DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

PHARMACEUTICAL COMPOSITION COMPRISING ANTIHISTAMINE AND DECONGESTANT, PROCESS OF PREPARATION AND USE THEREOF

AUROBINDO PHARMA LTD HAVING REGISTERED OFFICE AT
THE WATER MARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes the invention and the manner in which it is to be performed:
FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition for oral administration comprising antihistamine and decongestant and process of preparation thereof.

The present invention relates to a pharmaceutical composition comprising Fexofenadine or pharmaceutically acceptable salt and Pseudoephedrine or pharmaceutically acceptable salt thereof and process of preparation thereof.

The present invention also relates to compositions comprising antihistamine and decongestant for use in the treating allergic rhinitis associated with sneezing, rhinorrhea, runny nose, itchy nose, itchy throat, itchy palate, itchy eyes, watery eyes and nasal congestion symptom like common cold, cold like flu symptom, hay fever, upper respiratory allergies, sinus congestion, and the related symptoms.

The present invention also relates to method of using the pharmaceutical composition comprising Fexofenadine or pharmaceutically acceptable salt and Pseudoephedrine or pharmaceutically acceptable salt thereof which comprises administration of the composition for treating allergic rhinitis associated with sneezing, rhinorrhea, runny nose, itchy nose, itchy throat, itchy palate, itchy eyes, watery eyes and nasal congestion symptom like common cold, cold like flu symptom, hay fever, upper respiratory allergies, sinus congestion, and the related symptoms.

BACKGROUND OF THE INVENTION

Rhinitis refers to an inflammatory disorder of the nasal passages. The symptoms of rhinitis typically consist of sneezing, rhinorrhoea, nasal congestion, and increased nasal secretion. Untreated rhinitis may lead to other disorder including infection of the sinuses, ears and upper respiratory tract.

Two types of oral medication are commonly used to treat rhinitis: decongestant and antihistamine. Decongestant and antihistamine differ in mechanism of action, therapeutic effects, and side effects. It is common practice to combine the use of these two to bring about more complete symptom relief of rhinitis than is possible with either entity alone.

Fexofenadine is the major active metabolite of terfenadine, is an antihistamine with selective peripheral H1-receptor antagonist activity and Pseudoephedrine is an adrenergic (vasoconstrictor) agent; is an orally active sympathomimetic amine and exerts a decongestant action on the nasal mucosa.

SUDAFED® 12 HOUR (Pseudoephedrine hydrochloride) Extended release Tablet 120 mg got approved in the USA Market on Oct 31, 1991. Inactive ingredients of SUDAFED® 12 HOUR tablet are candelilla wax, FD&C blue no. 1, aluminum oxide, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, propylene glycol, shellac, talc & titanium dioxide.

US 5895663 Perrigo discloses a method for producing extended-release tablets comprising the steps of dry mixing at least one active ingredient (Pseudoephedrine) with about 20% to about 40% by final tablet weight of hydroxypropylmethylcellulose (HPMC) and about 25% to about 50% by final tablet weight of microcrystalline cellulose; and directly compressing said mixture to form tablets.

SUDAFED® 24 HOUR (Pseudoephedrine hydrochloride) Extended release Tablet 240 mg got approved in the USA Market on Dec 15, 1992. Inactive ingredients of SUDAFED® 24 HOUR tablet are cellulose triacetate, hydroxypropylcellulose, hypromellose, iron oxide, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80, povidone, propylene glycol, shellac, sodium chloride, titanium dioxide.

ALLEGRA® ALLERGY (Fexofenadine hydrochloride) Tablet 60 mg and 180 mg got approved in the USA Market on Jan 24, 2011. Inactive ingredients of ALLEGRA® ALLERGY tablet are croscarmellose sodium, D&C red 28, D&C red 33, FD&C blue 1, gelatin, hydroxypropylcellulose, hydroxypropyl methylcellulose, magnesium stearate, microcrystalline cellulose, PEG-135, pharmaceutical ink, pregelatinized starch, titanium dioxide, colloidal silicon dioxide, polyethylene glycol, povidone.

US 3687956 UCB SA, US 3878217 Richardson Merrell Inc., US 4254129 Richardson Merrell Inc. & US 4285957 Aventis Inc. discloses a new piperidine derivatives and its compositions with therapeutic use thereof.

