FIELD OF THE INVENTION
This invention in general relates to a multiparticulate based pharmaceutical composition comprising a drug or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof and pharmaceutically acceptable excipient. More particularly, the pharmaceutical composition are formulated as powder for oral suspension dosage form which can be dispensed in a unit dose pack. The invention also provides a process for manufacturing such compositions.

BACKGROUND OF THE INVENTION
Pharmaceutical suspensions are one of the most favorable dosage forms for pediatric and geriatric patients and patients who experience swallowing difficulties in comparison to tablets and capsule dosage forms. In addition, there are other advantages like
a) dispensing of hydrophobic, insoluble or poorly soluble drugs
b) better absorption
c) pleasant mouth feel
d) taste masking of bitter drugs
The available extended release ready to use suspension suffer from drawbacks such as drug leaching, flocculation and sedimentation of solid particles at the bottom of the container. Extended release (ER) Multiparticulate systems (MUPs) overcome problems related to ready to use ER suspension. Also ER powder for oral suspension are advantageous compared to ready-to-use suspensions, mainly due to their improved stability in storage conditions.

US Patent Number 9962336 assigned to Sun Pharmaceutical discloses stable extended release reconstituted powder for suspension, wherein the powder for suspension comprises of multiple coated cores of active and is reconstituted with the suspension base comprising suspending agents and osmogents.

US Publication Number 20080118570 assigned to Wockhardt as per publication, discloses extended release suspensions employing ion-exchange resins. Although ion-exchange resin systems provide the desired extended release of the active ingredient without significant leaching during storage. However, these systems are complicated and not suitable for many active ingredients.

The present invention relates to the extended release MUPs of pharmaceutically active substances, offered as powder for oral suspension which contain at least one pharmaceutically active substance and a swellable outer layer. In contact with water, the outer layer of the pellets swells and form a suspension. Extended release MUPs are advantageous in case of large single dose drugs, since a tablet or a capsule, would be too voluminous for oral intake. Furthermore, there are certain drugs, where multiple unit dosage forms are particularly advantageous to overcome local irritation of the gastrointestinal tract after peroral administration.

The prior arts mentioned above discloses coated cores of actives, wherein the active is layered over inert core. There is a long-felt need for ER Powder for suspension (POS) of drugs which are suitable for oral administration while maintaining a suitable bioavailability of the drug and/or its active metabolite(s) and patient compliant taste after oral administration and provide extended release (ER) drug release profile and enhance patient compliance. The present invention aims to provide multiparticulate based extended release pharmaceutical composition comprising drug or pharmaceutically acceptable salts thereof in powder for oral suspension which is reconstituted with a liquid medium before administration.

Further, the formulated extended release powder for oral suspension is expected to exhibit desirable technical attributes like pourability, viscosity, dissolution, stability, re-suspendability and re-dispersibility upon reconstitution complying with demanding requirements and regulations of health and medicine regulatory agencies across the world.
The inventors of the present invention propose MUPs based ER Powder for oral suspension of drugs, which exhibits desired pharmaceutical technical attribute.

SUMMARY OF THE INVENTION
It is an object of this invention to provide an extended release powder for suspension formulation.
Another object of this invention is that the suspending agent is present in the outer coat which swells to form a suspension on admixture with water.
Another object of the invention is to formulate extended release powder for oral suspension which is expected to exhibit desirable technical attributes like pourability, viscosity, dissolution, stability, re-suspendability and re-dispersibility upon reconstitution.

DESCRIPTION OF THE INVENTION
The present invention can be more readily understood by reading the following detailed description of the invention and study of the included examples.
As used herein, the term “composition”, as in pharmaceutical composition, is intended to encompass a drug product comprising and active or its pharmaceutically acceptable salt or derivative thereof, and the other inert ingredient(s) (pharmaceutically acceptable excipients). Such pharmaceutical compositions are synonymous with “formulation” and “dosage form”. Pharmaceutical composition of the invention include, but is not limited to, powder for oral suspension, pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres, powder, granules, spheroids and the like. Preferably, the pharmaceutical composition refers to powder or granules. More preferably, the pharmaceutical composition refers to powder for oral suspension or granules for oral suspension.

The term “multiparticulate” used herein refers to a plurality of discrete or aggregated particles, pellets, beads, spheroids, spheres or mixture thereof, irrespective of their size, shape or morphology.

The term “core” as used herein refers to pellets/spheres comprising a drug, at least a diluent, sweetener, binder and optionally one or more other excipients.

The term “active core” as used herein refers to pellets/spheres comprising a drug or drug coated inert pellets.

