DESC:FIELD OF THE INVENTION
The present invention relates to a pharmaceutical composition of Chlorzoxazone or salt thereof, its process of preparation and method of use of said pharmaceutical composition.

More particularly, the present invention relates to a novel low dose pharmaceutical composition of Chlorzoxazone or salt thereof, its process of preparation and method of use of said pharmaceutical composition.

BACKGROUND OF THE INVENTION
Drugs that are totally water-insoluble, or are at least poorly water-soluble can pose significant challenges in formulation development. This can limit its bioavailability, therapeutic effectiveness, and overall performance in the body.

Some common drawbacks associated with poorly water-soluble drugs and drugs having formulation difficulties, are that they present limited bioavailability, inconsistent drug release, reduced stability, formulation complexities or the like.

Chlorzoxazone is a centrally acting muscle relaxant used to treat muscle spasm and the resulting pain or discomfort. Chemically, Chlorzoxazone is 5-Chloro-2-benzoxazolinone and its molecular weight is 169.57. Its empirical formula is C7H4ClNO2. Chlorzoxazone is represented by compound of structural formula I.

Formula I
Chlorzoxazone is a white or practically white, practically odorless, crystalline powder. Chlorzoxazone is slightly soluble in water; sparingly soluble in alcohol, in isopropyl alcohol, and in methanol; soluble in solutions of alkali hydroxides and ammonia.
Chlorzoxazone tablet was first approved by U.S. FDA on Prior to Jan 1, 1982 under the brand name PARAFLEX for Ortho Mcneil Pharmaceutical Inc. It is available in 250 mg strength. The product is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions.

Chlorzoxazone tablet 500 mg was first approved by U.S. FDA on Jun 15, 1987 under the brand name PARAFON FORTE DSC for Janssen Research and Development LLC. The product is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions.

Chlorzoxazone tablet 375 mg and 750 mg are approved by U.S. FDA for Mikart LLC. The product is indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute, painful musculoskeletal conditions.

Currently, the commercially available product and product known in the prior art for Chlorzoxazone are available in the form of Tablet, said products suffers from adverse effects such as repeated administration of dosage form, further its limited bioavailability often necessitates high doses, resulting in potential side effects and increased cost.

Therefore, there is an unmet need in the art to provide a novel supra bioavailable low dose formulation of a Chlorzoxazone or salt thereof that can provide improved bioavailability, allowing for lower dosage, minimizes the adverse effect, enhanced therapeutic efficacy, potential reduction in side effects, cost-effective treatment option and patient compliance in the treatment of muscle spasm.

OBJECTS OF THE INVENTION
Accordingly, it is an object of the present invention to provide low dose composition of Chlorzoxazone or salt thereof.

It is another object of the present invention to provide supra bioavailable composition of Chlorzoxazone or salt thereof.

It is another object of the present invention to provide supra bioavailable low dose composition of Chlorzoxazone or salt thereof, wherein the composition contains at least 5% dose reduction when compared with reference tablet strength [375mg, 500mg & 750mg].

It is another object of the present invention to provide supra bioavailable low dose composition of Chlorzoxazone or salt thereof which provides less adverse effects.

It is another object of the present invention to provide supra bioavailable low dose composition of Chlorzoxazone or salt thereof in the treatment of muscle spasm.

It is yet another object of the present invention to provide a method for treating muscle spasm involving administration of supra bioavailable low dose composition of Chlorzoxazone or salt thereof.

It is another object of the present invention to provide supra bioavailable low dose composition of Chlorzoxazone or salt thereof which provides better therapeutic efficacy and patient compliance in the treatment of muscle spasm.

SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a pharmaceutical composition of Chlorzoxazone or salt thereof.

In one aspect, the present invention relates to a novel supra bioavailable low dose pharmaceutical composition of Chlorzoxazone or salt thereof

In another aspect, there is provided a novel supra bioavailable low dose pharmaceutical composition, comprising:
a) Chlorzoxazone or salt thereof; and
b) One or more suitable pharmaceutically acceptable excipient.

In another aspect, there is provided a novel supra bioavailable low dose pharmaceutical composition, comprising:
a) Chlorzoxazone or salt thereof;
b) One or more other Active Pharmaceutical Ingredient(s); and
c) One or more suitable pharmaceutically acceptable excipient.

In another aspect, the present invention also relates to a process of preparation of a novel supra bioavailable low dose pharmaceutical composition, comprising:
a) Chlorzoxazone or salt thereof; and
b) One or more suitable pharmaceutically acceptable excipient.

In another aspect, the present invention particularly relates to a novel supra bioavailable low dose pharmaceutical composition comprising Chlorzoxazone or salt thereof and its process of preparation and its use for the treatment of muscle spasm.