US 4929605 Merrell Dow Pharma discloses a pharmaceutical composition in solid unit dosage form comprising (a) a therapeutically effective amount of a piperidinoalkanol compound (a-[4-(l,l-dimethylethyl)phenyl]-4-(hydroxydiphenylmethyl)-1-piperidinebutanol), or a pharmaceutically acceptable salt thereof, (b) pharmaceutically acceptable nonionic or cationic surfactant in an amount of from about 0.1% to about 6% by weight of the composition, and (c) pharmaceutically acceptable carbonate salt in an amount of from about 2% to about 50% by weight of the composition.

ALLEGRA-D® 12 HOUR ALLERGY AND CONGESTION (Fexofenadine hydrochloride; Pseudoephedrine hydrochloride) Extended Release Tablet 60 mg/120 mg got approved in the USA market on Jan 24, 2011. Allegra-D® 12 Hour is a histamine H1 -receptor antagonist and is an adrenergic (vasoconstrictor) agent/ decongestant/ sympathomimetic amine. Inactive ingredients of Allegra-D® 12 Hour film coated ER Tablet are microcrystalline cellulose, croscarmellose sodium, magnesium stearate, carnauba wax, stearic acid, silicon dioxide, hypromellose, polyethylene glycol.

US 4996061 Merrell Dow Pharma discloses a pharmaceutical composition in the form of a multiple-compression tablet comprising (a) a discrete zone made with Formulation (A) which comprises a carrier base material combined with a therapeutically effective decongestant amount of a sympathomimetic drug, or a pharmaceutically acceptable salt thereof, the carrier base material begin a mixture of (I) one or more pharmaceutically acceptable water-soluble nonionic cellulose ethers in an amount from about 18% to about 50% by weight of Formulation (A), (ii) one or more pharmaceutically acceptable anionic surfactants in an amount from about 2% to about 20% by weight of Formulation (A), and (iii) one or more other pharmaceutically acceptable excipients, wherein said carrier base material provides a sustained release of the sympathomimetic drug, and (b) a discrete zone made with Formulation (B) which comprises a second carrier base material combined with a therapeutically effective antihistaminic amount of a piperidinoalkanol, or a pharmaceutically acceptable salt thereof, the second carrier base being a mixture of (i) calcium carbonate in an amount from about 0.5% to about 25% by weight of Formulation (B), (ii) one or more pharmaceutically acceptable nonionic surfactants in an amount from about 1% to about 10% by weight of Formulation (B), and (iii) one or more other pharmaceutically acceptable excipients, wherein Formulation (B) optionally also contains a therapeutically effective decongestant amount of a sympathomimetic drug, or a pharmaceutically acceptable salt thereof, and wherein said second carrier base material provides an immediate release of the piperidinoalkanol and of any sympathomimetic drug.

US 6039974 Aventis Inc. discloses pharmaceutical composition in the form of bilayer tablet comprising, (a) a first discrete zone made with formulation (A) which comprises, a therapeutically effective decongestant amount of a sympathomimetic drug, or a pharmaceutically acceptable salt thereof, in an amount of about 18% to about 39% by weight of Formulation (A), and a first carrier base material, the first carrier base material comprising a mixture of; (I) carnauba wax in an amount of about 59% to about 81% by weight of Formulation (A); and (ii) a suitable antiadherent in an amount of about 0.25% to about 2.00% by weight of Formulation (A); wherein said first carrier base material provides a sustained release of the sympathomimetic drug; and (b) a second discrete zone made with Formulation (B) which comprises a therapeutically effective antihistaminic amount of a piperidinoalkanol, or a pharmaceutically acceptable salt thereof, in an amount of about 15% to about 30% by weight of Formulation (B) and a second carrier base material, the second carrier base comprising a mixture of; (I) a cellulose diluent in an amount of about 27% to about 73% by weight of Formulation (B); (ii) pregelatinized starch in an amount of about 15% to about 30% by weight of Formulation (B); (iii) a suitable disintegrant in an amount of about 0.25% to about 6.00% by weight of Formulation (B); and (iv) a suitable lubricant in an amount of about 0.25% to about 2.00% by weight of Formulation (B); wherein said second carrier base material provides an immediate release of the piperidinoalkanol or the pharmaceutically acceptable salt thereof.

