FIELD OF THE INVENTION
This invention in general relates to a taste masked pharmaceutical composition comprising valacyclovir or its pharmaceutically acceptable salts thereof and pharmaceutically acceptable excipient(s). More particularly, the pharmaceutical composition is a powder for oral suspension or ready to use oral suspension dosage form. The invention also provides a process for manufacturing such compositions.
BACKGROUND OF THE INVENTION
Valacyclovir is the L-valyl ester of the antiviral drug aciclovir. Chemically, valacyclovir is known as L-valine, 2-[(2-amino-l,6-dihydro-6-oxo-9H-purin-9-yl)methoxy]ethyl ester. It is commercialized as the monohydrochloride salt. In the United States, valacyclovir is available as Valtrex® caplets for oral administration from GSK. Each caplet contains valacyclovir hydrochloride equivalent to 500 mg or 1 gram valacyclovir. Valacyclovir is indicated in adult patients for the treatment and/or prophylaxis of cold sores (herpes labialis), recurrent episodes, suppressive therapy, genital herpes and herpes zoster. Valacyclovir is also indicated for the treatment of cold sores and chicken pox in pediatric patients.
The package insert of Valtrex® describes an oral suspension (25 mg/mL or 50 mg/mL) formulation that may be prepared extemporaneously from the 500 mg tablets by crushing said tablets and processing with other excipients. US4957924 patent assigned to Burroughs Wellcome discloses valacyclovir and a process of preparation thereof. It also discloses pharmaceutical compositions containing valacyclovir.
US5879706 patent assigned to Glaxo Wellcome discloses tablet compositions of valacyclovir and colloidal silicon dioxide, along with other excipients, and a process for the preparation thereof.

US20120149720 patent application assigned to Ranbaxy discloses a taste-masked pharmaceutical formulation comprising valacyclovir and sweetening agents, wherein the sweetening agents comprise of at least one sugar or sugar alcohol and at least one artificial sweetener, wherein the compositions are prepared by dry blending. Moreover, the said patent publication does not discloses any composition with intragranular sweetener, which is disadvantageous considering strongly bitter taste and high dose of valacyclovir and this ultimately leads to poor palatability and/or patient incompliance.
US20170202843 patent application assigned to Pharmathen SA discloses a powder for oral suspension comprising valacyclovir in complex with an ion exchange resin, wherein the ratio of valaciclovir to the ion exchange resin is 1:0.8. Valacyclovir is extremely bitter in taste and this undesirable taste negatively influences palatability and patient compliance, especially with pediatric and geriatric patients, who are unable to swallow.
In the above mentioned prior arts, various applicants tried to prepare oral suspensions of valacyclovir by masking the bitter taste using artificial sweeteners or ion exchange resins. Taste masking using ion exchange resin is a cumbersome and a time consuming process. Further, dose of valacyclovir is high and varying from 250 mg to 1000 mg. Taste masking in case of dosage form with high dose of drug is always challenging for a formulation scientist to develop a suitable dosage form with desired technical attributes.
There is a long-felt need for palatable valacyclovir formulation to be available in liquid form or powder for suspension composition. The inventors of the present invention have prepared alternate pharmaceutical taste masked pharmaceutical composition of valacyclovir or pharmaceutically acceptable salt thereof, which exhibits desirable pharmaceutical technical attributes like pH, assay, pourability, viscosity, re-suspendability, re-dispersibility, sedimentation volume, bulk and

tapped density, dissolution and stability, prepared by a process, which is simple, cost effective and reproducible.
SUMMARY OF THE INVENTION
It is a principal object of the present invention to provide a taste masked pharmaceutical composition comprising an antiviral drug with one or more pharmaceutically acceptable excipient and/or carrier and process for its preparation.
It is also a principal object of the present invention to provide a taste masked pharmaceutical composition comprising valacyclovir or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipients and/or carrier and process for its preparation.
Another object of the present invention is to develop a taste masked powder composition suitable for reconstitution comprising:
a) an intragranular portion comprising valacyclovir or its pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable binder and at least a sweetener;
b) an extragranular portion comprising at least one suspending agent and one or more pharmaceutically acceptable excipients;
wherein the valacyclovir or its pharmaceutically acceptable salts thereof and suspending agent have a ratio ranging from about 10:0.1 to about 10:5 by weight.
Another object of the present invention is to develop a taste masked powder composition suitable for reconstitution comprising:
a) an intragranular portion comprising valacyclovir or its pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable binder and at least a sweetener;