DETAIL DESCRIPTION OF THE INVENTION
The term "composition" or "pharmaceutical composition" or "supra bioavailable low dose pharmaceutical composition" as used herein synonymously include dosage forms such as a tablet, capsule, powder, granules, pellets, caplets, pills, soft gelatin capsules, mini tablets, solution, syrup, suspension, emulsion, elixir, solution concentrate or the like.

The term “composition”, as in "supra bioavailable low dose pharmaceutical composition", is intended to encompass a drug product(s) comprising Chlorzoxazone or salts thereof and other inert ingredient(s) (pharmaceutically acceptable excipients).

The present invention relates to a novel supra bioavailable low dose pharmaceutical composition comprising Chlorzoxazone or salt thereof, for oral administration and at least one pharmaceutically acceptable excipient.

The term “Chlorzoxazone” is used in broad sense to include not only “Chlorzoxazone” per se but also its pharmaceutically acceptable salts, solvates, hydrates, enantiomers, derivatives, isomers, polymorphs, prodrugs thereof.

The term “Pharmaceutically acceptable salts” or “salt thereof” as used herein, includes those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, which are well known in the art.

Pharmaceutically acceptable salts include, but are not limited to, any of the salts or cocrystals of Chlorzoxazone selected from citrate, hydrochloride, hydrobromide, sulphate, phosphate, maleate, formate, acetate, nitrate, mesylate, succinate, benzoate or the like.

The term supra-bioavailability according to present invention means product displays an extent of absorption appreciably larger than the approved product, of Chlorzoxazone.

The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

A novel supra bioavailable low dose pharmaceutical composition comprising Chlorzoxazone or salt thereof, according to the present invention requires lower dose when compared with approved marketed product.

In one embodiment, the present invention provides a pharmaceutical composition of Chlorzoxazone or salt thereof.

In one embodiment, the present invention provides a novel supra bioavailable low dose pharmaceutical composition comprising:
a) Chlorzoxazone or salt thereof; and
b) One or more suitable pharmaceutically acceptable excipient.

In one embodiment, the present invention provides a novel supra bioavailable low dose pharmaceutical composition comprising:
a) Chlorzoxazone or salt thereof;
b) One or more other Active Pharmaceutical Ingredient(s); and
c) One or more suitable pharmaceutically acceptable excipient.

In one embodiment, the present invention provides a process of preparation of a novel supra bioavailable low dose pharmaceutical composition comprising:
a) Chlorzoxazone or salt thereof; and
b) One or more suitable pharmaceutically acceptable excipient.

In another embodiment, the present invention also relates to a process of preparation of a novel supra bioavailable low dose pharmaceutical composition comprising:
a) Chlorzoxazone or salt thereof; and
b) One or more suitable pharmaceutically acceptable excipient.

In another embodiment, the one or more other Active Pharmaceutical Ingredient(s) from the group consisting of nonsteroidal anti-inflammatory drug (NSAID), analgesic, antipyretic, muscle relaxants, antispasmodic, sedatives, Gabapentinoids, antacids or the like.

In another embodiment, the pharmaceutically acceptable excipients are selected from the group consisting of diluents or filler, disintegrants, binders, solubilizing agent, surfactant, absorption enhancer, superdisintegrants, lipidic excipient, oily vehicle, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent and any other excipient known to the art for making low dose supra bioavailable pharmaceutical composition or pharmaceutical composition.

The concentrations of Chlorzoxazone or salt thereof, excipients and the manufacturing process has been optimized in such way that it provides Supra bioavailable composition of Chlorzoxazone or salt thereof; when compared with tablet strength [375mg, 500mg & 750mg] of Chlorzoxazone. Therefore, due to Supra bioavailability, it provides at least 5% reduction of Chlorzoxazone dose when compared with reference tablet strength [375mg, 500mg & 750mg] of Chlorzoxazone.

The Supra bioavailable composition may comprise any suitable amount of the Chlorzoxazone or salt thereof in order to produce an effective blood level of the Chlorzoxazone in the treatment of muscle spasm. The weight percentage of Chlorzoxazone or salt thereof can be 20 % to 90 %, preferably 25 % to 85 % based on the total weight of composition. The amount of Chlorzoxazone or salt thereof according to the present invention may ranges from 1mg to 1000mg, 10mg to 800mg, 50mg to 700mg. Further, the amount of Chlorzoxazone or salt thereof may be lesser than the reference tablet strength [375mg, 500mg & 750mg] of Chlorzoxazone.

The examples of diluent or filler according to present invention include but not limited to group comprising of citric acid, mannitol, carboxymethyl cellulose (carmellose), calcium hydrogen phosphate, sodium carboxymethyl cellulose (carmellose sodium), hydroxypropyl cellulose, corn starch, potato starch, microcrystalline cellulose, anhydrous lactose, lactose monohydrate and the mixtures thereof.