US 7618649 Schering Corp discloses extended release oral dosage composition a bilayer solid composition comprising (a) an immediate release layer comprising an anti-allergic effective amount of desloratadine and at least one pharmaceutically acceptable excipient and pharmaceutically acceptable antioxidant (b) a sustained release second layer comprising an effective amount of a nasal decongestant, e.g. pseudoephedrine sulfate and a pharmaceutically acceptable sustained release agent wherein the composition contains less than about 2% of desloratadine decomposition products.

US 8263124 Dr Reddy's Laboratories Ltd., discloses a pharmaceutical composition comprising: (a) a tablet layer comprising an antihistaminic drug, a cellulose derivative, a polyol, a starch derivative, and a disintegrant; and (b) a tablet layer comprising a decongestant drug and a sustained release compound.

US 2010/0143471 Lupin Ltd., discloses a pharmaceutical composition consisting essentially of: 30 mg fexofenadine or salts thereof in immediate release form; and 60 mg pseudoephedrine or salts thereof; in a controlled release matrix consisting essentially of hydrogenated vegetable oil as a rate controlling agent; for the treatment of allergic rhinitis and associated symptoms in pediatric population.

ALLEGRA-D® 24 HOUR ALLERGY AND CONGESTION (Fexofenadine hydrochloride; Pseudoephedrine hydrochloride) Extended Release Tablet 180 mg/240 mg got approved in the USA market on Jan 24, 2011. Inactive ingredients of Allegra-D® 24 Hour film coated ER Tablet are microcrystalline cellulose, sodium chloride, cellulose acetate, polyethylene glycol, povidone, hypromellose, croscarmellose sodium, copovidone, magnesium stearate, silicon dioxide, talc, titanium dioxide. The tablets are finished with a commercially available film-coating consisting of the following excipients: isopropyl alcohol, methyl alcohol, methylene chloride, acetone, FD&C Blue No. 1, aluminum oxide.

US RE39069 and US 6613357 Osmotica Corp. discloses multi-layered osmotic device for the controlled delivery of one or more active agent comprises: a) a compressed core contains first active agent, an osmotic agent and povidone for controlled and continuous release of drug; b) a semipermeable membrane of cellulose esters and polyethylene glycol, surrounding the core and having a preformed passageway c) an inert water soluble polymer coat comprising poly(vinylpyrrolidone)-(vinyl acetate) copolymer surrounding the semipermeable membrane and plugging the passageway in the wall; and d) an external coat comprising, optionally povidone and polyethylene glycol, and a second active agent for immediate release of the drug.

US 5314697 Schering Corporation, discloses a film-coated extended release oral dosage composition containing the nasal decongestant pseudoephedrine sulfate in a unique polymer matrix core and a film-coating on such core containing the non-sedating antihistamine, loratadine, and use of the said composition for treating patients showing the signs and symptoms associated with upper respiratory diseases and nasal congestion.

US 6469009 UCB SA discloses a pharmaceutical composition which comprises therapeutically effective amount of a mixture of Pseudoephedrine hydrochloride and Cetirizine hydrochloride for the treatment of rhinitis.

US 6521254 J-Med Pharmaceuticals discloses an oral dosage unit consisting essentially of: (a) an antihistamine in an amount and formulation to exhibit antihistaminic activity in a human for greater than 22 hours; and (b) a decongestant in an amount and formulation to exhibit stimulatory activity in a human for less than 16 hours. US 6521254 also discloses the treatment for rhinitis in a human.

US 6994871 Andrx Pharmaceuticals Inc. discloses a controlled release pharmaceutical formulation consisting essentially of (A) a compressed matrix core consisting of: (i) 10 to 50 weight percent based on the total weight of the matrix core of a decongestant or pharmaceutically acceptable salt thereof; (ii) 50 to 90 weight percent based on the total weight of the matrix core of a hydrogel forming polymer "selected from the group consisting of hydroxypropyl methylcellulose, carboxymethylcellulose calcium, carboxymethylcellulose sodium, guar gum, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, acrylic acid crosslinked with polyalkenyl ethers or divinyl glycol, sodium alginate and polyethylene oxide"; (iii) 0 to 20 weight percent based upon the total weight of the matrix core of a filler selected from lactose, starch, dextrose or sucrose; (iv) 0 to 5 weight percent based on the total weight of the matrix core of a glidant; (v) 0 to 10 weight percent based on the total weight of the matrix core of one or more lubricants; (B) an immediate release coating on said compressed matrix core which consists essentially of: (i) 0.01 to 10 weight percent based on the total weight of the formulation of an antihistamine (ii) 0 to 20 weight percent based upon the total weight of the formulation of a pharmaceutically acceptable binder which allows for immediate release of the antihistamine (iii) 0 to 10 weight percent based on the total weight of the formulation of a lubricant; and (iv) 0 to 10 weight percent based on the total weight of the formulation of an antiadherent; and (C) optionally a polishing agent or color coating that coats the immediate release coating.