b) an extragranular portion comprising at least one suspending agent and one
or more pharmaceutically acceptable excipients; wherein the valacyclovir or its pharmaceutically acceptable salts thereof and suspending agent have a ratio ranging from about 10:0.1 to about 10:5 by weight, further wherein the composition maintain a sedimentation volume ratio of more than about 0.8 to about 1 for at least 8 to 10 hours after the composition is reconstituted into a suspension.
Another object of the present invention is to develop a pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof by a manufacturing process, which is consistent and therefore feasible for industrial production, while maintaining stability and pharmaceutical equivalence to the reference formulation(s). The present invention relates to a taste masked pharmaceutical composition comprising valacyclovir or its pharmaceutically acceptable salt thereof and one or more excipients.
Another object of the present invention is to develop taste masked powder or multiparticulates based pharmaceutical composition of valacyclovir or its pharmaceutically acceptable salts thereof, wherein the composition exhibited desired technical attribute like, pH, assay, pourability, viscosity, re-suspendability, re-dispersibility, sedimentation volume, bulk and tapped density, dissolution and stability.
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 valacyclovir or 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, dry powder, ready to use suspension and pellets, beads, minitabs, spherules, beadlets, microcapsules, millispheres, microspheres, suspension, solution, powder, granules, spheroids and the like filled in sachet. Preferably, the pharmaceutical composition refers to powder or granules. The term "multiparticulate" used herein refers to a plurality of discrete or aggregated particles, pellets, beads, spheroids, powders, granules, spheres or mixture thereof, irrespective of their size, shape or morphology. "Valacyclovir" as used herein refers to the free acid form, its salts, esters, solvates, polymorphs, enantiomers, derivatives or mixtures thereof. Preferably, the salt of valacyclovir is hydrochloride salt.
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 "intragranular" (part/phase/portion) as used herein refers to the components of formulation of the present invention that are within granules. The term "extragranular" (part/phase/portion) as used herein refers to those components of formulation of the present invention that are outside the granules. The term "excipient" means a pharmacologically inactive component such as a diluent, binder, lubricant, surfactant, carrier, sweetener, flavouring agents, colouring agents, glidants, disintegrants, superdisintegrants, antioxidants, water-soluble polymers, water-insoluble polymers, release controlling agents, solvents, preservatives, alkalizing agents, buffering agents, effervescent forming agents, co-processed excipients, antiadherants, viscosity modifier, suspending agent, or the like. Co-processed excipients are also covered under the scope of present invention. Combination of excipients performing the same function may also be used to achieve desired formulation characteristics.
The term "free of ion exchange resin" as used herein refers to the pharmaceutical composition of valacyclovir or pharmaceutically acceptable salt thereof, which does not contain any ion exchange resin.

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 composition and/or to the individual intragranular and/or extragranulart portion and/or any individual part or combination of part(s) used or in total weight of the multiparticulate composition.
The term "taste mask pharmaceutical composition" used herein refers to a composition that masks the taste of bitter drugs, using a combination of binder and at least a sweetener.
The term "sedimentation volume ratio" refers to a ratio of the final volume of sediment (Vu) to the original volume of sediment (VO) before settling.
In an embodiment of the present invention relates to a taste masked pharmaceutical composition comprising valacyclovir or its pharmaceutically acceptable salt thereof and one or more excipients selected from the group consisting of a diluent, binder, sweetener, suspending agent, flavoring agent, preservatives and mixtures thereof, wherein the said composition is free of ion exchange resin.
In an embodiment of the present invention relates to a taste masked pharmaceutical powder composition comprising valacyclovir or its pharmaceutically acceptable salt thereof with one or more pharmaceutically acceptable excipient and/or carrier and process for its preparation.
In another embodiment of the present invention relates to a taste masked pharmaceutical composition comprising:

