DESC:
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)

&

THE PATENTS (AMENDMENT) RULES, 2006

COMPLETE SPECIFICATION
(See Section 10 and Rule 13)

“SUSTAINED RELEASE READY TO USE SUSPENSION COMPRISING DEXTROMETHORPHAN”

SUN PHARMACEUTICAL INDUSTRIES LIMITED
SUN House, 201 B/1, Western Express Highway,
Goregaon (East), Near Jay Coach, Mumbai,
Maharashtra – 400 063, India

The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan hydrobromide polistirex granules and chlorpheniramine maleate polistirex granules, and at least one liquid carrier containing one or more pharmaceutically acceptable excipients. The invention further provides methods of formulating liquid suspensions which provides a desired in vitro dissolution profile.

BACKGROUND OF THE INVENTION
The combination of dextromethorphan hydrobromide and chlorpheniramine maleate is used for the temporary relief of cough, sneezing, or runny nose due to the common cold, hay fever or other upper respiratory allergies. Dextromethorphan hydrobromide is a cough suppressant and chlorpheniramine maleate is an antihistamine. The immediate release formulation are to be taken 4 to 6 times a day, and has side effects such as drowsiness, dizziness or trouble sleeping primarily due to immediate release of chlorpheniramine maleate.
Dextromethorphan hydrobromide and chlorpheniramine maleate are cationic in nature. The Polistirex complex of drugs is formed via chemical linkage owing to ionic interaction between anionic group of sulfonic acid (in sodium polystyrene sulfonate) and cationic drugs. Upon entering into intestinal fluid, the strong cations such as sodium, potassium etc., induce drug release from polistirex complex while acting as counter ions. In this manner, the gradual drug release occurs which helps to maintain 12 hour drug concentration in plasma giving sustained effect.
The approved products based on polistirex technology include, for example, Delsym® (Dextromethorphan Polistirex extended release Suspension 30 mg/5 mL) and Tuzistra XR® (Codeine Polistirex and Chlorpheniramine Polistirex extended release oral Suspension 20+4 mg/ 5 mL).
U.S. Patent No. 5,980,882A discloses a pharmaceutical composition comprising a drug-resin complex and a chelating agent, wherein the composition is in the form of a solid or a gel; and wherein the drug in the drug-resin complex is selected from dextromethorphan, codeine, morphine, hydrcodone, pseudoephedrine, or phenylpropanolamine.
PCT Publication No. WO 1998/027961A2 discloses a sustained release pharmaceutical composition comprising: sulfonate cationic exchange resins that are cross-linked with divinyl benzene, the resins having the pharmacologically active drug dextromethophan bound thereto, wherein the drug/resin complexes are coated with a mixture of ethyl cellulose and water soluble polymers.
U.S. Patent No. 4,788,055A discloses an antitussive pharmaceutical composition suitable for controlled, sustained release of dextromethorphan comprising a sulfonated polystyrene resin in salt-form crosslinked with cross-linking agent, and at least one pharmaceutically acceptable adjuvant.
PCT Publication No. WO 1991/013612A1 discloses a composition for controlled and sustained release of a pharmaceutically acceptable drug comprising a drug-resin complex formed from an ion-exchange resin and a pharmacologically active drug, wherein the drug is dextromethorphan, phenylpropanolamine, noscapine, pseudoephedrine or chlorpheniramine, or a pharmaceutically acceptable salt thereof.
U.S. Patent No. 4,762,709A discloses an ionic drug adsorbed on ion exchange resin particles to form a coated drug-resin complex, said ion exchange resin particles of the coated drug-resin complex having been treated with an impregnating agent selected from the group consisting of polyethylene glycol, propylene glycol, mannitol, lactose and methylcellulose and subsequently coated with a water-permeable diffusion barrier; a second ionic component bearing the same charge as said ionic drug adsorbed on ion exchange resin particles to form a second ionic component-resin complex, said ion exchange resin particles of the second ionic component-resin complex are uncoated
U.S. Patent No. 4,996,047 discloses an oral pharmaceutical composition in unit dosage form consisting essentially of irregularly shaped ion-exchange resin particles and a pharmacologically active drug bound thereto, and wherein said drug-resin complex particles have been subsequently coated with a water-permeable diffusion barrier and wherein said composition provides controlled release of said active drug.
Despite significant progress, there is no ready to use, stable sustained-liquid oral suspension containing dextromethorphan hydrobromide and chlorpheniramine maleate, which provides taste masking, improves stability and quality of the product suitable for twice-a-day administration, leads to lesser somnolence, and enhances the patient compliance.
Thus, there is a need in the art to develop sustained release liquid dosage forms with better pharmacologic properties and stability suitable for once or twice-a-day administration. Thus, the sustained release formulation will improve the patient compliance by reducing dosage frequency.
The inventors of the present invention have conducted intensive studies and surprisingly found that the complexation of dextromethorphan hydrobromide and chlorpheniramine maleate with sodium polystyrene sulfonate allows for dosage regime of twice daily (12 hours apart) for the intended indications. Furthermore, it results into taste masking and improvement in the stability thereby enhancing patient compliance and quality of product.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules and at least one liquid carrier containing one or more pharmaceutically acceptable excipients. The invention further provides methods of formulating liquid suspensions which provides a desired in vitro dissolution profile, which can be used to predict the in vivo bioequivalence. The medication is indicated for the temporary relief of cough, due to throat irritation, sneezing and running nose.
In one aspect the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising:
i) dextromethorphan polistirex granules coated with a semi-permeable membrane;
ii) chlorpheniramine polistirex granules; and
iii) at least one liquid carrier containing one or more pharmaceutically acceptable excipients.
In another aspect the present invention provides ready to use, stable sustained release formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane comprises from about 75% to about 80% (w/w) dextromethorphan polistirex granules.
In yet another aspect the present invention provides ready to use, stable sustained release formulation comprising dextromethorphan polistirex granules comprises from about 30% to 35 % (w/w) of dextromethorphan hydrobromide and from about 65% to about 70% (w/w) of sodium polystyrene sulfonate.
In another aspect the present invention provides ready to use, stable sustained release formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, wherein the semi-permeable membrane is ethylcellulose which comprises from about 1% to about 25% or about 1% to about 15% or about 1% to about 5% by weight of the drug-polistirex granules.
In yet another aspect the formulation according to present invention, wherein ethylcellulose further comprises an impregnation agent selected from polyethylene glycol having a concentration of from about 1% to about 10% or about 1% to 5%, preferably about 1%, about 2%, about 2.2%, 2.3% or about 2.5% by weight of the drug-polistirex granules.
In one aspect of the present invention the ready to use, stable sustained release formulation comprises chlorpheniramine polistirex granules, wherein the granules contains about 50% (w/w) of chlorpheniramine maleate and about 50% (w/w) of sodium polystyrene sulfonate.
In yet another aspect the formulation according to the present invention, the pH of the suspension is between about pH 3 and about pH 5, preferably about 3.75; and the viscosity is between about 250 and about 750 cps.
In a further aspect the formulation according to present invention comprises an aqueous based liquid carrier.
In one aspect the formulation according to present invention comprises excipients, wherein the excipient is selected from preservative, thickener, pH adjuster, chelating agent, sweetener or mixture thereof.
In an aspect the formulation according to present invention is provided in pharmaceutically acceptable doses ranging from about 5 mL to about 15 mL.
In an aspect the formulation according to the present invention comprises dextromethorphan and chlorpheniramine, wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide and chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In another aspect the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising:
i) dextromethorphan polistirex granules, about 9 mg;
ii) dextromethorphan polistirex sustained release granules, about 103 mg;
iii) chlorpheniramine polistirex granules, about 8 mg;
iv) methylparaben, about 10 mg; propylparaben, about 1mg; xanthan gum, about 15 mg; citric acid, about 10 mg; disodium edetate, about 15 mg; fructose, about 800 mg; sucrose, about 625 mg; or combination thereof; and
v) propylene glycol, about 200 mg;
wherein the pharmaceutically acceptable dose is made up to 5 mL using purified water.
The formulation according to above aspect, wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide and chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In another aspect the formulation according to present invention is in the form of a medicament for temporary relief of cough, throat irritation, sneezing and running nose.
In a further embodiment the present invention provides a process for the preparation of a ready to use, stable sustained release liquid oral suspension formulation comprising the steps of:
a) obtaining dextromethorphan polistirex sustained release granules;
b) obtaining chlorpheniramine polistirex granules; and
c) combining a pre-determined amount of drug-polistirex granules with a plurality of excipients in a container in aqueous based liquid carrier.
In an aspect according to present invention the formulation of the present invention provides a gradual release of chlorpheniramine maleate which leads to a lesser somnolence compared to immediate release syrup formulation.
The aforementioned aspects and embodiments, and other aspects, objects, features and advantages of the present invention will be apparent from the following detailed description.