US 2008/0085311 Dr Reddy's Laboratories Ltd., discloses a pharmaceutical composition comprising (a) a plurality of cellulose particle having a coating comprising pseudoephedrine hydrochloride, an outer coating comprising ethyl cellulose, and providing a modified release of pseudoephedrine or salt thereof into aqueous fluid, granulated with a granulating composition containing fexofenadine hydrochloride; and (b) one or more pharmaceutical excipients; compressed into tablet.

US 2012/0100221 Ranbaxy Laboratories Ltd. discloses a layered pharmaceutical composition comprising a combination of an antihistamine and a decongestant. The layered composition includes (i) an antihistamine layer, which includes: (a) therapeutically effective amount of an antihistamine or its pharmaceutically effective salts; and (b) one or more pharmaceutically acceptable excipients; (ii) a decongestant layer, which includes: (a) a core, which includes therapeutically effective amount of decongestant or its pharmaceutically effective salts; (b) a coating over the core, which includes one or more rate-controlling polymers; and (c) one or more pharmaceutically acceptable excipients.

US 7014867 and US 7226614 UCB SA discloses a tablet comprising at least two distinct segments, one segment of which comprises as active ingredient predominantly cetirizine and a second segment of which comprises as active ingredient predominantly pseudoephedrine, said segments being composed and formed in such a way that the resulting tablet is substantially free of impurities formed by reaction of cetirizine with pseudoephedrine, wherein the interfacial surface area of the pseudoephedrine segment and cetirizine segment is less than 180 mm2 and with the proviso that the tablet comprises less than 5% by weight, relative to the total weight of the tablet, of an alkalinizing agent. US 7226614 also discloses a method for treating disorders or conditions associated with rhinitis, cold, flu, cold-like and flu like symptoms, and allergic rhinitis, relief of nasal congestion, seasonal rhinitis, rhinorrhea, nasal and ocular pruritus, redness of the eyes, tearing or sneezing.

There is a need for improved commercially viable pharmaceutical compositions of antihistamine & decongestant combinations for oral administration with effective manufacturing process.

The present invention relates to stable pharmaceutical composition for oral administration comprising antihistamine and decongestant and the process of preparation thereof. In particular, the present invention relates to a stable pharmaceutical composition comprising Fexofenadine or pharmaceutically acceptable salt and Pseudoephedrine or pharmaceutically acceptable salt thereof and process of preparation thereof.

SUMMARY OF INVENTION

Aspects of the present invention relates to pharmaceutical compositions comprising antihistamine and decongestant along with one or more pharmaceutically acceptable excipients.

Aspects of the present invention relates to pharmaceutical compositions comprising fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients.

Aspects of the present invention relates to an extended release tablet comprising: (a) antihistamine and decongestant; (b) diluent or filler; (c) disintegrant; (d) binder; (e) glidant or lubricant, and (f) coating agent.

Aspects of the present invention relates to an extended release tablet comprising: (a) fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof; (b) diluent or filler; (c) disintegrant; (d) binder; (e) glidant or lubricant, and (f) coating agent.

Aspects of the present invention relates to an extended release tablet comprising: (a) fexofenadine hydrochloride and pseudoephedrine hydrochloride; (b) diluent or filler; (c) disintegrant; (d) binder; (e) glidant or lubricant, and (f) coating agent.

Aspects of the present invention relates to an extended release bilayered tablet comprising: (a) a first layer comprises, a therapeutically effective amount of decongestant, or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; and (b) a second layer comprises, a therapeutically effective amount of antihistamine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

Aspects of the present invention relates to an extended release tablet comprising: (a) a core comprising therapeutic effective amount of decongestant or its pharmaceutically acceptable salt thereof, and one or more excipients; (b) optionally seal coating on core; (c) extended release coating on seal coated core; (d) optionally seal coating on extended release coated core and; (e) a drug layering on extended release coated core comprising therapeutic effective amount of antihistamine or its pharmaceutically acceptable salt and one or more excipients.