The term "excipient" means a pharmacologically inactive component such as a diluent, lubricant, surfactant, carrier, or the like. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for veterinary as well as human pharmaceutical use. Reference to an excipient includes both one and more than one such excipient. Co-processed excipients are also covered under the scope of present invention. Further, excipient may be in the form of powders or in the form of dispersion. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.

As used herein, the terms “suspending agent” and “thickening agent” and “viscosity enhancing agent” are synonymous.

As used herein, the terms “Drug” and “Active Pharmaceutical Ingredient” are synonymous.

As used herein, the term "about" means ± approximately 10% of the indicated value.
The term “w/w” as used herein refers the total weight of the core composition.

The “dry powder composition” or “Unit dosage form” or “powder for oral suspension” can be in the form of powder, granules, pellets, bead, cores, spheroids or multiparticulates.

The phrase “pharmaceutical composition,” as used herein, refers to tablets, orally disintegrating tablets, capsules, pellets, sachets, powder for oral suspension, ready to use suspension, chewable tablets and the like.

The term “sachet” as used herein refers to any suitable container, package or bag to contain the dry powder composition. The sachet may be formed of any suitable material, including plastic, metal foil, paper or a combination thereof. Sachet can be three layered with sandwiched polyethylene terephthalate (PET)/aluminium/polyethylene layers or four layered or more with addition of more layers of PET/aluminium/polyethylene to provide robust protection to moisture sensitive drugs. The sachet may be provided with any suitable means for opening thereof, including a perforated region or a nick in the edge of the sachet for ease of tearing. The sachet may be of any suitable size. The sachet is sealed using any appropriate method. Particularly, the sachet is disposable. Sachet can be a child resistant container.

In an embodiment of the present invention relates to an extended release multiparticulate pharmaceutical composition comprising
a) an inert core
b) drug layer: comprising one or more active pharmaceutical ingredient
c) optionally a seal coat: comprising one or more water soluble and/or water insoluble polymers
d) extended release coat: comprising a release controlling polymer and one or more pharmaceutically acceptable excipient and
e) optionally a seal coat
f) an outer coat: comprising one or more pharmaceutical excipients.

In an embodiment of the present invention relates to an extended release multiparticulate pharmaceutical composition comprising
a) a core: comprising one or more active, a release controlling polymer and one or more pharmaceutically acceptable excipients
b) optionally a seal coat: comprising one or more water soluble and/or water insoluble polymers
c) an outer coat: comprising one or more pharmaceutical excipients.

In another embodiment, the present invention relates to the multiparticulate based pharmaceutical composition, wherein the excipients in the outer layer are selected from the group comprising suspending/thickening agent, a binder, a filler, a surfactant, an anti- tacking agent, a plasticizer, a lubricant, a glidant, a disintegrant, an alkaline substance, a diluent, a tonicity adjusting agent, a wetting agent, a buffering substance, a colorant, a preservative, and any combination thereof.

In yet another embodiment, the present invention relates to multiparticulate based composition wherein the suspending agent comprises at least one of polysaccharide, acrylic or methacrylic polymer, cellulose derivative, polyethylene glycol, alginic acid, sodium alginate, carbomer, gelatin, magnesium aluminum silicate, poloxamer, polyvinyl alcohol, and naturally occurring or synthetic gum.

In yet another embodiment, the present invention relates to an extended release multiparticulate pharmaceutical composition wherein the coated core swells to form a suspension when dispersed in an aqueous medium.

Another embodiment of the present invention relates to an extended release multiparticulate pharmaceutical composition wherein the viscosity of the composition is atleast 100 cps.

Another embodiment of the present invention relates to an extended release multiparticulate pharmaceutical composition wherein the diameter of the coated core is atleast 50 µm.

Yet another embodiment of the present invention relates to an extended release multiparticulate pharmaceutical composition wherein the composition is in the form of pellets, granules, beads, spheroids, mini-tablets or powder for oral suspension to be dispensed as capsules or in sachets.

In another embodiment, the present invention relates to an extended release multiparticulate pharmaceutical composition wherein one or more active is selected from oxcarbazepine, metformin, or their pharmaceutically acceptable salts thereof.

Another embodiment of the present invention relates to the multiparticulate based pharmaceutical composition wherein the seal coat does not impart extended release profile to the active.

In another embodiment of the present invention relates to the multiparticulate based pharmaceutical composition wherein suspending agent is not present in admixture with the core.

In another embodiment of the present invention relates to the multiparticulate based pharmaceutical composition which does not comprise proton pump inhibitor as an active agent.