BRIEF DESCRIPTION OF THE DRAWING
Figure 1: shows an in vitro dissolution profile in release media over time.
Figure 2: shows an in vitro dissolution profile in 0.1N HCl, over time.
Figure 3: shows an in vitro dissolution profile in 4.5 pH phosphate buffer, over time.
Figure 4: shows an in vitro dissolution profile in 6.8 pH phosphate buffer, over time.

DESCRIPTION OF THE INVENTION
The present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and at least one liquid carrier containing one or more pharmaceutically acceptable excipients.
As used herein the specification following definitions apply unless clearly indicated otherwise. For example, the term "pharmaceutically acceptable", refers to a compound (active ingredient or excipient) that is not biologically or otherwise undesirable, i.e., the compound may be incorporated into a pharmaceutical formulation of the invention and administered to a patient without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the formulation in which it is contained.
The term “stable” as used herein means that in the pharmaceutical formulation dextromethorphan hydrobromide and chlorpheniramine content do not degrade much and complies with pharmacopeia limits of impurities. The formulation of the present invention contains not more than 10%, not more than 9%, not more than 8%, not more than 7%, not more than 6%, not more than 5%, not more than 4%, not more than 3%, not more than 2%, not more than 1%, of the total impurities when stored for at least one day, at least two days, at least three days, at least four days, at least five days, at least six days, at least seven days, for at least 2 weeks, at least 3 weeks, at least 4 weeks, at least 6 weeks, at least 8 weeks, for at least 3 months, at least 6 months, for at least 1 year, or at least 2 years at ambient or refrigerated conditions. Further, the liquid suspension is characterized by having no substantial change in the in vitro dissolution release profile upon storage.
The term “formulation”, as used herein refers to formulation or pharmaceutical preparation or pharmaceutical composition or composition. Such terms can be used interchangeably to define the present formulation / composition.
The term “dextromethorphan”, as used herein, refers to dextromethorphan and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof. Preferably dextromethorphan is present as dextromethorphan hydrobromide or dextromethorphan hydrobromide monohydrate. Dextromethorphan hydrobromide is a cough suppressant. In some embodiments, dextromethorphan is present in an amount of about 0.1% w/w to about 20% w/w, about 0.5% w/w to about 20% w/w, about 1% w/w to about 20% w/w, about 1% w/w to about 15% w/w, about 1% w/w to about 10% w/w, about 1% w/w to about 5% w/w, or about 1% to 3% of the sustained-release formulation. In other embodiments, dextromethorphan is present in about 0.5% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, about 5% w/w, about 6% w/w, about 7% w/w, about 8% w/w, about 9% w/w, or about 10% w/w of the sustained-release formulation. In some embodiments, the dextromethorphan or its salt is present in a concentration of about 1 mg/mL to about 20 mg/mL, about 1 mg/mL to about 10 mg/ml, about 1mg/ml to about 5mg/ml in the liquid suspension formulation. In some embodiments, the dextromethorphan or its salt is present in a concentration of about 30 mg in a pharmaceutically acceptable dose of 5 mL.
The term “chlorpheniramine”, as used herein, refers to chlorpheniramine and pharmaceutically acceptable salts thereof, including hydrates and solvates thereof, and crystalline or amorphous forms thereof. Preferably chlorpheniramine is present as chlorpheniramine maleate. Chlorpheniramine maleate is an antihistamine used to treat sneezing, itching, watery eyes, and runny nose caused by allergies or the common cold. In some embodiments, chlorpheniramine is present in an amount of about 0.05% w/w to about 5% w/w, about 0.2% w/w to about 5% w/w, about 0.2% w/w to about 3% w/w, about 0.2% w/w to about 2% w/w, or about 0.2% w/w to about 1% w/w of the sustained-release formulation. In other embodiments, chlorpheniramine is present in about 0.05% w/w, about 0.1% w/w, about 0.2% w/w, about 0.3% w/w, about 0.4% w/w, about 0.5% w/w, about 1% w/w, about 2% w/w, about 3% w/w, about 4% w/w, or about 5% w/w of the sustained-release formulation. In some embodiments, the chlorpheniramine or its salt is present in a concentration of about 0.2 mg/mL to about 5 mg/mL, about 0.5 mg/mL to about 2 mg/mL, about 0.8 mg/mL to about 2 mg/mL in the liquid suspension formulation. In some embodiments, the chlorpheniramine or its salt is present in a concentration of about 4 mg in a pharmaceutically acceptable dose of 5 mL.
As used herein the term “sustained-release” refers to dosage forms which provide a controlled supply of drug to an extended period of time. The sustained-release drug preparations may provide the convenience of daytime dosing where the dosage form can be administered to a patient first thing in the morning and provide therapeutic levels of the drug throughout the day. Further, the sustained-release drug preparation may deliver drugs in a manner that will maintain therapeutically effective plasma levels over a period of time that is significantly longer than that which is given by immediate release dosage form. This eliminates the need to interrupt sleep to take medication and can prevent missed doses, thus improving patient compliance compared to immediate release or other frequent administration (3-4 times a day) dosage forms.
The term “pharmaceutically acceptable excipients”, as used herein, includes excipients that may be added to the liquid carrier in order to mix with polistirex granules to form sustained release suspension formulation. Examples of suitable pharmaceutically acceptable excipients include, but are not limited to sweeteners, preservative, buffering agent, flavouring agent, complexing agent, viscosity enhancer, diluent, and mixtures thereof. Additional excipients such as glidants, bulking agents, tonicity agents and coloring agents are within the scope of the invention.
Examples of sweeteners include, but are not limited to, glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt™ (hydrogenated isomaltulose), lactitol, sorbitol, mannitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. In some embodiments, the suspension formulation preferably contains fructose, sucrose, sorbitol or mannitol as a sweetener.
Examples of preservatives include, but are not limited to, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, methylparaben, ethylparaben, propylparaben, butylparaben, benzoic acid, sodium benzoate, potassium sorbate, vanillin or a mixture thereof. In some embodiments, the suspension formulation preferably contains methylparaben, propylparaben or mixture thereof as preservative.
Examples of buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co-precipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include sodium citrate, citric acid, citric acid monohydrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. In some embodiments, the suspension formulation preferably contains citric acid as buffer. In some embodiments, the buffer is phosphate buffer, which comprises potassium phosphate monobasic and sodium hydroxide.
Examples of flavoring agents include, but are not limited to, tutti-frutti flavor, peppermint flavor, cherry flavor, strawberry and orange flavours and the like or others known in the art.
Examples of thickeners (viscosity enhancers) include, but are not limited to, dextrin, cellulose derivatives (ethylcellulose, hydroxyethyl cellulose, methylcellulose, carboxymethyl cellulose, microcrystalline cellulose, hypromellose, mixture of microcrystalline cellulose and sodium carboxymethyl cellulose and the like) , starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). In some embodiments, thickeners may act at as stabilizing agent. In some embodiments, the thickener is xanthan gum.
Examples of complexing agent (chelating agent), include, but are not limited to, ethylenediaminetetraacetic acid (EDTA), or an EDTA derivative such as disodium edetate or cyclodextrin or derivative thereof, such as 2-hydroxypropyl-ß-cyclodextrin, methyl-ß-cyclodextrin, randomly methylated-ß-cyclodextrin, ethylated-ß-cyclodextrin, triacetyl-ß-cyclodextrin, peracetylated-ß-cyclodextrin, carboxymethyl-ß-cyclodextrin, hydroxyethyl-ß-cyclodextrin, hydroxypropyl- ß -cyclodextrin, 2-hydroxy-3-(trimethylammonio)propyl-ß-cyclodextrin, glucosyl-ß-cyclodextrin, maltosyl-ß-cyclodextrin, sulfobutyl ether-ß-cyclodextrin, branched-ß-cyclodextrin, hydroxypropyl-?-cyclodextrin, randomly methylated-?-cyclodextrin, trimethyl-?-cyclodextrin, and any combination(s) thereof. In some embodiments, the chelating agent is disodium edetate.
Additional excipients such as glidants, lubricants, bulking agents, tonicity agents and coloring agents may be present in the formulation of the present invention.
Examples of glidants include, but are not limited to, fumed silicon dioxide, sodium aluminosilicate, calcium silicate, powdered cellulose, colloidal silicon dioxide, microcrystalline cellulose, corn starch, sodium benzoate, calcium carbonate, magnesium carbonate, talc, metallic stearates, calcium stearate, magnesium stearate, zinc stearate, magnesium lauryl sulfate, and magnesium oxide, or a mixture thereof.