Aspects of the present invention also relates to process of preparation of tablet dosage form comprising antihistamine and decongestant thereof along with one or more pharmaceutically acceptable excipients.

Aspects of the present invention also relates to process of preparation of tablet dosage form comprising fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients.

Aspects of the present invention relates to method of using the pharmaceutical composition comprising antihistamine and decongestant thereof which comprises administration of the composition to a subject in need thereof.

Aspects of the present invention relates to method of using the pharmaceutical composition comprising fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof which comprises administration of the composition to a subject in need thereof.

Aspects of the present invention relates to compositions comprising antihistamine and decongestant agents for use in the treatment for allergic rhinitis associated with sneezing, rhinorrhea, runny nose, itchy nose, itchy throat, itchy palate, itchy eyes, watery eyes and nasal congestion symptom like common cold, cold like flu symptom, hay fever, upper respiratory allergies, sinus congestion, and the related symptoms.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "a" or "an" means one or more unless otherwise specified.

Open terms such as "include," "including," "contain," "containing" and the like mean "comprising".

The term "treatment" or "treating" refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder.

The term "Administering" or "administration" means providing a drug to a patient in a manner that is pharmacologically useful.

The term "Patient" or "subject" means an animal, preferably a mammal, more preferably human, in need of therapeutic intervention.

The term "Dosage form" means one or more compounds in a medium, carrier, vehicle, or device suitable for administration to a patient. "Oral dosage form" means a dosage form suitable for oral administration.

The term "or" can be conjunctive or disjunctive.

The term “% by weight” is based on the weight of the tablet.

The term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combinations of the specified ingredients in the specified amounts.

The term "pharmaceutically acceptable" means molecular entities and compositions that are of sufficient purity and quality for use in the formulation of a composition or medicament of the present invention. Since both human use (clinical and over-the-counter) and veterinary use are equally included within the scope of the present invention, a formulation would include a composition or medicament for either human or veterinary use.

The term "pharmaceutically acceptable salt" refers includes, for example, a salt with an alkali metal such as lithium, sodium, potassium, etc.; a salt with an alkaline earth metal such as calcium, magnesium, etc.; a salt with zinc or aluminum; a salt with an organic base such as ammonium, choline, diethanolamine, lysine, ethylenediamine, t-butylamine, t-octylamine, tris(hydroxymethyl) aminomethane, N-methyl glucosamine, triethanolamine and dehydroabietylamine; a salt with an inorganic acid such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or a salt with an organic acid such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, etc.; or a salt with an acidic amino acid such as aspartic acid, glutamic acid, etc.

The term “effective amount” as provided herein is defined as an amount of the agent at least sufficient to provide the desired therapeutic effect.

To provide a more concise description, some of the quantitative expressions given herein are not qualified with the term "about". It is understood that whether the term "about" is used explicitly or not, every quantity given herein is meant to refer to the actual given value, and it is also meant to refer to the approximation to such given value that would reasonably be inferred based on the ordinary skill in the art, including approximations due to the experimental and/or measurement conditions for such given value.

Antihistamines suitable for use in the practice of the invention include, but are not limited to, astemizole, antazoline, azatadine, azelastine, bilastine, bepotastine, acrivastine, brompheniramine, bromazine, chlorphenamine, dexchlorpheniramine, dexbrompheniramine, diphenhydramine, dimenhydrinate, clemastine, cyclizine, chlorcyclizine, cetirizine, levocetirizine, carebastine, cyproheptadine, carbinoxamine, desloratadine, loratidine, desloratadine doxylamine, dimethindene, ebastine, epinastine, efletirizine, fexofenadine, hydroxyzine, ketotifen, levocabastine, mizolastine, mequitazine, mianserin, noberastine, olopatadine, orphenadrine, meclizine, norastemizole, picumast, pyrilamine, promethazine, rupatadine, terfenadine, quifenadine, tripelennamine, temelastine, trimeprazine, and triprolidine or pharmaceutically acceptable salt thereof.

Decongestants suitable for use in the practice of the invention include, but are not limited to, pseudoephedrine, phenylephedrine, phenylpropanolamine, levmetamfetamine, naphazoline, xylometazoline and oxymetazoline or pharmaceutically acceptable salt thereof.