In yet another embodiment of the present invention relates to the multiparticulate based pharmaceutical composition, wherein the core comprises an inert seed coated with a drug layer comprising a drug and release controlling polymer and further layered with an outer layer of a mixture comprising a thickening agent and one or more excipients which when dispersed in an aqueous medium, the coated cores swells to form a suspension.

In one embodiment the present invention relates to a process for the preparation of a multiparticulate based pharmaceutical composition, wherein the process comprises the steps of:
(i) preparing cores comprising an active ingredient and a release controlling polymer and one or more pharmaceutically acceptable excipients by dissolving/dispersing in a suitable solvent;
(ii) drying the cores to LOD (loss on Drying) in the range of 3-6%
(iii) optionally applying a seal coat comprising water soluble and/or water insoluble polymer over the cores of step (i);
(iv) applying an outer coat comprising suspending agent and one or more excipients on the coated cores of step (ii).
(v) dispensing the coated cores in sachet or bottles.

In another embodiment of the present invention relates to a process for the preparation of a multiparticulate pharmaceutical composition, wherein the process comprises of :
a) coating the inert core with a drug layer comprising one or more active pharmaceutical ingredients and its pharmaceutically acceptable salts, esters and derivatives thereof.
b) optionally applying the seal coating of a water soluble/insoluble polymer on the drug coated core;
c) coating the resultant product with extended release coat comprising a release controlling polymer and one or more pharmaceutically acceptable excipient
d) optionally applying a seal coat on the extended release coated core and
e) applying outer coat on the core of step (d) wherein outer core comprises of one or more pharmaceutical excipients
f) dispensing the coated cores in sachet or bottles.

The pharmaceutical composition of the present invention can be packaged in a suitable pack/container such as amber colored polyethylene terephthalate (PET) bottle, glass bottle, high density polyethylene (HDPE) bottle, low density polyethylene (LDPE) bottle, polypropylene (PP) bottle, packets, pouches, sachets and the like. The glass or plastic bottle is provided with a child proof closure. The package can include a syringe (marked in mL) or a dispensing cup (marked in mL) for ease of dosing.

The drugs that are suitable for use in this invention in terms of chemical nature are acidic, basic, amphoteric, or zwitterionic molecules. Such drugs include small molecules, and selected larger molecules as well, including chemical moieties and biologicals, such as, e.g., a protein or a fragment thereof (e.g., a peptide, polypeptide, etc), enzyme, antibody or antibody fragment.
The drugs that are suitable for use in these preparations include drugs for the treatment of respiratory tract disorders such as, for example, antitussive expectorants, bronchodilators and antihistamines. Other drugs useful for the invention include drugs for the treatment of digestive tract disorders such as, for example, digestive tract antispasmodics, drugs for the treatment of central nervous system disorders such as, antipsychotic drugs, antianxiety drugs, antidepressants, SSRI, antipyretic analgesics; opioid analgesics; and drugs for the treatment of respiratory system disorders, hypotensive drugs, a peripheral vasodilators/vasoconstrictors, antidiabetics, antihypertensives, antianginal, chemotherapeutic drugs, antimuscarinics, beta adrenergic receptor blockers, antituberculosis drugs all individually or in combinations.

In another embodiment of the present invention, there is provided a process for the preparation of a powder for suspension composition, granules or multiparticulates of drug or its pharmaceutically acceptable esters, salts, solvates, polymorphs, enantiomers or mixtures thereof by using conventional methods known in the art but not limited to blending, mixing, granulation, hot-melt extrusion, spray drying, spray coating techniques. Suitable solvents include aqueous or organic solvents. Preferable solvents include, but are not limited to, water, esters such as ethyl acetate; ketones such as acetone; alcohols such as methanol, ethanol, isopropanol, butanol; dichloromethane, chloroform, dimethyl acetamide (DMA), dimethyl sulfoxide (DMSO), ether, diethyl ether and combinations thereof. Preferably, the solvent used during wet mass preparation is water.
In an another embodiment of the present invention, the multiparticulates of active pharmaceutical ingredient or its pharmaceutically acceptable salts and derivatives thereof significantly decreased the food effect, prepared by extrusion spheronization and hot melt extrusion, thereby increasing the patient's medication flexibility and compliance.

Another embodiment of the present invention also provides a process for the preparation of a solid oral multiparticulate pharmaceutical composition of active pharmaceutical ingredient or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, comprising the steps of; (a) dry blending the drug and excipients, (b) wet granulation (aqueous or non-aqueous) of the mass, (c) extrusion through a screen of defined mesh size to compact the wet mass into cylindrical strands, (d) spheronization of cylindrical strands in a spheronizer to convert the cylindrical strands into spheres, (e) seal coating of the spheres, (f) coating of the spheres with release controlling polymers over the seal coating, and (g) optionally coated with an outer seal coat over the extended release coating layer and finally applying outer coat comprising suspending agent and one or more pharmaceutically acceptable excipients.