Examples of lubricants include, but are not limited to, magnesium stearate, colloidal silicon dioxide, talc, calcium stearate, stearic acid, PEG, glyceryl monostearate, potassium benzoate, sodium stearyl fumarate, glyceryl behenate, mineral oil, or a mixture thereof.
Examples of coloring agents include, but are not limited to, FD&C Red No. 3, FD&C Red No. 20, FD&C Red No. 40, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&C Orange No. 5, caramel, ferric oxide, ponceau red and mixtures thereof.
The term “liquid carrier” as used herein includes purified water, polyhydric alcohol such as propylene glycol or a mixture thereof. The formulation of the present invention is substantially free of alcohol. The term “substantially free" of alcohol means that the formulation contains less than about 2%, less than about 1%, less than about 0.5%, less than about 0.2%, or less than about 0.1% or less than about 0,05% by weight or by volume of alcohol.
As used herein, the term “about”, refers to any value which lies within the range defined by a variation of up to ±10% of the value.
The formulation of the present invention is suitable for administration twice a day over a 24 hour period. The formulation may be administered with food, before food or after food.
The present invention further provides various embodiments. In some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein the pH of the suspension is between about pH 3 and pH 5, preferably about pH 3.75, and the viscosity is between about 250 cps and about 750 cps.
In one embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, and the viscosity is between about 250 and about 750 cps.
In another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein the pH of the suspension is between about 3 and about 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein the pharmaceutically acceptable dose is 5 mL to 15 mL, preferably 5 mL or 10 mL.
In yet another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide in a pharmaceutically acceptable dose of 5 mL.
In further embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In a further embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, providing taste masking, improved stability and quality to the formulation suitable for twice-a-day administration, leads to lesser somnolence, and enhances the patient compliance.
In one embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide and chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing methylparaben, propylparaben and xanthan gum, wherein the pH of the suspension is between about pH 3 and about 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps.
In a further embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing citric acid, disodium edetate, fructose and sucrose; and wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps.
In one embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing methylparaben, propylparaben, xanthan gum, citric acid, disodium edetate, fructose, sucrose, ponceau red and cherry flavor, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps.
In another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing methylparaben, propylparaben, xanthan gum, citric acid, disodium edetate, fructose, sucrose, ponceau red and cherry flavor, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide in a pharmaceutically acceptable dose of 5 mL.
In yet another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing methylparaben, propylparaben, xanthan gum, citric acid, disodium edetate, fructose, sucrose, ponceau red and cherry flavor, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In further embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing methylparaben, propylparaben, xanthan gum, citric acid, disodium edetate, fructose, sucrose, ponceau red and cherry flavor, wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide and chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In one embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising: i) about 9 mg dextromethorphan polistirex granules; ii) about 103 mg dextromethorphan polistirex sustained release granules; iii) about 8 mg chlorpheniramine polistirex granules; iv) about 10 mg methylparaben, about 1mg propylparaben, about 15 mg xanthan gum, about 10 mg citric acid, about 15 mg disodium edetate, about 800 mg fructose, about 625 mg sucrose or combination thereof; and v) about 200 mg propylene glycol; wherein the pharmaceutically acceptable dose is made up to 5 mL using purified water.
In another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising: i) about 9 mg dextromethorphan polistirex granules; ii) about 103 mg dextromethorphan polistirex sustained release granules; iii) about 8 mg chlorpheniramine polistirex granules; iv) about 10 mg methylparaben, about 1mg propylparaben, about 15 mg xanthan gum, about 10 mg citric acid, about 15mg disodium edetate, about 800 mg fructose, about 625 mg sucrose or combination thereof; and v) about 200 mg propylene glycol; wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide in a pharmaceutically acceptable dose of 5 mL.
In yet another embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising: i) about 9 mg dextromethorphan polistirex granules; ii) about 103 mg dextromethorphan polistirex sustained release granules; iii) about 8 mg chlorpheniramine polistirex granules; iv) about 10 mg methylparaben, about 1 mg propylparaben, about 15 mg xanthan gum, about 10 mg citric acid, about 15 mg disodium edetate, about 800 mg fructose, about 625 mg sucrose or combination thereof; and v) about 200 mg propylene glycol; wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In an embodiment, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising: i) about 9 mg dextromethorphan polistirex granules; ii) about 103 mg dextromethorphan polistirex sustained release granules; iii) about 8 mg chlorpheniramine polistirex granules; iv) about 10 mg methylparaben, about 1 mg propylparaben, about 15 mg xanthan gum, about 10 mg citric acid, about 15 mg disodium edetate, about 800 mg fructose, about 625 mg sucrose or combination thereof; and v) about 200 mg propylene glycol; wherein the pH of the suspension is between about pH 3 and about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps, and wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide and chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
In one embodiment of the present invention there is provided a process for the preparation of a ready to use, stable sustained release liquid oral suspension formulation comprising the steps of:
(a) obtaining dextromethorphan polistirex sustained release granules;
(b) obtaining chlorpheniramine polistirex granules; and
(c) combining a pre-determined amount of drug-polistirex granules with a plurality of excipients in a container in aqueous based liquid carrier.
The above steps (a) to (c) can be accomplished by following the methods well known to a person of ordinary skill in the art including, for example, the methods as discussed hereinafter.
Drug-Polistirex Granules
Binding of dextromethorphan or chlorpheniramine to polistirex “sodium polystyrene sulfonate” (Amberlite IRP-69) can be accomplished by using methods well known to a person of ordinary skill in the art. Dextromethorphan hydrobromide and chlorpheniramine maleate are cationic in nature, the polistirex complex is formed via chemical linkage owing to ionic interaction between anionic group of sulfonic acid (in sodium polystyrene sulfonate) and cationic drugs. The drug-polistirex complex thus formed is collected by filtration and dried using conventional drying techniques, for example, the drying of the complex is accomplished using fluidized bed dryer. Upon entering into intestinal fluid, the strong cations such as sodium, potassium etc., induce drug release from polistirex complex while acting as counter ions.
The amount of dextromethorphan hydrobromide that can be loaded onto polistirex ranges from about 25% to about 40%, preferably about 30%, about 31%, about 32%, about 33%, about 34% or about 35% by weight of the loaded dextromethorphan-polistirex granules. In a preferred embodiment, typically dextromethorphan-polistirex ratio is about 1:2. The amount of chlorpheniramine maleate that can be loaded onto polistirex ranges from about 40% to about 60%, preferably about 45%, about 46%, about 47%, about 48%, about % 49% or about 50% by weight of the loaded chlorpheniramine- polistirex granules. In a preferred embodiment, typically chlorpheniramine-polistirex ratio is about 1:1. In a particular embodiment, the amount of drug loaded on polistirex granules provides a drug release profile to achieve a desired in vivo serum concentration profile.
Thus, in some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein dextromethorphan polistirex granules coated with a semi-permeable membrane contains about 75% to about 80% (w/w) dextromethorphan polistirex granules.
In some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane; chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein dextromethorphan polistirex granules contains about 30% to about 35 % (w/w) of dextromethorphan hydrobromide and about 65% to about 70% (w/w) of sodium polystyrene sulfonate.
Impregnation of Drug-Polistirex Granules
Drug-polistirex granules thus formed can be impregnated with a humectant selected from polyethylene glycol, sorbitol, mannitol, xanthan gum, alginate, propylene glycol or a mixture thereof. Preferably, the humectant is polyethylene glycol. Alternatively, the humectant can be added as an ingredient during drug-polistirex complexation formation step. The treatment of drug-polistirex granules with humectant (e.g., polyethylene glycol) enables effective coating and effectively prolongs the release of drugs from drug-polistirex granules. The amount of humectant comprises from about 10% to about 40%, about 15% to 30%, or about 20% to 30% by weight of the drug-polistirex complex.
