 1.002 1.005 1.011
Assay-API (%) 90 - 110 99.2 100.8 100.0 102.3
Organic impurities (w/w, By HPLC) i)Zonisamide Related compound-A NMT 0.2%
ii)Methyl Zonisamide-NMT 0.2% i) Not Detected
ii) Not Detected i) Not Detected
ii) Not Detected i) Not Detected
ii) Not Detected i) Not Detected
ii) Not Detected
Nitrosamine Impurities (NDMA) - Not Detected - - -
Assay-Preservative (%) 90 - 110 97.5 100.6 98.9 104.1
Time % Release % Release % Release % Release
Dissolution – Degassed Water, 900mL, Paddle, 60 RPM 30 min 85 93 95 86.3
Particle size distribution (By Malvern) D10: Not more than 30 µm 8 7 8 12.1
D50: Not more than 60 µm 29 26 28 30.2
D90: Not more than 120 µm 74 63 74 62.1

Based on above results, it was observed that viscosity and dissolution profile of test product was comparable with RLD product.

Although the inventions herein have been described with reference to particular embodiments, it is to be understood that these embodiments are merely illustrative of the principles and application of the present invention. It is therefore to be understood that numerous modifications may be made to the illustrative embodiments and that other arrangements may be devised without departing from the spirit and scope of the present invention as described.

All publications, patents, and patent applications cited in this application are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated herein by reference.
,CLAIMS:1. A pharmaceutical composition for oral suspension dosage form comprising a) about 5 mg/mL to about 50 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 3.5 mg/mL to about 8 mg/mL of xanthan gum; c) about 1 mg/mL to about 10 mg/mL of silicified microcrystalline cellulose; d) about 10 mg/mL to about 20 mg/mL of combination of sodium carboxymethylcellulose and microcrystalline cellulose; e) about 0.5 mg/mL to about 10 mg/mL of sodium benzoate; f) about 1 mg/mL to about 10 mg/mL of citric acid monohydrate; g) about 1 mg/mL to about 10 mg/mL of sodium citrate dihydrate; h) about 1 mg/mL to about 10 mg/mL of sucralose; i) flavouring agent; and j) optionally other pharmaceutically acceptable excipients.

2. The pharmaceutical composition as claimed in claim 1, wherein zonisamide is present in an amount of about 20 mg/mL.

3. The pharmaceutical composition as claimed in claim 1, wherein xanthan gum is present in an amount of about 5 mg/mL.

4. The pharmaceutical composition as claimed in claim 1, wherein combination of sodium carboxymethylcellulose and microcrystalline cellulose is present in an amount of about 17 mg/mL.

5. The pharmaceutical composition as claimed in claim 1, wherein microcrystalline cellulose is present in an amount of about 15 mg/mL.

6. The pharmaceutical composition as claimed in claim 1, wherein the oral suspension has a pH of 3.5 to 5.5, wherein the composition is stable for at least 6 months when stored at 25° C. and 40% relative humidity.

7. The pharmaceutical composition as claimed in claim 1, wherein the stable oral suspension dosage form present comprising a) about 0.5 % w/v to about 5 % w/v of zonisamide or pharmaceutically acceptable salt thereof; b) about 0.35 % w/v to about 0.8 % w/v of xanthan gum; c) about 0.1% w/v to about 1 % w/v of silicified microcrystalline cellulose; d) about 1% w/v to about 2 % w/v of combination of sodium carboxymethylcellulose and microcrystalline cellulose; e) about 0.05 % w/v to about 1 % w/v of sodium benzoate; f) about 0.1 % w/v to about 1 % w/v of citric acid monohydrate; g) about 0.1 % w/v to about 1 % w/v of sodium citrate dihydrate; h) about 0.1 % w/v to about 1 % w/v of sucralose; i) flavouring agent and j) optionally other pharmaceutically acceptable excipients; wherein stable pharmaceutical composition of zonisamide is substantially free of nitrosamine impurity.

8. The pharmaceutical composition as claimed in claim 1, wherein the oral suspension having particle size distribution of Zonisamide of D10 in the range of 5 to 30 µm, D50 in the range of 15 to 60 µm and D90 in the range of 30 to 120 µm.

9. A stable pharmaceutical composition of zonisamide comprising a) about 20 mg/mL of zonisamide or pharmaceutically acceptable salt thereof; b) about 5 mg/mL of xanthan gum; c) about 4 mg/mL of silicified microcrystalline cellulose; d) about 13 mg/mL of combination of microcrystalline cellulose and sodium carboxymethylcellulose; e) about 1 mg/mL of sodium benzoate; f) about 3.9 mg/mL of citric acid monohydrate; g) about 3.9 mg/mL of sodium citrate dihydrate; h) about 3 mg/mL of sucralose; and i) flavouring agent.

10. A stable pharmaceutical composition of zonisamide; wherein the composition is prepared by steps of 1. Dissolving of sucralose, and sodium benzoate in purified water under stirring to get clear solution, 2. Addition of Microcrystalline cellulose & Sodium carboxymethylcellulose, xanthan gum, and Silicified microcrystalline cellulose in step 1 under stirring and homogenized to get homogeneous gel mass, 3. Addition of zonisamide and strawberry flavor, in step 1 under continuous stirring, 4. Dissolving of sodium citrate dihydrate and citric acid monohydrate in purified water, to prepare buffer solution, 5. Addition of buffer solution and Making up the final volume.