In another embodiment of the present invention, there is provided a process for the preparation of a multiparticulates by using methods known in the art but not limited to blending, mixing, granulation, hot-melt extrusion, extrusion spheronization, spray drying, spray coating techniques. The formulation so formed may be administered directly or incorporated into/processed to pharmaceutical compositions for oral administration.

In another embodiment of the invention, wet granulation can be performed using Rapid mixer granulator, Fluid bed granulator, Planetary mixer and the like; dry blending can be performed in V-blender or key blender; spheronization can be performed using Fuji Paudal spheronizer or by any other method known in the art.

In another embodiment of the invention, release controlling polymers are selected from hydroxyethyl cellulose, hydroxypropyl cellulose, sodium alginate, carbomer, sodium carboxymethyl cellulose, xanthan gum, guar gum, locust bean gum, polyvinyl alcohol and hydroxypropyl methylcellulose.

The hydrophilic release controlling polymer that can be used in the present invention is hydroxypropyl cellulose and hydroxypropyl methylcellulose. The matrix forming polymer comprises from about 1% to about 70%, preferably from about 5% to about 50% and most preferably from 15% to 50% by weight of the coated sustained release composition. The hydrophilic polymer described above can also be used as a constituent of the coating layer.

Hydrophobic release controlling polymer that can be used in the present invention are selected from the group comprising of cellulose ether such as ethyl cellulose, cellulose acetate, polyvinyl acetate, methacrylic acid esters neutral polymer, polyvinyl alcohol-maleic anhydride copolymers, hydroxypropyl methyl cellulose phthalate, EUDRAGIT® EPO, EUDRAGIT® E100, EUDRAGIT® E 12,5, EUDRAGIT® L 12,5, EUDRAGIT® FS 30 D, EUDRAGIT®RSPO, EUDRAGIT® RLPO, EUDRAGIT® RL30D, EUDRAGIT® RL12,5, EUDRAGIT® S 100, hydrogenated castor oil, waxes and the like. Even the commercially available dispersion of film formers namely, EUDRAGIT® L-30D, EUDRAGIT® NE 30D, AQUACOAT® ECD-30, SURELEASE® E-7, EUDRAGIT® RS 30D, EUDRAGIT® RL 30D, etc. may be used for the purpose of providing sustained release composition. Preferably the hydrophobic polymer that can be used in the present invention is ethyl cellulose, hydroxypropyl methyl cellulose phthalate, EUDRAGIT® RSPO, EUDRAGIT® S 100 and hydrogenated castor oil.

Diluents or fillers or carriers are substances which usually provide bulk to the composition. Various useful fillers or diluents include, but are not limited to microcrystalline cellulose, calcium carbonate, anhydrous dibasic calcium phosphate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, calcium sulphate, cellulose powdered, cellulose acetate, compressible sugar, confectioner's sugar, dextrates, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltodextrin, maltose, mannitol, polydextrose, simethicone, sodium alginate, sodium chloride, sorbitol, starch, pregelatinized starch, sucrose, trehalose and xylitol, or mixtures thereof. The diluent is present in an amount of about 1% w/w to about 98% w/w of the total composition.

Various water-soluble polymers used to form a barrier/seal or film over the core. Examples include but are not limited to cellulose derivatives such as soluble alkyl- or hydroalkylcellulose derivatives such as methylcellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxymethylethyl cellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, etc., acidic cellulose derivatives, dextrins, starches and starch derivatives, polymers based on carbohydrates and derivatives thereof, natural gums such as gum Arabic, xanthans, alginates, polyacrylic acid, polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone, chitosan and derivatives thereof, shellac and derivatives thereof, waxes and fat substances. If desired, the films may contain additional adjuvants for coating such as plasticizers, polishing agents, colorants, pigments, antifoaming agents, opacifiers, antisticking agents, and the like.