In some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein the drug-polistirex granules is impregnated with polyethylene glycol having a concentration of about 1% to about 25%, about 1% to about 15%, or about 1% to about 5% by weight of the drug-polistirex granules.
Coating of impregnated Drug-Polistirex Granules
The impregnated drug-polistirex granules are coated with a semi-permeable membrane comprising a water-permeable film-forming polymer selected from ethylcellulose, methylcellulose, hydroxylpropylmethylcellulose (HPMC), hydroxyethly-cellulose (HEC), cellulose acetate phthalate, HEC phthalate, HPMC phthalate or acrylic acid ester or a mixture thereof. Preferably polymer is ethyl cellulose, which is commercially produced with different viscosity grades. The ethylcellulose types are usually distinguished by their nominal viscosities, molecular weights and ethoxy substitutions, and are collectively referred to as “Premium Ethylcellulose Polymers”, for example an ethyl cellulose having the content of ethoxyl group from 44 to 50% and viscosity of about 41% to 49%. In certain embodiments, the polymer is selected from EthocelTM, Aquacoat®, EudragitT® or Surelease®, preferably Ethocel 45 Centipoise (cps). The polymer is optionally admixture with plasticizers, pigments and other substances to alter the characteristics of the coating. The plasticizers for ethylcellulose may include, for example, castor oil, hydrogenated vegetable oil, dibutyl sebacate, diethyl phthalate, tributyl citrate or triacetin. Preferably, the plasticizer is hydrogenated vegetable oil.
The amount of water-permeable, film-forming polymer comprises from about 1% to about 25%, about 1% to about 15%, or about 1% to about 5% by weight of the drug-polistirex complex. The amount of plasticizer comprises from about 1% to about 10% or about 1% to about 5%, preferably, about 1%, about 2%, about 2.2%, about 2.3% or about 2.5% by weight of the drug-polistirex complex.
Any coating procedure which provides a contiguous coating on each granule of drug-polistirex complex without significant agglomeration of granules may be used. Coatings may be applied with a fluid-bed coating apparatus such as GPCG (Glatt-Powder-Coater-Granulator). In a preferred embodiment, The PEG impregnated drug- polistirex complex was coated with Ethocel 45 cps and hydrogenated vegetable oil in the ratio of about 70 to about 30 in GPCG using bottom spray method. The suitable solvent used for coating purpose includes, for example dichloromethane, acetone or combination thereof (90:10).
Thus, in some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein semi-permeable membrane (film-forming polymer) is ethyl cellulose having a concentration of from about 1% to about 25%, about 1% to about 15%, or about 1% to about 5% by weight of the drug-polistirex granules.
In some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein semi-permeable membrane (film-forming polymer) is ethyl cellulose further comprises hydrogenated vegetable oil, and wherein the concentration of hydrogenated vegetable oil is from about 1% to about 5%, preferably, about 1%, about 2%, about 2.2%, about 2.3% or about 2.5% by weight of the drug-polistirex granules.
Sustained Release Liquid Oral Suspension
In preparing the sustained release liquid oral suspension, the coated drug-polistirex granules are incorporated into a pre-formulated aqueous based liquid carrier which is entirely or predominantly water. Preferably, the carrier is a suspension of the pharmaceutical formulation in an aqueous vehicle containing a plurality of pharmaceutically acceptable excipients such as preservative, thickener, pH adjuster, chelating agent or sweetener as discussed hereinabove.
The preparation of aqueous based liquid carrier involves one or more steps. In first step, the solvent (e.g., propylene glycol, PG) phase is prepared by dissolving preservatives such as methylparaben and propylparaben, followed by dispersing thickener such as xanthan gum into it. The aqueous suspension base is prepared which is composed of a buffer such as citric acid, chelating agent such as disodium edetate, sweetener such as fructose and sucrose. Next, the PG phase is added to the aqueous phase under stirring, followed by addition of colouring agents such as Ponceau red 4R Supra and flavoring agents such as cherry flavor. Examples of solvent include propylene glycol, glycerin, sorbitol solution and the like which is used as a co-solvent with water to assist solubilization and incorporation of water-insoluble ingredients into the formulation. The formulations of this invention contain from about 5% to about 20%, from about 5% to about 15% or from about 5% to 10% of co-solvent in a pharmaceutically acceptable dose of 5 mL.
Thus, in some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein the aqueous based carrier contains a co-solvent, wherein the amount of co-solvent comprises from about 5% to about 20%, from about 5% to about 15% or from about 5% to about 10% in a pharmaceutically acceptable dose of 5 mL.
In certain embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein the aqueous based carrier contains propylene glycol, wherein the amount of propylene glycol comprises from about 5% to about 15% or from about 5% to about 10% in a pharmaceutically acceptable dose of 5 mL.
In certain embodiments, the invention provides for sustained release liquid drug suspensions that are bioequivalent to a target product, for example Delsym®. In a preferred embodiment, the invention provides for sustained release liquid drug suspensions comprising dextromethorphan-polystirex complex coated with a film forming polymer, chlorpheniramine-polystirex complex, and at least one liquid carrier, wherein the formulation thus formed is bioequivalent to Delsym® drug suspension, which contains 30 mg of dextromethorphan hydrobromide in a dose of 5 mL.
In an aspect the formulation according to present invention provides an oral sustained release drug preparations which provides the convenience of daytime dosing where the dosage form can be administered to a patient in the morning and provide therapeutic levels of the drug throughout the day. Thus, the sustained release formulation will improve the patient compliance by reducing dosage frequency. In an aspect the formulation is devoid of side effects like drowsiness, dizziness as found in immediate release formulations of chlorpheniramine.
In a further aspect the formulation according to present invention provides a gradual release of chlorpheniramine maleate in such a way that it leads to a lesser somnolence compared to immediate release syrup formulations. Thus the side effects like drowsiness, dizziness or trouble sleeping primarily due to immediate release of chlorpheniramine maleate can be avoided or reduced.
In one aspect the formulation according to present invention is for thrice a day administration, preferably twice a day administration. Such dosing regimen leads to a lesser Somnolence and enhance the patient compliance.
In some embodiments, the present invention provides a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients, wherein the said oral suspension formulation is devoid of side effects like Somnolence.
In some embodiments the present invention provides a method for treating cough, throat irritation, sneezing and running nose by administering a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients. In an aspect the method includes thrice a day administration. In yet another aspect the method includes twice a day administration.
In another embodiments the present invention provides a method for reducing the dosing frequency in treatment of cough, throat irritation, sneezing and running nose by administering a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients.
In some embodiment present invention provides methods for alleviating the symptoms of cough, throat irritation, sneezing and running nose by administering the formulation according to the present invention.
In one embodiment the present invention provides a method for reducing the drowsiness or somnolence associated with various cough formulation including immediate release formulations, wherein the method comprises administering a administering a ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients.
In some embodiments the present invention provides a method for treating cough, throat irritation, sneezing and running nose by administering a ready to use, stable sustained release liquid oral suspension formulation prepared by a process comprising the steps of:
(a) obtaining dextromethorphan polistirex sustained release granules;
(b) obtaining chlorpheniramine polistirex granules; and
(c) combining a pre-determined amount of drug-polistirex granules with a plurality of excipients in a container in aqueous based liquid carrier.
The present invention is illustrated below by reference to the following examples. However, one skilled in the art will appreciate that specific methods and results discussed are merely illustrative of the invention, as innumerable variations, modifications, applications, and extensions of these embodiments and principles can be made without departing from the spirit and scope of the invention.