a) an intragranular portion comprising valacyclovir or its pharmaceutical^ acceptable salt thereof, one or more pharmaceutical^ acceptable binder and at least a sweetener;
b) an extragranular portion comprising at least one suspending agent and one or more pharmaceutical^ acceptable excipients;
wherein the valacyclovir or its pharmaceutical^ acceptable salts thereof and suspending agent have a ratio ranging from about 10:0.1 to about 10:5 by weight.
In another embodiment of the present invention relates to a taste masked powder composition suitable for reconstitution comprising:
a) an intragranular portion comprising valacyclovir or its pharmaceutical^ acceptable salt thereof, one or more pharmaceutical^ acceptable binder and at least a sweetener;
b) an extragranular portion comprising at least one suspending agent and one or more pharmaceutical^ acceptable excipients;
wherein the valacyclovir or its pharmaceutical^ acceptable salts thereof and suspending agent have a ratio ranging from about 10:0.1 to about 10:5 by weight, further wherein the composition maintain a sedimentation volume ratio of more than about 0.8 to about 1 for at least 8 to 10 hours after the composition is reconstituted into a suspension.
Another embodiment of the present invention relates to a taste masked pharmaceutical composition, wherein the process comprises of:
a) blending valacyclovir or its pharmaceutically acceptable salt thereof with one or more excipients;
b) granulating the blend with a granulating liquid comprising binder, and at least a sweetener and/or one or more excipients;
c) optionally the wet mass is extruded and spheronized in an extrusion spheronizer;
d) drying the valacyclovir granulate; and

e) blending with one or more excipients selected from the group consisting of a diluent, binder, sweetener, flavoring agent, preservatives and mixtures thereof; wherein the said composition is free of ion-exchange resin.
Yet another embodiment of the present invention relates to a pharmaceutical composition in a multiparticulate form comprising valacyclovir or pharmaceutically acceptable salt thereof, spray coated with acrylate polymers or water insoluble polymers to mask the bitter taste of the drug. The multiparticulate formulation may comprises one or more excipients selected from the group consisting of a diluent/carrier, buffering agent, suspending agent, sweeteners, flavouring agent, preservatives and mixtures thereof.
Another embodiment of the present invention relates to a taste masked pharmaceutical composition in a multiparticulate form comprising about 0.1% w/w to about 85% w/w valacyclovir or pharmaceutically acceptable salt thereof; spray coated with acrylate polymers or water insoluble polymers in an amount of about 0.1%) w/w to about 10%> w/w; and optionally mixed with one or more excipients selected from the group consisting of a diluent, binder, sweetener, flavoring agent, preservatives and mixtures thereof, wherein the composition is free of ion exchange resin.
Another embodiment of the present invention relates to a taste masked powder pharmaceutical composition comprising about 0.1%> w/w to about 85% w/w valacyclovir or pharmaceutically acceptable salt thereof.
Another embodiment of the present invention relates to a taste masked powder pharmaceutical composition of valacyclovir or pharmaceutically acceptable salt thereof, wherein the composition has a pH range from 3-7. Preferable a pH range from 4.5-6.5.

Yet another embodiment of the present invention relates to a taste masked pharmaceutical composition in the form of a granule comprising valacyclovir or pharmaceutically acceptable salt thereof and a polymer, prepared by hot melt extrusion process.
Another embodiment of the present invention relates to a taste masked pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof adsorbed on diluents like microcrystalline cellulose (MCC), lactose, mannitol and the like; optionally mixed with one or more excipients selected from the group consisting of a diluent/carrier, buffering agent, viscosity modifier, suspending/thickening agent, sweeteners, flavouring agent, preservatives and mixtures thereof.
In another embodiment of the present invention relates to a taste masked pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof, complexed with cyclodextrin and optionally mixed with one or more excipients selected from the group consisting of a diluent/carrier, binding agents, buffering agent, viscosity modifier, suspending/thickening agent, sweeteners, flavoring agent, preservatives and mixtures thereof.
Another embodiment of the present invention relates to a multiparticulate based pharmaceutical composition comprising
a) a core comprising valacyclovir or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients,
b) coated with one or more water insoluble polymers, and
c) optionally mixing the coated core with one or more excipients selected from the group consisting of a diluent, buffering agent, suspending agent, sweetener, flavouring agent, preservative and mixtures thereof, wherein the composition is free of ion exchange resin.