The diluents according to present invention may be present in an amount from about 5% to about 85% by weight with respect to total weight of the pharmaceutical composition.

The examples of disintegrants according to present invention include but not limited to group comprising of croscarmellose sodium, croscarmellose potassium, carboxymethyl cellulose, chitosan, carboxymethyl cellulose calcium, carboxymethyl cellulose sodium, crospovidone, hydroxypropyl cellulose, methyl cellulose, starch, sodium starch glycolate, light anhydrous silicic acid, low substituted hydroxypropylcellulose, lactose, sucrose, starch, silicified microcrystalline cellulose, polarcilin potassium, crosslinked polyvinylpyrrolidone, ethyl hydroxyethyl cellulose, modified cellulose gum; moderately cross-linked starch, modified starch, hydroxylpropyl starch and pregelatinized starch; calcium alginate, sodium alginate, alginic acid, chitosan, colloidal silicon dioxide, docusate sodium, guar gum, agar, locust bean, karaya, pectin and tragacanth, magnesium aluminium silicate, polyvinylpyrrolidone or mixture thereof.

The disintegrants according to present invention may be present in an amount from about 1%-15% by weight with respect to total weight of the pharmaceutical composition.

The examples of binders according to present invention include but not limited to group comprising of microcrystalline cellulose, alginic acid, potato starch, corn starch, wheat starch, ethyl cellulose, gelatin, cellulose-based polymers like methylcellulose, ethylcellulose, hydroxylated derivatives, hydroxyethyl cellulose, carboxymethyl cellulose sodium, hydroxymethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, dihydroxy propylcellulose, hypromellose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetosuccinate, acrylic polymers and polyethylene glycols, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, copovidone, sodium starch glycolate, starch, trehalose, flurane, sucrose, D-mannitol, sodium alginate, cellulose gum, pregelatinized starch, guar gum, pullulan, gum arabic, bentonites, sugars, invert sugars, polyvinyl pyrrolidone, polyacrylamides, polyvinyloxoazolidone, polyvinyl alcohols, or mixture thereof.

The examples of solubilizing agents or solubility enhancer according to present invention include but not limited to group comprising of cyclodextrin and/or its derivatives, 2-Hydroxypropyl-beta-cyclodextrin (Kleptose), polyethylene glycol, polyvinylpyrrolidone, poloxamer, propylene oxide, ethylene oxide, dextran, sugars such as sucrose, lactose or dextrose, mannitol, sorbitol or lactitol, sodium chloride or mixture thereof.

The solubilizing agents or solubility enhancers according to the present invention may be present in an amount from about 1%-40% by weight with respect to total weight of the pharmaceutical composition.

The examples of surfactants according to the present invention include but not limited to group comprising of cationic, anionic, nonionic or amphoteric agents, polysorbate, the monooleate, the monolaurate, the monopalmitate, the monostearate, the trioleate, the tristearate or any other ester of polyoxyethylenated sorbitan, glycerides of polyoxyethylenated fatty acids, poloxamers, ethylene oxide/propylene oxide block copolymers, lecithin, stearyl alcohol, cetearyl alcohol, cholesterol, cetyl alcohol, spans and tweens, ethoxylated oils, including ethoxylated castor oils, such as cremophor or mixture thereof.

The examples of absorption enhancer according to the present invention include but not limited to group comprising of sodium lauryl sulphate, sodium caprate or chitosans, and also P-glycoprotein (P-gp) inhibitors, such as polysorbates, sorbitan esters, poloxamer block copolymers, PEG-35 castor oil, PEG-40 hydrogenated castor oil, ethoxydiglycol, propylene glycol mono-di-caprylate, glycerol monocaprylate, glyceryl fatty acids (C8-C18) ethoxylated, glyceryl monooleate, d-alpha tocopheryl polyethylene glycol 1000 succinate, polycarbonate, sodium glycocholate, sodium taurocholate, triacetin, combinations thereof or the like.

The examples of super-disintegrant according to present invention include but not limited to group comprising of gellan gum, locust bean gum, guar gum, mango peel pectin, croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, combinations thereof or the like.

The examples of lipidic excipient according to the present invention include but not limited to group comprising of glycerol macrogolglycerides, Lauroyl macrogolglycerides (Gelucire), Caprylocaproyl Polyoxyl-8 glycerides (Labrasol), polyethylene glycol derivatives, or mixtures thereof.

The examples of oily excipient according to the present invention include but not limited to group comprising of vegetable oils (Soyabean oil, Peanut oil, and olive oil), medium chain triglycerides, fatty acids and their esters, fatty alcohols, amphiphilic oil, glycerol oleate derivative or mixtures thereof.