EXAMPLES
Example 1:
Composition of Polistirex granules
S. No. mg / 100 mg Ingredients
Dextromethorphan Polistirex granules 33.33%w/w
1 33.333 Dextromethorphan hydrobromide
2 66.667 Sodium Polystyrene Sulfonate (Amberlite IRP 69)
Dextromethorphan Polistirex Sustained release granules 26.20%w/w
1 78.616 Dextromethorphan Polistirex granules 33.33%w/w
2 15.724 Polyethylene glycol 3350
3 3.962 Ethyl Cellulose 45 cps
4 1.698 Hydrogenated Vegetable oil
Chlorpheniramine Polistirex Sustained release granules 50%w/
1 50.000 Chlorpheniramine maleate
2 50.000 Sodium Polystyrene Sulfonate (Amberlite IRP 69)

Composition of Suspension
S. No. mg / 5mL Ingredients
1 10.00 Methylparaben
2 1.00 Propylparaben
3 200.00 Propylene Glycol
4 15.00 Xanthan Gum (Keltrol T/ Xantural 180)
5 10.000 Citric acid (anhydrous)
6 50.000 Disodium Edetate
7 800.000 Fructose (Krystar 300)
8 625.000 Sucrose
9 1.000 Ponceau red 4R Supra CI no. 16255
10 10.000 Cherry flavor 054384C (Firmenich)
11 103.032 Dextromethorphan Polistirex Sustained Release Granules 26.20% w/w
12 9.000 Dextromethorphan Polistirex Granules 33.33% w/w
13 8.000 Chlorpheniramine Polistirex Sustained Release Granules 50% w/w
14 q.s. up to 5 mL Purified water