Another embodiment of the present invention relates to a multiparticulate based pharmaceutical composition comprising
a) an inert core comprising mannitol or microcrystalline cellulose
b) drug layer comprising valacyclovir or pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients
c) coated with one or more water insoluble polymers and
d) optionally mixing the coated core with one or more excipients selected from the group consisting of a diluent/carrier, buffering agent, suspending/thickening agent, sweeteners, flavouring agent, preservatives and mixtures thereof, wherein the composition is free of ion exchange resin.
In yet another embodiment of the present invention, multiparticulate system based composition of valacyclovir or pharmaceutically acceptable salt thereof is in the form of powder for oral suspension.
In accordance with another embodiment of the present invention relates to a taste masked pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof with one or more one or more excipients and desirable amount of silicon dioxide, preferably colloidal or amorphous silicon dioxide, which provides better cushioning effect between the filler particles leading to quicker dissolution and smoother mouth feel.
Another embodiment of the present invention, relates to process for the preparation of a powder for oral suspension composition, granules or multiparticulates of valacyclovir or pharmaceutically acceptable salt thereof, which is suitable for suspension in water and/ or water miscible suitable solvents to form an orally administrable product which comprises admixing, at ambient temperature and humidity conditions.

In another embodiment of the present invention, there is provided a process for the preparation of a ready to use liquid suspension of valacyclovir or pharmaceutically acceptable salt thereof, comprising combining various components using conventional equipments such as overhead stirrers, ultrasonifiers, mills, homogenizers operating at an RPM range of about 100-8000 RPM, or as per requirement, manufacturing and heating tank with or without vacuum application assembly known in the art or industry practice. Many different orders of adding components to the stirrer can be employed. This can be followed by addition of liquid carrier (such as aqueous and/or non-aqueous), suspending agent, sweetening agent, taste masking agent and the like. pH of the suspension is adjusted to desired value using aqueous buffering agents as needed.
In accordance with still another embodiment of the present invention, there is provided a taste masked pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof, wherein valacyclovir has a particle size distribution D90 less than about 200 urn. Preferable, the particle size of valacyclovir or pharmaceutically acceptable salt thereof has D90 less than about 100 um.
In another embodiment, the solid oral multiparticulate oral pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof, wherein the particle size of pellets/spheres have an average diameter of about 0.6 mm to about 1.2 mm; preferably from about 0.7 mm to about 1.0 mm.
In another embodiment of the present invention, the pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof having a bulk density in the range from 0.45 g/ml to 0.60 g/ml and tapped density in the range from 0.71 g/ml to 0.84 g/ml.
In another embodiment, the powder for oral suspension comprising valacyclovir or pharmaceutically acceptable salt thereof provides a powder formulation

suitable for reconstitution to form a suspension comprising one or more suspending agents. The suspending agent is effective for maintaining a sedimentation volume ratio of more than about 0.8 to about 1.2 for at least 8-10 hours after the powder formulation is reconstituted into an aqueous medium, preferably, effective for more than about 0.9 to about 1.0. In some embodiments, the valacyclovir or pharmaceutically acceptable salt thereof and the suspending agent have a ratio ranging from about 10:1 to about 10:5 by weight more particularly, the ratio is about 5:1 by weight.
In another embodiment, the powder for oral suspension comprising valacyclovir or pharmaceutically acceptable salt thereof can be administered by sprinkling the pellets / spheres / granules / spheroids encapsulated in hard gelatin capsule or packed in sachets on teaspoonful full of applesauce or apple juice wherein the composition exhibited stability for at least 10 minutes.
In yet another embodiment, the taste masked pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof, wherein the said composition provides an in vitro of at least about 85% of valacyclovir within 15 minutes under USP dissolution apparatus II in 900 ml of 0.1N HC1 at 50 rpm.
Another aspect of the present invention provides a taste masked pharmaceutical composition of an active ingredient as a unit or multiple dose pack comprising valacyclovir or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.
Another aspect of the present invention provides a process for the preparation comprising the steps of:
a) Preparing a taste masked pharmaceutical composition of valacyclovir or its pharmaceutically acceptable salts thereof;
b) Filling the taste masked pharmaceutical composition into a unit dose pack; and