The oral dosage form may be provided in any pharmaceutically acceptable solid dosage form. Preferably, the solid dosage form includes, for example, solid preparation such as tablets, pills, granules, capsules, powders and others. In embodiments, the solid dosage form is an oral tablet or capsule formulation. In an embodiment, the solid dosage form is an oral tablet.

“Pharmaceutically acceptable excipients” are the components added to pharmaceutical formulation to facilitate manufacture, enhance stability, control release, enhance product characteristics, enhance bioavailability, and enhance patient acceptability, etc. Pharmaceutical acceptable excipients includes, but not limited to, diluents/fillers, binders, disintegrants, sugar, lubricants, glidants, compression aids, colors, sweeteners, preservatives, surfactants, suspending agents, dispersing agents, film formers, flavors, printing inks, etc.

In certain embodiments of the present invention the formulation includes a diluent or filler to increase the bulk of the composition. Diluents according to the present invention include, but not limited to, lactose, microcrystalline cellulose, sucrose, mannitol, xylitol, erythritol, sorbitol, maltitol, calcium citrate, calcium phosphate, and calcium aluminometasilicate. Examples of the bulking agents or fillers also include cellulose derivatives, such as microcrystalline cellulose or wood cellulose, lactose, sucrose, starch, pregelatinized starch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch, modified corn starch, inorganic salts such as calcium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates, maltodextrin, and compressible sugars and mixtures of two or more above bulking agents or fillers can also be used.

In certain embodiments of the present invention the formulation includes a binder or controlling agent to hold the ingredients in the composition together. Exemplary binders include, but not limited to, cellulose and its derivatives including, hydroxypropyl methylcellulose, hydroxypropyl cellulose, cellulose acetate, ethyl cellulose, methylcellulose and hydroxyethyl cellulose, carboxymethylcellulose; starch and its derivatives; pregelatinized starch, hydrocolloids; sugar; polyvinyl pyrrolidone, copovidone, methacrylic acid copolymers and combination comprising one or more of the foregoing binders.

In certain embodiments of the present invention the formulation includes a disintegrant. Examples of disintegrants suitable for use herein include, but not limited to, croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, corn starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose and other known disintegrants.

In certain embodiments of the present invention the formulation includes a surfactant. Surfactants are compounds which are capable of improving the wetting of the drug and/or enhancing the dissolution. Examples of surfactants for use in accordance with the present invention include but are not limited to ionic- and nonionic surfactants or wetting agents commonly used in the formulation of pharmaceuticals, such as ethoxylated castor oil, polyglycolyzed glycerides, acetylated monoglycerides, sorbitan fatty acid esters, poloxamers, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene derivatives, monoglycerides or ethoxylated derivatives thereof, diglycerides or polyoxyethylene derivatives thereof, sodium docusate, sodium lauryl sulfate, cholic acid or derivatives thereof, lecithins, phospholipids, combinations thereof, and the like.

In certain embodiments of the present invention the formulation includes a lubricant and glidants. Lubricants and glidants aids in the processing of powder materials. Exemplary lubricants suitable for use herein include magnesium stearate, zinc stearate, calcium stearate, talc, carnauba wax, stearic acid, palmitic acid, sodium stearyl fumarate, sodium lauryl sulfate, glyceryl palrnitostearate, palmitic acid, myristic acid and hydrogenated vegetable oils and fats. Exemplary glidants suitable for use herein include talc, colloidal silicon dioxide, silicic acid, cornstarch, calcium silicate, magnesium carbonate, magnesium oxide, magnesium silicate, starch, castor wax and the like.

In an embodiment, the present invention provides a pharmaceutical composition comprising antihistamine and decongestant along with one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention provides a pharmaceutical composition comprising fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides an extended release tablet comprising: (a) antihistamine and decongestant; (b) diluent or filler; (c) disintegrant; (d) binder; (e) glidant or lubricant, and (f) coating agent.

In an embodiment, the present invention provides an extended release tablet comprising: (a) fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof; (b) diluent or filler; (c) disintegrant; (d) binder; (e) glidant or lubricant, and (f) coating agent.

In another embodiment, the present invention provides an extended release tablet comprising: (a) fexofenadine hydrochloride and pseudoephedrine hydrochloride; (b) diluent or filler; (c) disintegrant; (d) binder; (e) glidant or lubricant, and (f) coating agent.