The examples of bioadhesive agents or mucoadhesion promoting agents according to the present invention include but not limited to group comprising of carbomers, sodium, hydroxypropylcellulose, carbopol 934 P, methocel, polycarbophil, sodium hyaluronate and other natural or synthetic bioadhesives, cellulose derivatives such as modified cellulose gum and, more particularly, methyl cellulose, ethyl hydroxyethyl cellulose, carboxymethyl cellulose, starch derivatives such as modified starch, sodium starch glycolate and, more particularly, moderately cross-linked starch; acrylic polymers, polyvinylpyrrolidone; polyethylene oxide (PEO), chitosan (poly-(D-glucosamine); natural polymers such as poly co-(methylvinyl ether/maleic anhydride); and crosscarmellose (e.g. crosscarmellose sodium) or mixture thereof.

The examples of polymers or release modifying agent include but not limited to cellulosic polymers, such as hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), hydroxyethylcellulose (HEC), methylcellulose (MC), powdered cellulose such as microcrystalline cellulose, cellulose acetate, sodium carboxymethylcellulose, calcium salt of carboxymethylcellulose, ethylcellulose; alginates, gums such as guar and xanthan gums; cross-linked polyacrylic acid derivatives such as Carbomers available in various molecular weight grades; carageenan; polyvinyl pyrrolidone and its derivatives such as crospovidone; poloxamer, polyethylene oxides; and polyvinyl alcohol, polyethylene glycol, glyceryl monostearate, polyvinyl pyrrolidone, mixtures of glyceryl monostearate, a mixture of mono, di and tri-glycerides, glycerylmonolaurate, glyceryl behenate, paraffin, white wax. Suitable pH-sensitive enteric polymers include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, ethylhydroxycellulose phthalate, styrene-maleic monoester copolymer, methyl acrylate-methacrylic acid copolymer, methacrylate-methacrylic acid-octyl acrylate copolymer or mixture thereof.

The examples of carriers according to the present invention include but not limited to group comprising of mannitol, carbohydrates, e.g., sugars, such as lactose, dextrose solution, propylene glycol, polyethylene glycols, miglyol or mixtures thereof.

The examples of plasticizers according to the present invention include but not limited to group comprising of polyalkylene oxides, such as polyethylene glycols, polypropylene glycols, polyethylene-propylene glycols, organic plasticizers with low molecular weights, such as glycerol, glycerol monoacetate, diacetate or triacetate, triacetin, polysorbate, cetyl alcohol, propylene glycol, sorbitol, sodium diethylsulfosuccinate, triethyl citrate, polyvinyl alcohol, polyvinyl methyl ether, triacetin; mannitol, xylitol, and sorbitol or mixtures thereof.

The examples of penetration enhancers according to the present invention include but not limited to group comprising of bile salts, such as sodium cholate, sodium glycocholate, 1-N-dodecyl-2-pyrrolidone-5-carboxylic acid, 2-pentyl-2-oxo-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 2-dodecyl-2-oxo-1-pyrrolidineacetic acid, 1-azacylioheptan-2-one-dodecylacetic acid, menthol, propylene glycol, glycerol monostearate, sorbitol monolaurate, glycerol dilaurate, tocopherol acetate, phosphatidyl choline, glycerol, polyethyleneglycol, monoglycerides, diglycerides, triglycerides, lecithin, tween surfactants, sorbitan surfactants, sodium lauryl sulfate; salts and other derivatives of saturated and unsaturated fatty acids, surfactants, such as cyclodextrins and caged molecules; coloring agents; and flavors, cyclodextrin derivatives like hydroxypropyl, hydroxyethyl, glucosyl, maltosyl, ß-cyclodextrin derivatives or mixtures thereof.

The examples of bases according to the present invention include but not limited to group comprising of hydrophilic bases include, for example, polyethylene glycol, polyvinylpyrrolidone, dextran, glucose, polyoxyethylene, castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan higher fatty acid ester, citric acid, tartaric acid, glycine, ß-alanine, lysine hydrochloride and meglumine or mixture thereof.

The examples of lubricant according to the present invention include but not limited to group comprising of calcium stearate, magnesium stearate, Sodium stearyl fumarate, fumaric acid, calcium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, colloidal silica, sucrose fatty acid esters, stearic acid, zinc stearate, hydrogenated vegetable oil, mineral oil, glyceryl behenate, polyoxyethylene glycols, sodium benzoate, dimethicone or liquid paraffin, or mixture thereof.

The lubricant according to the present invention may be present in an amount from about 0.1% to about 10% by weight with respect to total weight of the pharmaceutical composition, preferably 0.1-5% w/w.