In another embodiment of the invention, water insoluble polymers suitable for use in the present invention include, but are not limited to, cellulose acetate phthalate (CAP), cellulose acetate trimellitate (CAT), hydroxypropylmethylcellulose phthalate (HPMCP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), hydroxypropylcellulose acetate phthalate (HPCAP), hydroxypropylmethylcellulose acetate phthalate (HPMCAP), ethylcellulose (EC), polyvinyl acetate phthalate methylcellulose acetate phthalate (MCAP) and methacrylic acid copolymers or its derivatives. Kollicoat® from Evonik Industries, Colorcon, Eastman Chemical and BASF Fine Chemicals respectively. Acrylate polymers or Methacrylic acid copolymers or its derivatives are selected from the group comprising different grades of Poly(butyl methacrylate, (2-dimethylaminoethyl) methacrylate, methyl methacrylate) 1:2:1, Poly(methacrylic acid, methyl methacrylate) 1:2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.2, Poly(ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride) 1:2:0.1, Poly(methacrylic acid, ethyl acrylate) 1:1.

Binders impart cohesiveness to formulation. Various useful binders include, but are not limited to hypromellose, acacia, alginic acid, carbomer, sodium carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch, polyvinyl alcohol or polyethylene oxide, or mixtures thereof. The binder may constitute from about 1% w/w to about 20% w/w by the pharmaceutical composition.

Glidants improve flowability and accuracy of dosing. Since the present invention relates to an oral pharmaceutical composition, it is imperative to use glidant(s) to achieve desirable flowability of the active. Glidants used in the composition include, but are not limited to, tribasic calcium phosphate, calcium silicate, cellulose, powdered, colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, starch and talc or mixtures thereof. The amount of glidant ranges from about 0.1% w/w to about 5% w/w by weight of the composition.

Surfactants or surface-active agents improve wettability of the dosage form and/or enhance its dissolution. Surfactants contemplated in the present invention include but are not limited to anionic surfactants, amphoteric surfactants, non-ionic surfactants and macromolecular surfactants. Suitable examples of anionic surfactants include but are not limited to sodium lauryl sulphate, sodium cetyl stearyl sulphate or sodium dioctyl sulphosuccinate etc. Suitable example of an amphoteric surfactant include but is not limited to lecithin. Suitable examples of non-ionic surfactants include but is not limited to cetyl alcohol, stearyl alcohol, cetyl stearyl alcohol, cholesterol, sorbitan fatty acid esters such as sorbitan mono-oleate, polyoxyethylene sorbitan fatty acid esters such as polysorbate 80, polysorbate 20, polyoxyethylene fatty acid glycerides such as macrogol 1000 glycerol monostearate, polyoxyethylene fatty acid esters such as polyoxyl 40 stearate, polyoxyethylene fatty alcohol ethers such as polyoxyl 10 oleyl ether, glycerol fatty acid esters such as glycerol monostearate, commercially available SEPITRAP® 80 or SEPITRAP® 4000 etc. The surfactant may constitute from about 0% w/w to about 5% w/w by weight of coated pellets/spheres.

Various useful preservatives include, but are not limited to, parabens such as methylparaben, propylparaben, butyl paraben and their salts, sorbic acid, sodium sorbate, potassium sorbate, calcium sorbate, benzoic acid, sodium benzoate, potassium benzoate, calcium benzoate, methyl hydroxybenzoate, ethyl para-hydroxybenzoate, sodium ethyl para-hydroxybenzoate, sodium metabisulphite, chlorhexidine, diazolidinyl urea, sodium citrate, butylated hydroxyl toluene (BHT), butylated hydroxyl anisole (BHA), tocopherol, ethylenediamine tetraacetic acid, propyl gallate, quaternary compounds, e.g. benzalkonium chloride and cetylpyridinium chloride, phenyl ethyl alcohol and the like. In particular, the preservative is selected from benzoic acid and its salts and parabens. The preservative is present in an amount of about 0.001% w/w to about 3% w/w.

Anticaking agent helps to re-suspend the ingredients suspended in the formulation. Generally, suspension formulations contain micronized particles of active ingredients and inactive ingredients, which settle at the bottom of the container and form a thin hard cake, which is not easily re-suspendable after shaking. Anticaking agent helps to improve the re-suspendability of the formulation. Various useful anticaking agents include, but are not limited to, colloidal silica and/or colloidal silicon dioxide, calcium phosphate tribasic, magnesium oxide, magnesium silicate, calcium silicate or the like.

Various useful antioxidants include, but are not limited to, ascorbic acid, tert-butylhydroquinone, sodium pyrosulfite, glutathione, sodium bisulfite, sodium sulfite, a-tocopherol, a-tocopherol acetate, monothioglycerol, cysteine, ascorbyl palmitate, acetylcysteine, dithiothreitol, sodium metabisulfite, thiourea, sodium thiosulfate, butylated hydroxy anisole (BHA), butylated hydroxytoluene (BHT) and propyl gallate.