Manufacturing Process for Dextromethorphan Polistirex SR Granules
Step 1: Complexation
The complexation of dextromethorphan hydrobromide with sodium polystyrene sulfonate was carried out at elevated temperature up to 70°C for 1 hour (wherein the ratio of drug to resin is 1:2). The drug-resin complex was collected by filtration, followed by drying using fluidized bed dryer (FBD).
Step 2: Impregnation with Polyethylene Glycol (PEG)
The dried drug-resin complex was transferred to rapid mixer granulator (RMG) bowl and polyethylene glycol (PEG, 40% w/w) was added while mixing with slow impeller speed. 20% of PEG 3350 was added to drug-resin complex. The PEGylated drug-resin complex was dried and sifted through 40# American Standard Test Sieve Series (ASTM).
Step 3: Coating
The PEG impregnated drug-resin complex was coated with Ethocel 45 cps: hydrogenated vegetable oil (70:30) in GPCG (Glatt-Powder-Coater-Granulator) using bottom spray method. The solvent mixture of dichloromethane and acetone was used in the ratio of 90 to 10.
Manufacturing Process for Chlorpheniramine Polistirex Granules
The complexation of chlorpheniramine maleate with sodium polystyrene sulfonate was carried out for about 1 hour, wherein drug : resin ratio is 1:1. The drug-resin complex was collected by filtration, followed by drying using tray drier.
Manufacturing Process for Suspension
• Propylene glycol (PG) phase was prepared by dissolving methylparaben and propylparaben followed by dispersing xanthan gum into it,
• Aqueous suspension base was prepared by dissolving citric acid, disodium edetate, fructose and sucrose,
• Addition of PG phase to aqueous phase under stirring,
• Addition of Ponceau red 4R Supra and Cherry flavor 054384C (Firmenich); and
• Sprinkling of polistirex granules followed by volume make-up using purified water.