In an embodiment, the present invention provides an extended release bilayered tablet comprising: (a) a first layer comprises, a therapeutically effective amount of decongestant, or a pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients; and (b) a second layer comprises, a therapeutically effective amount of antihistamine or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides an extended release tablet comprising: (a) a core comprising therapeutic effective amount of decongestant or its pharmaceutically acceptable salt thereof, and one or more excipients; (b) optionally coating the core with a seal coating; (c) coating the seal coated core which include extended release polymer; (d) optionally seal coating on extended release seal coated core and; (e) a drug layering on extended release coated core comprising therapeutic effective amount of antihistamine or its pharmaceutically acceptable salt and one or more excipients.

In another embodiment, the present invention provides an extended release tablet comprising: (a) a core comprising therapeutic effective amount of decongestant or its pharmaceutically acceptable salt thereof, and one or more excipients; (b) coating the core with a seal coating; (c) coating the seal coated core which include cellulose derivative extended release polymer; (d) seal coating on extended release seal coated core and; (e) a drug layering on extended release coated core comprising therapeutic effective amount of antihistamine or its pharmaceutically acceptable salt and one or more excipients.

In a preferred embodiment, the present invention provides an extended release tablet comprising: (a) a core comprising therapeutic effective amount of decongestant or its pharmaceutically acceptable salt thereof, and one or more excipients; (b) coating the core with a seal coating; (c) extended release coating the seal coated core which include cellulose acetate as extended release polymer; (d) seal coating on extended release seal coated core which include Copovidone and; (e) a drug layering on extended release coated core comprising therapeutic effective amount of antihistamine or its pharmaceutically acceptable salt and one or more excipients.

In a preferred embodiment, the present invention provides a tablet comprising: (i) a fexofenadine hydrochloride layer coated over the pseudoephedrine hydrochloride layer comprising a therapeutically effective amount of fexofenadine hydrochloride and one or more pharmaceutically acceptable excipients; (ii) a pseudoephedrine hydrochloride layer comprising: (a) a rate-controlling core comprising an effective amount of pseudoephedrine hydrochloride and one or more pharmaceutically acceptable excipients; (b) a seal coat; (c) a coating comprising one or more rate-controlling polymers and one or more other pharmaceutically acceptable excipients; (d) a seal coat.

In an embodiment, the present invention also provides a process of preparation of tablet dosage form comprising antihistamine and decongestant thereof along with one or more pharmaceutically acceptable excipients.

In another embodiment, the present invention also provides a process of preparation of tablet dosage form comprising fexofenadine and pseudoephedrine or pharmaceutically acceptable salt thereof along with one or more pharmaceutically acceptable excipients.

In an embodiment, the present invention provides a method of using the pharmaceutical composition comprising antihistamine and decongestant thereof which comprises administration of the composition to a subject in need thereof.

In another embodiment, the present invention provides a method of using the pharmaceutical composition comprising fexofenadine and pseudoephedrine or pharmaceutically acceptable salt thereof which comprises administration of the composition to a subject in need thereof.

Preferably, dosage forms in accordance with the embodiments depicted herein are manufactured by standard techniques. Granules can be prepared by methods well known to those skilled in the art. Examples of such methods include wet granulation, dry granulation, layering granulation, melt-granulation, and impregnated-granulation. In preferred embodiments, the present invention Granules can be prepared by wet granulation.

In a particular embodiment, for example the extended release bilayered tablet dosage form may be manufactured by the dry mixing and wet granulation technique. The extended release layer manufactured by the dry mixing technique, the drug, carrier and optionally other excipients were sifted together in the blender and blending for appropriate time. The immediate release layer manufactured by the wet granulation technique, the drug, carrier and optionally other excipients were sifted together in rapid mixer granulator for appropriate time and dry the material in Fluid bed dryer at specific condition for appropriate time. The granules were milled through Quadro comill with suitable screen and finally sifted through appropriate sieve. The sifted granules were mixed with remaining ingredients (Extragranular part) in the blender for appropriate time. Next, the lubricant and other excipient materials were added to the blend and were mixed for appropriate time. The composition is compressed into bilayered tablets using bilayer compression machine.

In a particular embodiment, for example the extended release tablet dosage form may be manufactured by dry blending and drug layering technique. In the dry blending technique prepare as core tablet containing the drug, carrier, and optionally other excipients were sifted together in blender and blending for appropriate time and compress the core tablet. The core tablet are coated through functional polymer coating by using a coating pan for appropriate condition and time. In the drug layering technique making coating suspension containing, the drug, carrier, and optionally other excipients are spraying on the coated core tablet by using coating pan.