The examples of glidant according to the present invention include but not limited to group comprising of colloidal silica, pyrogenic silica, hydrated sodium silicoaluminate, magnesium stearate, sodium stearyl fumarate, fumed silica (colloidal silicon dioxide), starch, talc, calcium phosphate tribasic, powdered cellulose, magnesium oxide; magnesium silicate, magnesium trisilicate, stearic acid, calcium stearate or mixture thereof.

The examples of basic agents according to the present invention include but not limited to group comprising of sodium perborate monohydrate, sodium percarbonate, sodium dichloroisocyanurate, sodium hypochlorite, calcium hypochlorite, tris, tartrate, acetate, phosphate or mixture thereof.

The examples of chelators according to the present invention include but not limited to group comprising of ethylene diamine tetra acetic acid (EDTA), proteins, polysaccharides, polynucleic acids, glutamic acid, histidine, organic diacids, polypeptides, phytochelatin, hemoglobin, chlorophyll, humic acid, phosphonates, transferrin, desferrioxamine, and combinations thereof.

The examples of sweeteners according to the present invention include but not limited to group comprising of dipotassium glycyrrhizinate, aspartame, stevia, thaumatin, saccharose, glucose, fructose, Stevia Rebaudiana (Stevioside); sugar alcohols such as sorbitol, mannitol, xylitol, and the like. Also contemplated are hydrogenated starch hydrolysates and the synthetic sweetener Acesulfame, particularly the potassium salt (acesulfame-K), and sodium and calcium salts thereof, and natural intensive sweeteners, or mixture thereof.

The examples of flavoring agent according to the present invention include but not limited to group comprising of fruit flavor, peppermint flavor, lemon, lemon-lime, orange, sour cherry, flavor of mint, oleoresins or extracts derived from plants, leaves, flowers, fruits, stems and combinations thereof. mint oils, cocoa, and citrus oils such as lemon, orange, grape, grapefruit and fruit essences including apple, pear, peach, strawberry, raspberry, plum, pineapple, apricot or other fruit flavors or mixture thereof.

The examples of pH regulating agent according to the present invention include but not limited to group comprising of sodium bicarbonate or potassium bicarbonate, sodium phosphate, tartaric acid, propionic acid, lactic acid, maleic acid, succinic acid, phosphoric acid, boric acid, succinic acid/monosodium succinate, monosodium phosphate/disodium phosphate, and boric acid/sodium borate and monosodium glutamate or mixture thereof.

The examples of the preservatives according to the present invention include but not limited to group comprising of phenethyl alcohol, benzyl alcohol, p-hydroxybenzoate esters, chlorobutanol, dehydroacetic acid, sorbic acid or mixtures thereof.

The examples of the antioxidants according to the present invention include but not limited to group comprising of butylated hydroxytoluene (BHT), hydrogen sulfite, ascorbic acid, sodium ascorbate, erythorbic acid, sodium nitrite, propyl gallate (PG), butylhydroxyanisol (BHA), sodium metabisulfate, sodium tartrate, buthionine-sulphones, and penta-, hexa- and heptathionine-sulphoximine), metal chelators (e.g, .alpha.-hydroxy-fatty acids, palmitic acid, phytic acid, lactoferrin, lactic acid, and malic acid, humic acid, bile acid, bile extracts, bilirubin, biliverdin, EDTA, EGTA, and DTPA), vitamins (e.g., vitamin E, vitamin C, ascorbyl palmitate, benzoates (e.g. coniferyl benzoate), uric acid, mannose, selenium (e.g., selenium-methionine), stilbenes (e.g. stilbene oxide and trans-stilbene oxide), superoxide dismutase (SOD) or mixtures thereof.

The examples of the coloring agents according to the present invention include but not limited to group comprising of carmine, caramel, ß-carotene, titanium oxide, talc, riboflavin sodium phosphate, hydrogenated starch hydrolysate, food, drug and cosmetic colors (FD&C), drug and cosmetic colors (D&C), or external drug and cosmetic colors (Ext. D&C). These colors are dyes, their corresponding lakes, and certain natural and derived colorants, yellow aluminum lake natural pigments (examples: beta-carotene, chlorophyll, and colcothar), water-insoluble lake pigments (examples: aluminum salts of the above water-soluble edible tar pigments), water-soluble edible tar pigments (examples: edible pigments such as food red No. 2, food red No. 3, food yellow No: 4, food yellow No. 5, food blue No. 1, and food blue No. 2), blue lake, titanium dioxide, natural coloring agents such as grape skin extract, beet red powder, annato, carmine, turmeric, paprika or mixtures thereof.

The examples of solvents according to the present invention include but not limited to group comprising of aqueous or inert organic solvents or inorganic acids, alcohols, ketones, esters, ethers, aliphatic hydrocarbons, halogenated solvents, cycloaliphatic solvents, aromatic solvents, heterocyclic solvents, and mixtures thereof. Typical solvents include acetone, diacetone alcohol, methanol, ethanol, isopropyl alcohol, water, hydrochloric acid (HCl), aqueous solvents containing inorganic salts (such as sodium chloride, calcium chloride, and the like), and mixtures thereof (such as acetone and water, acetone and methanol, acetone and ethyl alcohol, methylene dichloride and methanol, and ethylene dichloride and methanol) or mixture thereof.