Example 2: Dissolution Profile of Dextromethorphan Hydrobromide
Dissolution testing was performed using the protocol described below and compared with Delsym® drug suspension as there is no such combination exist in sustained release form internationally. In Delsym® suspension (Reference), dextromethorphan content is equivalent to 30 mg of dextromethorphan hydrobromide in a dose of 5 mL. To prepare a bioequivalent suspension, the formulation was manufactured using the details as outlined in Example 1 (Test product), and the dissolution methodology described herein below is based on creating a robust in vitro dissolution test that will correlate with in vivo studies.
A known quantity of drug suspension is placed in dissolution media which contains 500 mL of 0.1N hydrochloric acid (HCl) for the first hour. After the first hour, pH is finally brought up to about 6.8 by adding 900 phosphate buffer. The dissolution procedure involves USP-II, agitating the sample at a 50 rpm. The suspension dissolution profile was created that are based upon ingestion pH ranges, and mimics three pH parameters as acceptable for multimedia dissolution tests. The results of the dissolution assay are shown in Figures 1-4 and Table 1-4 as below:
Table-1: Follow on Dissolution data: (Comparative dissolution with Delsym)
Time (Hr) DELSYM Ex-1 formulation
1 15 (11-21) 22 (21-24)
3 45 (42-51) 51 (48-53)
6 58 (55-65) 64 (60-68)
9 62 (59-65) 70 (65-74)
12 64 (62-68) 75 (68-78)
Media: 500 mL 0.1N HCl for 1 Hr. followed by pH 6.8 phosphate buffer 900 ml; (Release media), USP-II apparatus; 50 RPM.

Table-2: In vitro dissolution profile in 0.1N HCl, (Comparative dissolution with Delsym)
Time (Hr) DELSYM Ex-1 formulation
0.5 12 (11-15) 18 (16-20)
1 15 (12-20) 21 (19-23)
1.5 17 (14-24) 23 (20-25)
3 23 (17-33) 28 (25-30)
6 29 (21-40) 33 (30-35)
9 32 (23-43) 37 (33-39)
12 33 (25-45) 39 (35-42)
Media: 500 mL 0.1N HCl; USP-II apparatus; 50 RPM.
Table-3: In vitro dissolution profile in pH 4.5, phosphate buffer: (Comparative dissolution with Delsym)
Time (Hr) DELSYM Ex-1 formulation
1 28 (23-33) 30 (29-32)
2 37 (33-42) 38 (36-41)
3 43 (39-50) 43 (41-47)
4 48 (44-54) 47 (45-51)
6 55 (50-61) 52 (50-57)
8 60 (55-65) 56 (55-61)
9 61 (56-66) 58 (57-63)
10 62 (58-68) 60 (58-65)
12 64 (60-68) 63 (61-67)

Media: 900 mL pH 4.5 phosphate buffer; USP-II apparatus; 50 RPM.

Table-4: In vitro dissolution profile in pH 6.8 phosphate buffer: (Comparative dissolution with Delsym)
Time (Hr) DELSYM Ex-1 formulation
1 29 (26-34) 32 (31-35)
2 40 (36-47) 41 (38-44)
3 47 (43-54) 47 (44-50)
4 52 (48-59) 52 (48-55)
6 59 (54-67) 58(55-60)
8 63 (58-72) 62 (60-64)
9 65 (61-74) 65 (62-66)
10 67 (62-76) 66 (64-68)
12 69 (64-78) 69 (67-71)

Media: 900 mL pH 6.8 phosphate buffer; USP-II apparatus; 50 RPM.
Any phosphate buffer can be used to achieve the desired pH in the in vitro dissolution testing; preferably the phosphate buffer comprises potassium phosphate and sodium hydroxide.

Example 3
Stability data of Formulation of Example-1
Example-1 samples were kept for stability study for a period of 3, 6 and 12 months. Following which the pH, viscosity, assay by HPLC, related substance and dissolution study was performed to assess the stability of the samples. The details of stability study is provided in below table 5 (for 25oC/60% RH stage) and table 6 (for 40oC/75%RH).
Table 5: Stability data of Ex-1 formulation at 25oC (±2)/60%RH (±5)
Test Limit Initial 3 month 6 month 12 month
pH 3.0-5.0 3.73 4.08 3.80 4.10
Viscosity 250-750 cps 430 370 388 450
Assay of Dextromethorphan HBr (Label claim 30 mg) 27.0-33.0
(90.0-110.0%) 29.0 mg (96.7%) 30.7 mg (102.33%) 30.91 mg (103.0%) 29.0 mg (96.68%)
Assay of Chlorpheniramine maleate (Label claim 4.0 mg) 3.6-4.4
(90.0-110.0%) 3.95 mg (98.8%) 3.99 mg (99.75%) 4.06 mg (101.5%) 3.81 mg (95.32%)
RS- Dextromethorphan HBr Dextromethorphan Impurity C NMT 1.0% Not detected Not detected Not detected Not detected
RS- Dextromethorphan HBr Unk. Imp. (Highest unknown) NMT 0.5% Not detected Not detected Not detected Not detected
RS- Dextromethorphan HBr Total Impurity NMT 2.0% Not detected Not detected Not detected Not detected
RS-Chlorpheniramine maleate Unk. Imp. (Highest unknown) NMT 0.5% Not detected Not detected Not detected Not detected
RS-Chlorpheniramine maleate Total Impurities. NMT 2.0% Not detected Not detected Not detected Not detected
Dissolution
Dextromethorphan HBr 1 Hr. NMT 40% 24.5 22.3 23.7 30.0
6 Hr. 50 - 80% 68.8 61.8 61.8 71.5
12 Hr. NLT 55% 81.0 77.5 73.0 85.89
Dissolution
Chlorpheniramine maleate 2 Hr. NMT 20% 2.3 1.5 1.1 1.3
4 Hr. 25 - 60% 51.3 35.2 32.8 35.5
6 Hr. NLT 60% 80.8 73.5 70.6 73.1
HBr: Hydrobromide; NMT: Not more than; NLT: Not Less than, Hr. Hour