c) Sealing the pack.
Another embodiment of the present invention provides a taste masked pharmaceutical composition, which can be consumed directly from the packet. Alternatively, the dry powder composition may be formulated for reconstitution in water or any other suitable liquid. The reconstituted composition can be a dispersion or suspension.
In another embodiment, of the present invention, relates to a pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof is expected to be stable at 40 °C and 75% relative humidity at least for a period of about 3 months.
Another embodiment of the present invention, relates to a pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof in an amount from about lmg to about lOOOmg, preferably from about 250 mg to about lOOOmg.
In further embodiment, the present invention includes method of using the pharmaceutical composition comprising valacyclovir or pharmaceutically acceptable salt thereof in the treatment of Cold Sores (Herpes Labialis), Genital Herpes, Herpes Zoster and Chicken pox.
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 valacyclovir or its pharmaceutically acceptable salts thereof by using conventional methods known in the art but not limited to blending, mixing, dry granulation, wet granulation, hot-melt extrusion, extrusion-spheronization, pelletization, spray drying and/or spray coating techniques. 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. 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.
Another embodiment of the present invention also provides a process for the preparation of a solid oral multiparticulate pharmaceutical composition of valacyclovir or pharmaceutically acceptable salt 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) coating of the spheres using acrylate polymers and/or water insoluble polymers (f) mixing with one or more excipients and dispensing in a sachet.
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) for ease of dosing. Pack chosen are made of material, which is non-reactive with the suspension and powder for reconstitution. Containers for use in the storage of the oral suspensions may be used to administer a multiple or unit dose of valacyclovir. 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 or any other material known in the art.

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, calcium phosphate, dibasic anhydrous, calcium phosphate, dibasic dihydrate, calcium phosphate tribasic, 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 5 to about 98% w/w of the total composition.
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% to about 20% 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 O.P/o to about 5% 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% to about 5% by weight of coated pellets/spheres.
Disintegrants selected from the group consisting of crospovidone, modified starches, croscarmellose sodium, sodium starch glycolate, low substituted Hydroxypropyl cellulose and carboxymethylcellulose calcium. These disintegrants are also known as superdisintegrants. The disintegrant may constitute from about 0% to about 20% by weight of the pharmaceutical composition.
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% to about 85% by weight of the composition
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 - 1.0 % w/w and is satisfactory. Although flavoring agent in lesser concentrations than 0.1% 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.
Suitable coloring agent are selected from the group consisting of 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. The final formulations may be coated or uncoated.
Suitable suspending agents are selected from the group consisting of gums such as xanthan gum, carrageenan gum, acacia, guar gum, locust bean gum, gum tragacanth; celluloses such as hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, sodium carboxymethylcellulose, mixture of microcrystalline cellulose and carboxymethylcellulose (Avicel® RC); 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 20% w/w of the composition. In a particular embodiment, the dry powder compositions are free of suspending agents.
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. Various useful isotonizing agent include, but are not limited to, sodium chloride, mannitol, D-sorbitol, glucose, glycerin or the like.
In another embodiment, the pharmaceutical composition of the present invention comprising valacyclovir or its pharmaceutically acceptable salts thereof from about 50 mg to about 1000 mg in the formulation, preferably 250-1000 mg, more preferably 250-500 mg.
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% to about 10% by weight of the pharmaceutical 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, hydroxymethyl ethyl 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, acrylate and 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 consisting of 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, Eudragit® EPO, Eudragit® El00, Eudragit®E12,5.
In another embodiment the present invention includes particle size of free drug particulate form of valacyclovir or its pharmaceutically acceptable salts thereof, wherein particle diameter at 90% cumulative volume (D90) is less than about 200 um, preferably less than 100 um. 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.
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. 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 of valacyclovir hydrochloride may be prepared by using quantitative formula as given in the following examples:
Table 1: Formulation of valacyclovir hydrochloride powder for oral suspension

Table 2: Unit dose sachet formulation of valacyclovir hydrochloride powder for oral suspension
Table 3: Multiparticulate systems (MUPs) of Valacyclovir Hydrochloride
Table 4: Multiparticulate systems (MUPs) of Valacyclovir Hydrochloride

Example XII: MUPs based Powder for oral suspension
*Preferred method of manufacture: All above-mentioned formulations can be manufactured by spray coating of drug particles or adsorption of drug particles on diluent and mixing with excipients or Extrusion-spheronization or wet granulation or pelletization technique.
Table 5: Ready to use suspension