The examples of taste masking agent according to the present invention include but not limited to group comprising of ionic exchange resins including a water-insoluble organic or inorganic matrix material having covalently bound functional groups that are ionic or capable of being ionized under appropriate conditions. The organic matrix may be synthetic (e.g., polymers or copolymers or acrylic acid, methacrylic acid, sulfonated styrene or sulfonated divinylbenzene) or partially synthetic (e.g., modified cellulose or dextrans). The inorganic matrix may be, for example, silica gel modified by the addition of ionic groups. Most ion exchange resins are cross-linked by a crosslinking agent, such as divinylbenzene, sodium bicarbonate, cyclodextrin inclusion compounds, adsorbates or mixture thereof.

The examples of anti-foaming agents according to the present invention include but not limited to group comprising of certain alcohols (cetostearyl alcohol), insoluble oils (castor oil), stearates, polydimethylsiloxanes and other silicones derivatives, ether and glycols or mixture thereof.

The examples of flow agents and opacifiers according to the present invention include but not limited to group comprising of such as the oxides of magnesium, aluminum, silicon, titanium or mixture thereof.

The examples of antiadherent according to the present invention include but not limited to group comprising of talc, corn starch, colloidal silica, DL-leucine, sodium lauryl sulphate, stearates or mixture thereof.

The examples of stabilizing agent according to the present invention include but not limited to group comprising of tocopherol, cyclodextrin tetrasodium edetate, nicotinamide, thermo-setting gels such as pectin, carageenan, and gelatin, yellow ferric oxide, red ferric oxide, black iron oxide or mixture thereof.

The examples of antistatic agents according to the present invention include but not limited to group comprising of micronized or nonmicronized talc, colloidal silica, treated silica or precipitated silica or mixtures thereof.

The examples of viscosity adjusters according to the present invention include but not limited to group comprising of alginate, carrageenan, hydroxypropyl methyl cellulose, locust bean gum, guar gum, xanthan gum, dextran, gum arabic, gellan gum or mixtures thereof.

The examples of coating agents according to the present invention include but not limited to a film coating agent or the like. for example, an opadry film coating agents or film coating agent known in the prior art for pharmaceutical dosage form.

In another aspect, the present invention provides a process of manufacturing supra bioavailable composition of Chlorzoxazone or salt thereof along with one or more pharmaceutically acceptable excipients.

The Suprabioavailable composition of Chlorzoxazone or salt thereof along with one or more pharmaceutically acceptable excipients may be manufactured by the techniques known in the art for capsule, i.e., hard and soft gelatin capsule, tablet, concentrated solutions, granules, beads, sachet, gel cap, lozenge, pastille, pill and powder.

The Supra bioavailable composition of Chlorzoxazone or salt thereof along with one or more pharmaceutically acceptable excipients may be manufactured by process such as direct compression, dry granulation, wet granulation, roller compaction, hot melt extrusion, encapsulation, hand (manually) filling, machine filling, plate process, rotary die process and reciprocating die process.

The Supra bioavailable composition of Chlorzoxazone or salt thereof according to the present invention is preferably manufactured by a process which involves dispersion of the Chlorzoxazone with one or more solubilizing agent. Further, addition of one or more pharmaceutically acceptable excipients to form a homogenous mixture. The said homogenous mixture were converted into the suitable dosage form like capsule, i.e., hard and soft gelatin capsule, tablet, concentrated solution, granules, beads, sachet, gelcap, lozenge, pastille, pill and powder.

The primary mechanism of action by which a solid dispersion according to present invention leads to improved bioavailability is usually avoidance of the slow dissolution process. The drug for absorption can be enhanced by formulation of the drug in solid dispersion which in turn enhanced oral bioavailability enabling reduction in dose and more consistent temporal profiles of drug absorption.

The Supra bioavailable low dose composition of Chlorzoxazone or salt thereof according to the present invention provides improved bioavailability, allowing for lower dosage, minimizes the adverse effect, enhanced therapeutic efficacy, potential reduction in side effects, cost-effective treatment option and patient compliance in the treatment of muscle spasm.

The novel supra bioavailable low dose pharmaceutical composition of Chlorzoxazone or salt thereof according to the present invention may be packaged into the suitable container like bottles (glass and plastic), blister, strip, pouch or sachet, air tight, tamper resistant, light resistant containers and moisture proof packs and optionally oxygen busters or any packaging material suitable.