Table 6: Stability data of Ex-1 formulation at 40oC (±2)/75%RH (±5)
Test Limit Initial 1 month 3 month 6 month
pH 3.0-5.0 3.73 3.98 3.88 3.78
Viscosity 250-750 cps 430 360 360 387
Assay of Dextromethorphan HBr (Label claim 30 mg) 27.0-33.0
(90.0-110.0%) 29.0 mg (96.7%) 30.05 mg
(100.2%) 30.7 mg (102.33%) 30.61 mg (102.0%)
Assay of Chlorpheniramine maleate (Label claim 4.0 mg) 3.6-4.4
(90.0-110.0%) 3.95 mg (98.8%) 3.91 mg
(97.8%) 3.99 mg (99.75%) 4.02 mg (100.5%)
RS- Dextromethorphan HBr Dextromethorphan Impurity C NMT 1.0% Not detected Not detected Not detected Not detected
RS- Dextromethorphan HBr Unk. Imp. (Highest unknown) NMT 0.5% Not detected Not detected Not detected Not detected
RS- Dextromethorphan HBr Total Impurity NMT 2.0% Not detected Not detected Not detected Not detected
RS-Chlorpheniramine maleate Unk. Imp. (Highest unknown) NMT 0.5% Not detected Not detected Not detected Not detected
RS-Chlorpheniramine maleate Total Impurities. NMT 2.0% Not detected Not detected Not detected Not detected
Dissolution
Dextromethorphan HBr 1 Hr. NMT 40% 24.5 26.6 23.7 24.4
6 Hr. 50 - 80% 68.8 69.3 62.2 64.5
12 Hr. NLT 55% 81.0 83.9 79.8 77.9
Dissolution
Chlorpheniramine maleate 2 Hr. NMT 20% 2.3 1.1 1.2 1.1
4 Hr. 25 - 60% 51.3 38.7 35.9 32.1
6 Hr. NLT 60% 80.8 78.2 76.6 69.7
HBr: Hydrobromide; NMT: Not more than; NLT: Not Less than, Hr. Hour
The samples kept for stability study were found to be stable at least 12 month at 25oC (±2)/60%RH (±5) and for at least 6 months at 40oC (±2)/75%RH (±5). The impurity levels i.e. Dextromethorphan Impurity C, unknown impurity of dextromethorphan and chlorpheniramine and the total impurity were not detected and found to be within the specification limit for both the test conditions for at least 12 month at 25oC (±2)/60%RH (±5) and for at least 6 months at 40oC (±2)/75%RH (±5). The present formulation was found to be stable and with a dissolution profile within the specification for the entire stability period. ,CLAIMS:We Claim:
1. A ready to use stable sustained release oral suspension formulation comprising:
a) dextromethorphan polistirex granules coated with a semi-permeable membrane;
b) chlorpheniramine polistirex granules; and
c) at least one liquid carrier containing one or more pharmaceutically acceptable excipients.
2. The formulation as claimed in claim 1, wherein the dextromethorphan polistirex granules coated with a semi-permeable membrane comprises from about 75% to about 80% (w/w) dextromethorphan polistirex granules.
3. The formulation as claimed in claim 2, wherein the dextromethorphan polistirex granules comprises from about 30% to 35 % (w/w) of dextromethorphan hydrobromide and from about 65% to about 70% (w/w) of sodium polystyrene sulfonate.
4. The formulation as claimed in claim 1, wherein the dextromethorphan polistirex granules coated with the semi-permeable membrane, wherein the semi-permeable membrane is ethyl cellulose which comprises from about 1% to about 25% by weight of the drug-polistirex granules.
5. The formulation as claimed in claim 4, wherein ethyl cellulose further comprises an impregnation agent selected from polyethylene glycol having a concentration from about 1% to about 10% by weight of the drug-polistirex granules.
6. The formulation as claimed in claim 1, wherein the chlorpheniramine polistirex granules, comprises about 50% (w/w) of chlorpheniramine maleate and about 50% (w/w) of sodium polystyrene sulfonate.
7. The formulation as claimed in claim 1, wherein the pH of the suspension is between about pH 3 to about pH 5 and the viscosity is between about 250 to about 750 cps.
8. The formulation as claimed in claim 1, wherein the excipients are selected from preservative, thickener, pH adjuster, chelating agent, sweetener or mixture thereof.
9. A ready to use stable sustained release oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane and chlorpheniramine polistirex granules, wherein dextromethorphan content is equivalent to about 30 mg of dextromethorphan hydrobromide and chlorpheniramine content is equivalent to about 4 mg of chlorpheniramine maleate in a pharmaceutically acceptable dose of 5 mL.
10. A process for the preparation of a ready to use, stable sustained release liquid oral suspension formulation comprising the steps of:
a) obtaining dextromethorphan polistirex sustained release granules;
b) obtaining chlorpheniramine polistirex granules; and
c) combining a pre-determined amount of polistirex granules obtained from step a) and b) with a plurality of excipients in a container in aqueous based liquid carrier.
11. The formulation as claimed in claim 9, wherein the formulation further comprises an aqueous based carrier containing one or more pharmaceutically acceptable excipients selected from preservative, thickener, pH adjuster, chelating agent or sweetener, wherein the pH of the suspension is between about pH 3 to about pH 5, preferably about pH 3.75, the viscosity is between about 250 and about 750 cps.
12. The formulation as claimed in claim 9, wherein the said oral suspension formulation is devoid of somnolence side effect.
13. The formulation as claimed in claim 1 and 9, wherein the said ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable excipients alleviates the symptoms of cough, throat irritation, sneezing and running nose in a patient in need thereof.
14. The formulation as claimed in claim 1 and 9, wherein the said ready to use, stable sustained release liquid oral suspension formulation comprising dextromethorphan polistirex granules coated with a semi-permeable membrane, chlorpheniramine polistirex granules; and aqueous based carrier containing one or more pharmaceutically acceptable, reduces a dosing frequency for alleviation of symptoms of cough, throat irritation, sneezing and running nose.
15. The formulation as claimed in claim 13 or 14, wherein the said formulation is for thrice a day administration of the ready to use, preferably for twice a day administration.
16. The formulation as claimed in claim 13 or 14, wherein the said ready to use, stable sustained release liquid oral suspension formulation is prepared by a process comprising the steps of:
(a) obtaining dextromethorphan polistirex sustained release granules;
(b) obtaining chlorpheniramine polistirex granules; and
(c) combining a pre-determined amount of drug-polistirex granules obtained from step a) and step b) with a plurality of excipients in a container in aqueous based liquid carrier.