Various useful sweetening agents include, but are not limited to, sugar or a sugar alcohol such as sucrose, dextrose, sucralose, sorbitol, neotame, aspartame, Acesulfame K, fructose, mannitol and invert sugar and sugar substitutes such as saccharin sodium, aspartame. Sugar or a sugar alcohol can also act as filler. Preferably sweetening agent used is sodium saccharin, sucralose, neotame. The amount of sweetening agent ranges from about 0.05% w/w to about 85% w/w by weight of the composition

The effervescent couple are selected from citric acid or sodium hydrogen citrate and sodium bicarbonate but other physiologically acceptable and/alkaline or alkaline earth metal carbonate mixtures may be used, for example tartaric, adipic, fumaric or malic acid, and sodium, potassium or calcium bicarbonates or sodium glycine carbonate.

Various useful flavoring agents, include, but are not limited to, flavors such as banana, lemon, orange, grape, lime and grapefruit, vanilla, and fruit essence, including apple, banana, pear, peach, strawberry, raspberry, cherry, plum, wild cherry, walnut, chocolate, pineapple, apricot; synthetic flavor oils and flavoring aromatics and/or natural oils, extracts from plant leaves, flowers, fruits such as cinnamon oil, oil of wintergreen, peppermint oils, clove oil, citrus oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leaf oil, oil of nutmeg, oil of sage, oil of bitter almonds, mint and cassia oil; maltol, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid and combinations thereof. Preferably, wild cherry, walnut, chocolate, pineapple, apricot, Anise, banana and orange. Flavoring agent is present in the concentration of 0.1 w/w - 1.0 % w/w and is satisfactory. Although flavoring agent in lesser concentrations than 0. l% w/w or in higher concentrations than l% w/w can be used, use of flavoring agent concentration in the vicinity of 0.4 % w/w gives better composition. The concentration of flavoring agent is flavor specific and may be modulated depending upon the flavour/s used.

Suitable coloring agent are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents, natural coloring agents, natural juice concentrates, pigments such as iron oxide, titanium dioxide, and zinc oxide, and combinations thereof.

Suitable suspending or thickening or viscosity enhancing agents are selected from the group comprising gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth, gum arabic, and pectin, dextran, gelatin, polyethylene glycols, polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone, sugar alcohols such as xylitol and mannitol, colloidal silica and mixtures thereof. Celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, co-processed spray dried forms of microcrystalline cellulose and carboxymethyl cellulose sodium have been marketed under the trade names Avicel® RC-501, Avicel® RC-581, Avicel® RC-591, and Avicel® CL-611. polyvinylpyrrolidone; alginic acid; alginate; sodium alginate; bentonite; carbomers (carboxyvinyl polymers) such as those available under the trade name Carbopol®; cetostearyl alcohol; maltodextrin; polyvinyl alcohol; colloidal silicon dioxide, propylene carbonate; propylene glycol; sodium starch glycolate; starch; acrylic polymers etc. The suspending agents are present in an amount ranging from about 0.05% to about 30% w/w of the composition, preferably 1% w/w to 20% w/w. In a particular embodiment, the “active core” is further coated with a layer of suspending agent.

Various useful pH adjusting agent or buffering agents include, but are not limited to, citrate buffers, phosphate buffers, or any other suitable buffer known in the art including monosodium dibasic phosphate, gluconic acid, lactic acid, citric acid, acetic acid, sodium gluconate, sodium lactate, sodium citrate, sodium acetate potassium citrate, sodium bicarbonate, potassium bicarbonate, sodium dihydrogen phosphate and potassium dihydrogen phosphate.

In another embodiment, the pharmaceutical composition of the present invention comprise of a particle form comprising drug or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof from about 1 mg to about 1000 mg in the formulation, preferably 100-1000 mg, more preferably 250-1000 mg.
In accordance with still another embodiment of the present invention, there is provided a MUPs based ER powder for suspension comprising active pharmaceutical ingredient or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein active pharmaceutical ingredient has a particle size distribution D90 less than about 200 µm.

In another embodiment of the present invention relates to a MUPs based ER powder for suspension comprising active pharmaceutical ingredient or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof can be administered by sprinkling the pellets/spheres on teaspoonful full of applesauce or apple juice wherein the composition exhibited stability for at least 10 minutes.

In another embodiment, of the present invention, relates to a MUPs based ER powder for suspension comprising active pharmaceutical ingredient or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof is stable at 40 °C and 75% relative humidity.

Various useful taste masking agents include, but are not limited to, water soluble and/or insoluble polymeric excipient, water insoluble non-polymeric excipient, adsorbent, carbomer, alkali metal chlorides or an alkaline earth metal chlorides or a derivative thereof.