EXAMPLES:
The following Examples are provided solely for illustrative purposes and are not meant to limit the invention in any way.

Example 1:
Strengths 250 mg 333.33 mg 500 mg % w/w
No. Ingredients mg/tablets mg/tablets mg/tablets
Drug- dispersion
1. Chlorzoxazone 250.00 333.33 500.00 53.19
2. Polyethylene glycol 100.00 133.33 200.00 21.28
3. Polyvinylpyrrolidone 27.00 36.00 54.00 5.74
Intra-granulation
4. Microcrystalline cellulose 50.00 66.67 100.00 10.64
5. Pregelatinized starch 25.00 33.33 50.00 5.32
6. Sodium starch glycolate 8.00 10.67 16.00 1.70
7. Docusate sodium 5.00 6.67 10.00 1.06
Lubrication
8. Magnesium stearate 5.00 6.67 10.00 1.06
Total weight 470.00 626.67 940.00 100.00

Manufacturing Process:
1. Polyethylene glycol and dispersed Chlorzoxazone added into Polyvinylpyrrolidone and stir to get the homogeneous suspension.
2. Dry the drug dispersed material of step -1 up to 2- 3 hours at 50-700C.
3. Milled the dried material of step -2 through 0.8 mm after sifting through ASTM #40.
4. Intra-granular materials sift through through ASTM #40.
5. Sifted material of Step-3 and step-4 mixed in RMG for 10 minutes.
6. Sift Magnesium stearate through ASTM #60 and lubricated for 5 minutes.
7. Compressed the tablets by using compression machine.
8. Packed the finished product in suitable container or packing material.
Dissolution/Release Profile (Example 1):

Dissolution condition Medium: pH 6.8 phosphate buffer
Appts: Type II (Paddle)
RPM: 75
Volume: 1800 ml
Strengths 250mg 333.33mg 500mg
Time (Minutes) % Release of Chlorzoxazone

0 0 0 0
10 57 49 60
15 88 86 84
30 97 94 98
45 99 99 99
60 101 99 99
90 100 99 101

Example 2:
Strengths 250 mg 333.33 mg 500 mg % w/w
No. Ingredients mg/tablets mg/tablets mg/tablets
Drug- dispersion
1. Chlorzoxazone 250.00 333.33 500.00 53.19
2. Polyethylene glycol 50.00 66.67 100.00 10.64
3. Polyvinylpyrrolidone 37.00 49.33 74.00 7.87
Intra-granulation
4. Microcrystalline cellulose 68.00 90.67 136.00 14.47
5. Pregelatinized starch 25.00 33.33 50.00 5.32
6. Sodium starch glycolate 20.00 26.67 40.00 4.26
7. Docusate sodium 15.00 20.00 30.00 3.19
Lubrication
8. Magnesium stearate 5.00 6.67 10.00 1.06
Total weight 470.00 626.67 940.00 100.00

Manufacturing Process:
1. Polyethylene glycol and dispersed Chlorzoxazone added into Polyvinylpyrrolidone and stir to get the homogeneous suspension.
2. Dry the drug dispersed material of step 1 up to 2- 3 hours at 50-700C.
3. Milled the dried material of step 2 through 0.8 mm after sifting through ASTM #40.
4. Intra-granular materials sift through ASTM #40.
5. Sifted material of Step 3 and step 4 mixed in RMG for 10 minutes.
6. Sift Magnesium stearate through ASTM #60 and lubricated for 5 minutes.
7. Compressed the tablets by using compression machine.
8. Packed the finished product in suitable container or packing material.
Dissolution/Release Profile (Example 2):

Dissolution condition Medium: pH 6.8 phosphate buffer
Appts: Type II (Paddle)
RPM: 75
Volume: 1800 ml
Strengths 250mg 333.33mg 500mg
Time (Minutes) % Release of Chlorzoxazone

0 0 0 0
10 58 50 55
15 90 89 91
30 95 96 99
45 101 97 98
60 101 99 99
90 101 99 99

Example 3:
Strengths 250 mg 333.33 mg 500 mg % w/w
No. Ingredients mg/tablets mg/tablets mg/tablets
Drug- dispersion
1. Chlorzoxazone 250.00 333.33 500.00 53.19
2. Pluronic F127 20.00 26.67 40.00 4.26
3. Polyvinylpyrrolidone 20.00 26.67 40.00 4.26
Intra-granulation
4. Microcrystalline cellulose 100.00 133.33 200.00 21.28
5. Pregelatinized starch 55.00 73.33 110.00 11.70
6. Sodium starch glycolate 15.00 20.00 30.00 3.19
7. Docusate sodium 5.00 6.67 10.00 1.06
Lubrication
8. Magnesium stearate 5.00 6.67 10.00 1.06
Total weight 470.00 626.67 940.00 100.00