The above-mentioned examples IV and V of formulation of valacyclovir powder for oral suspension (initial samples) exhibited the desired in-vitro dissolution profile. The dissolution rate of the drug was determined using USPII (paddles) at 50 rpm and 900 ml 0. IN HC1 media, which is measured by UV method at 254 nm as shown in Table 6:
Table 6: Dissolution Data
It was observed that more than 85% of drug released in 15 mins.
Formulations of example IV and V were reconstituted to a strength of 250 mg/5
ml strength and pH was measured.
Results in terms of amount of valacyclovir hydrochloride present in the powder
for oral suspension were analyzed by validated ultraviolet (UV) method at 254 nm
and the same were presented in the Table 7 below:
Table 7: Data for Assay and pH
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of the invention.

WE CLAIM:
1. A taste masked powder composition suitable for reconstitution comprising:
c) an intragranular portion comprising valacyclovir or its pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable binder and at least a sweetener;
d) an extragranular portion comprising at least one suspending agent and one or more pharmaceutically acceptable excipients;
wherein the valacyclovir or its pharmaceutically acceptable salts thereof and suspending agent have a ratio ranging from about 10:0.1 to about 10:5 by weight.
2. The powder composition of claim 1, wherein the one or more excipients are selected from the group consisting of diluent, binder, lubricant, surfactant, sweetener, glidant, disintegrant, preservative, pH modifying agent.
3. The powder composition of claim 1, comprising about 0.1% w/w to about 85%) w/w valacyclovir or pharmaceutically acceptable salt thereof, wherein the composition has a pH range from 4.5-6.5.
4. The powder composition of claim 1, where in the valacyclovir or pharmaceutically acceptable salt thereof has a D90 less than about 100 urn.
5. The powder composition of claim 1, wherein the suspension is homogeneous within about 1 minute after reconstitution with water.
6. The powder composition of claim 1, wherein the binders are selected from the group consisting of hypromellose, sodium carboxymethylcellulose, gelatin, hydroxypropylcellulose, maltose, methylcellulose, povidone, copovidone, starch and/or mixtures thereof.

7. The powder composition of claim 1, wherein the sweeteners are selected from
the group consisting of sucrose, dextrose, sucralose, sorbitol, neotame,
aspartame, acesulfame K, fructose, mannitol, saccharin sodium and mixtures
thereof.
8. The powder composition of claim 1, wherein the suspending agent is selected
from the group consisting of xanthan gum, cellulose derivatives, alginates,
colloidal silicon dioxide or mixture thereof.
9. The powder composition of claim 1, wherein the sedimentation volume ratio is more than about 0.8 to about 1 for at least 8 to 10 hours after the composition is reconstituted into a suspension.
10. The powder composition of claim 1, wherein the bulk density of the granules is in the range of from 0.45-0.60 g.ml and tapped density of the granules is in the range of from 0.71-0.84 g/ml.
11. The powder composition of claim 1, which is prepared by a process selected from the group consisting of dry powder blending, dry granulation, wet granulation, extrusion-spheronization, pelletization and/or spray drying.
12. A taste masked powder composition suitable for reconstitution comprising:

c) an intragranular portion comprising valacyclovir or its pharmaceutically acceptable salt thereof, one or more pharmaceutically acceptable binder and at least a sweetener;
d) an extragranular portion comprising at least one suspending agent and one or more pharmaceutically acceptable excipients;
wherein the valacyclovir or its pharmaceutically acceptable salts thereof and suspending agent have a ratio ranging from about 10:0.1 to about 10:5 by weight, further wherein the composition maintain a sedimentation volume ratio of more than about 0.8 to about 1 for at least 8 to 10 hours after the composition is reconstituted into a suspension.

13. The powder composition of any of claims 1-12, wherein the said composition provides an in vitro of at least about 85% of valacyclovir within 15 minutes under USP dissolution apparatus II in 900 ml of 0. IN HC1 at 50 rpm.
14. The powder composition of any of claims 1-13, wherein the said composition is packed in a packaging material selected from the group consisting of a sachet, foil, pouch, capsule, bottle, container.