Suitable alkaline agents include, but are not limited to, pharmacologically alkali metal, alkaline earth metal or metal salts of weak acids such as sodium carbonate which can be anhydrous or hydrous, calcium carbonate and magnesium carbonate and the pharmacologically hydroxides and oxides of alkaline earth and earth metals such as magnesium hydroxide and magnesium oxide. The alkaline agent may constitute from about 0.1% to about 20% by weight of the pharmaceutical composition.

The final formulations may be coated or uncoated. For coating, additional excipients such as film-forming polymers, plasticizers, antiadherents and opacifiers are used.

In another embodiment the present invention includes particle size of free drug particulate form of drug or its pharmaceutically acceptable salts, esters, solvates, polymorphs, enantiomers or mixtures thereof, wherein particle diameter at 90% cumulative volume (d90) is less than about 100 µm, preferably less than 50 µm. Particle diameter at X% cumulative Particle size reduction can be performed by techniques including but not limited to fluid energy milling, ball milling, colloid milling, roller milling, hammer milling and the like. Particle size and particle size distribution can be measured by techniques such as Laser light scattering (e.g. Malvern Light Scattering), Coulter counter, microscopy and the like.

In yet another embodiment of the present invention, the multiparticulate based composition is packed in a packaging material selected from the group comprising of a foil, a pouch, a sachet, capsule, bottle, container or other suitable packages including calendar packs.

The pharmaceutical oral dosage form prepared by the above mentioned process can be subjected to in vitro dissolution evaluation according to Test 711 "Dissolution" in the United States Pharmacopoeia 37, United States Pharmacopoeial Convention, Inc., Rockville, Md., 2014 ("USP") to determine the rate at which the active substance is released from the dosage form, and the content of the active substance can be determined in solution by high performance liquid chromatography. When comparing the test and reference products, dissolution profiles should be compared using a similarity factor (f2). The similarity factor is a logarithmic reciprocal square root transformation of the sum of squared error and is a measurement of the similarity in the percent (%) of dissolution between the two curves.
f2 = 50 • log {[1 + (1/n)St=1n (Rt - Tt)2]-0.5 • 100}
Two dissolution profiles are considered similar when the f2 value is equal to or greater than 50.
Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail method for the preparation and testing of the pharmaceutical composition. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention. Following examples are set out to illustrate the invention and do not limit the scope of the present invention.

EXAMPLES
The following non-limiting examples are intended to further illustrate certain preferred embodiments of the invention. They are, however not intended to be limiting the scope of the present invention in any way.
Pharmaceutical composition may be prepared by using quantitative formula as given in the following examples:
Table 1:
Composition Example
I II
S. No. Ingredients %w/w
Core
1. Oxcarbazepine 0.1-98 --
2. Metformin Hydrochloride -- 0.1-98
3. Microcrystalline Cellulose 5-50 5-50
4. Hypromellose/Povidone 0.1-15 0.1-15
Intermediate layer
5. Water soluble polymer 0.5-30 0.5-30
6. Hypromellose /Povidone 0.1-20 0.1-20
7. Water/hydroalcoholic solvent q.s q.s
Extended release Layer
8. Methacrylate 2-60 2-60
9. Talc 0.5-2 0.5-2
10. Triethyl Citrate 0.5-2 0.5-2
11. Sodium lauryl sulfate -- 0.1-2
12. Purified Water/solvents q.s. q.s.
Outer layer
13. Thickening agent 0.01-30 0.01-30
14. Hypromellose /Povidone 0.1-20 0.1-20
15. Flavoring agent (optional) 0.1-2 0.1-2
16. Sweeteners (optional) 0.1-5 0.1-5

Preferred method of manufacture: Extrusion-spheronization/ wet granulation/ Fluidized bed coating