Manufacturing Process:
1. Pluronic F127 and dispersed Chlorzoxazone added into Polyvinylpyrrolidone and stir to get the homogeneous suspension.
2. Dry the drug dispersed material of step 1 up to 2- 3 hours at 50-700C.
3. Milled the dried material of step 2 through 0.8 mm after sifting through ASTM #40.
4. Intra-granular materials sift through ASTM #40.
5. Sifted material of Step 3 and step 4 mixed in RMG for 10 minutes.
6. Sift Magnesium stearate through ASTM #60 and lubricated for 5 minutes.
7. Compressed the tablets by using compression machine.
8. Packed the finished product in suitable container or packing material.
Example 4:
Strengths 250 mg 333.33 mg 500 mg % w/w
No. Ingredients mg/tablets mg/tablets mg/tablets
Drug- dispersion
1. Chlorzoxazone 250.00 333.33 500.00 53.19
2. Polyethylene glycol 100.00 133.33 200.00 21.28
3. Polyvinylpyrrolidone 5.00 6.67 10.00 1.06
Intra-granulation
4. Microcrystalline cellulose 47.00 62.67 94.00 10.00
5. Pregelatinized starch 25.00 33.33 50.00 5.32
6. Sodium starch glycolate 8.00 10.67 16.00 1.70
7. Docusate sodium 30.00 40.00 60.00 6.38
Lubrication
8. Magnesium stearate 5.00 6.67 10.00 1.06
Total weight 470.00 626.67 940.00 100.00

Manufacturing Process:
1. Polyethylene glycol and dispersed Chlorzoxazone added into Polyvinylpyrrolidone and stir to get the homogeneous suspension.
2. Dry the drug dispersed material of step 1 up to 2- 3 hours at 50-700C.
3. Milled the dried material of step 2 through 0.8 mm after sifting through ASTM #40.
4. Intra-granular materials sift through ASTM #40.
5. Sifted material of Step 3 and step 4 mixed in RMG for 10 minutes.
6. Sift Magnesium stearate through ASTM #60 and lubricated for 5 minutes.
7. Compressed the tablets by using compression machine.
8. Packed the finished product in suitable container or packing material. ,CLAIMS:1. A novel supra bioavailable low dose pharmaceutical composition, comprising:
a) Chlorzoxazone or salt thereof; and
b) One or more pharmaceutically acceptable excipient.
2. The pharmaceutical composition as claimed in claim 1, wherein the composition contains low dose of Chlorzoxazone or salt thereof when compared with reference tablet strength 375mg, 500mg and 750mg of Chlorzoxazone.
3. The pharmaceutical composition as claimed in claim 1, wherein amount of the Chlorzoxazone or salt thereof is in the range of 20% to 90% based on the total weight of composition.
4. The pharmaceutical composition as claimed in claim 2, wherein the composition contains less than 375mg, less than 500mg or less than 750mg of Chlorzoxazone or salt thereof.
5. The pharmaceutical composition as claimed in claim 2 and 4, wherein the composition contains at least 5% dose reduction of Chlorzoxazone or salt thereof.
6. The pharmaceutical composition as claimed in claim 1, wherein the one or more pharmaceutically acceptable excipient is selected from diluents, disintegrants, binders, solubilizing agent or solubility enhancer, surfactant, absorption enhancer, superdisintegrants, lipidic excipient, oily vehicle, bioadhesive agents or mucoadhesion promoting agent, polymers or release modifying agent, carriers, plasticiser, penetration enhancer, bases, lubricant, glidant, acidic agent, basic agent, chelators, sweeteners, flavoring agent, pH regulating agent, preservatives, antioxidants, coloring agents, solvents, taste masking agent, antifoaming agents, flow agents and opacifiers, antiadherent, stabilizing agent, antistatic agent, viscosity adjuster and coating agent.
7. The pharmaceutical composition as claimed in claim 6, wherein solubilizing agent or solubility enhancer is selected from the group consisting of cyclodextrin and/or its derivatives, 2-Hydroxypropyl-beta-cyclodextrin (Kleptose), polyethylene glycol, polyvinylpyrrolidone, poloxamer, propylene oxide, ethylene oxide, dextran, sugars such as sucrose, lactose or dextrose, mannitol, sorbitol or lactitol, sodium chloride or mixture thereof.
8. The pharmaceutical composition as claimed in claim 7, wherein the solubilizing agent or solubility enhancer are in the range of 1% to about 40% by weight with respect to total weight of the pharmaceutical composition.
9. The pharmaceutical composition as claimed in claim 1, wherein the composition is in the form of tablet, capsule, concentrated solution, granules, beads, sachet, gelcap, lozenge, pastille, pill or powder.
10. The pharmaceutical composition according to claim 1, wherein the composition is used for the treatment of muscle spasm.