Table 2:
Composition Example
I II III
S. No. Ingredients %w/w
Inert Core
1. Microcrystalline cellulose sphere 1-50 -- 1-50
2. Sugar spheres -- 1-50 --
Seal coat
3. Hydroxypropyl methyl cellulose 0.1-2 -- --
4. Ethyl cellulose -- -- 0.1-2
Drug Layer
5. Oxcarbamazepine 0.1-70 -- 0.1-70
6. Metformin Hydrochloride -- 0.1-70 --
7. Povidone / Hypromellose 0.1-5 0.1-5 0.1-5
8. Crospovidone (disintegrant) -- 1-20 1-20
9. Purified Water q.s q.s q.s
Seal Coating
10. Hypromellose 0.1-5 -- 0.1-5
11. Talc 0.5-5 -- --
12. Titanium dioxide 0.1-2 0.1-2 0.1-2
13. Polysorbate 80 0.1-2 0.1-2 --
14. Purified water q.s q.s q.s
Extended release Layer
15. Methacrylate polymer 0.5-5 0.5-5 0.5-5
16. Talc 0.5-2 0.5-2 0.5-2
17. Triethyl Citrate 0.5-2 0.5-2 0.5-2
18. Sodium lauryl sulfate -- 0.1-2 0.1-2
19. Purified Water/solvents q.s. q.s. q.s.
Outer layer
20. Suspending agent 0.01-30 0.01-30 0.01-30
21. Hypromellose /Povidone 0.1-20 0.1-20 0.1-20
22. Flavoring agent (optional) 0.1-2 0.1-2 0.1-2
23. Sweeteners (optional) 0.1-5 0.1-5 0.1-5

Preferred method of manufacture: Fluidized bed Pelletization
The extended release multiparticulate test composition of the present invention are expected to have desired technical attributes such as assay, dissolution, pourability, viscosity, stability, re-suspendability and re-dispersibility upon reconstitution.

WE CLAIM:
1. An extended release multiparticulate pharmaceutical composition comprising:
a) an inert core
b) drug layer: comprising one or more active pharmaceutical ingredient selected form oxcarbazepine or metformin and their pharmaceutical acceptable salts.
c) optionally a seal coat: comprising one or more water soluble or water insoluble polymers
d) extended release coat: comprising a release controlling polymer and one or more pharmaceutically acceptable excipient and
e) optionally a seal coat
f) an outer coat: comprising one or more pharmaceutical excipients.

2. An extended release multiparticulate pharmaceutical composition comprising:
a) a core: comprising one or more active pharmaceutical ingredient selected form oxcarbazepine or metformin and their salts, a release controlling polymer and one or more pharmaceutically acceptable excipients
b) optionally a seal coat: comprising one or more water soluble or water insoluble polymers
c) an outer coat: comprising one or more pharmaceutical excipients.

3. The extended release multiparticulate pharmaceutical composition of claim 1 and 2, wherein pharmaceutical excipient in the outer coat is selected from the group comprising suspending agent, a binder, a filler, a surfactant, an anti- tacking agent, a plasticizer, a lubricant, a glidant, a disintegrant, an alkaline substance, a diluent, a tonicity adjusting agent, a wetting agent, a buffering substance, a colorant, a preservative, and any combination thereof.

4. The composition of claim 3, wherein the suspending agent comprises of at least one of the polysaccharide, acrylic or methacrylic polymer, cellulose derivatives, polyethylene glycol, alginic acid, sodium alginate, carbomer, gelatin, magnesium aluminum silicate, poloxamer, polyvinyl alcohol, and naturally occurring or synthetic gum.

5. The extended release multiparticulate pharmaceutical composition of claim 1 and 2, wherein the coated core swells to form a suspension when dispersed in an aqueous medium.

6. The extended release multiparticulate pharmaceutical composition of claim 1 and 2 wherein the viscosity of the composition is at least 100 cps.

7. The extended release multiparticulate pharmaceutical composition of claim 1 and 2 wherein the diameter of the coated core is at least 50µm.

8. The multiparticulate based extended release pharmaceutical composition of claims 1 and 2, wherein the composition is in the form of pellets, granules, beads, spheroids, mini-tablets or powder for oral suspension.

9. The process for preparing an extended release multiparticulate pharmaceutical composition, wherein the process comprises of
a) coating the inert core with a drug layer comprising one or more active pharmaceutical ingredients and its pharmaceutically acceptable salts, esters and derivatives thereof
b) optionally applying the seal coating of a water soluble/insoluble polymer on the drug coated core
c) coating the resultant product with extended release coat comprising a release controlling polymer and one or more pharmaceutically acceptable excipient
d) optionally applying seal coat on the extended release coated core and
e) applying outer coat on the core of step (d) wherein outer core comprises of one or more pharmaceutical excipients.

10. The process of preparing multiparticulate based pharmaceutical composition, wherein the process comprises the steps of:
a) preparing cores comprising an active ingredient and a release controlling polymer and one or more pharmaceutically acceptable excipients by dissolving/dispersing in a suitable solvent;
b) drying the cores to LOD (loss on Drying) in the range of 3-6%
c) optionally applying a seal coat comprising water soluble and/or water insoluble polymer over the cores of step (i);
d) applying an outer coat comprising suspending agent and one or more excipients on the coated cores of step (ii).
e) dispensing the coated cores in sachet or bottles.