In certain embodiments of the present invention the formulation includes plasticizer. Suitable plasticizers include, but are not limited to, triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol (PEG), glycerin, triacetin, and triethyl citrate.

In certain embodiments of the present invention the formulation includes seal coat include, but are not limited to, polyvinyl alcohol, talc, titanium dioxide, glyceryl monocaprylocaprate and sodium lauryl sulfate.

In yet another embodiment, wherein the formulation is a tablet, the tablet may be further coated with a coating layer that provides cosmetic benefits to the dosage form. In certain embodiments, such a coating helps to protect the tablets. In certain embodiments such coating comprises hydroxypropyl methylcellulose, polyethylene glycol, polydextrose, titanium dioxide, and triacetin. In certain other embodiments such coating comprises hydroxypropyl methylcellulose 2910, polyethylene glycol 400, polydextrose, titanium dioxide, carnuba wax, and iron oxide yellow. In at least one embodiment such a coating layer comprises hydroxypropyl methylcellulose, and polyethylene glycol.

In certain embodiments fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt is administered with other antihistaminic and/or decongestant drug in fixed dose combination. In certain embodiments the fixed dose combination is either immediate release dosage form or extended release dosage form or in combination with immediate release and extended release in unit dosage form. In certain embodiments such finished dosage form is either monolayer tablet or bi-layer tablet or one drug layered on another drug through coating.

In an embodiment, the present invention provides compositions comprising fexofenadine or pharmaceutically acceptable salt and pseudoephedrine or pharmaceutically acceptable salt thereof for use in the treatment for allergic rhinitis associated with sneezing, rhinorrhea, runny nose, itchy nose, itchy throat, itchy palate, itchy eyes, watery eyes and nasal congestion symptom like common cold, cold like flu symptom, hay fever, upper respiratory allergies, sinus congestion, and the related symptoms.

The following examples are intended to serve as illustrations of the present invention only and do not restrict the scope of the invention in any manner whatsoever.

EXAMPLES
Example 1
Ingredients Qty/tablet (mg) % w/w
(mg)
Pseudoephedrine HCl ER Layer
Pseudoephedrine HCl 120.00 14.84
Hypromellose (Methocel K100 M Premium DC2) 375.00 46.37
Microcrystalline cellulose 29.70 3.67
Hydroxypropyl cellulose 36.70 4.53
Lactose monohydrate 6.00 0.74
Colloidal silicon dioxide 3.00 0.37
Ferric oxide 0.60 0.074
Stearic acid 6.00 0.74
Fexofenadine HCl IR Layer
Intragranular
Fexofenadine HCl 60.00 7.42
Pregelatinized starch 63.00 7.79
Microcrystalline cellulose 28.00 3.46
Colloidal silicon dioxide 1.00 0.12
Purified water q.s. q.s.
Extragranular
Microcrystalline cellulose 21.00 2.59
Croscarmellose sodium 25.00 3.09
Colloidal silicon dioxide 1.00 0.12
Stearic acid 2.00 0.24
Core tablet 780
Hypromellose (Methocel E5 premium LV) 26.00 3.21
Polyethylene glycol (Macrogol 6000) 1.28 0.15
Polyethylene glycol (Polyglycol 400) 1.29 0.15
Coated tablet 808.57

Manufacturing Procedure:
Pseudoephedrine hydrochloride ER layer:
Step 1: Pseudoephedrine hydrochloride, hypromellose (Methocel K100 M Premium DC2), microcrystalline cellulose and colloidal silicon dioxide, hydroxypropyl cellulose, lactose monohydrate, ferric oxide and stearic acid were co-sifted through a sieve.
Step 2: Step-1 material was mixed in blender.

Fexofenadine HCl IR Layer:
Step 1: Fexofenadine hydrochloride, pregelatinized starch, microcrystalline cellulose, and colloidal silicon dioxide were co-sifted through sieve.
Step 2: Step-1 material load in the Rapid Mixer Granulator and add require quantity of purified water.
Step 3: Granulate the Step-2, and if required add extra quantity of purified water.
Step 4: Dry the material of Step-3 in Fluid bed dryer.
Step 5: The material of Step-4 were milled through Quadro comill with a suitable screen and finally sifted through a sieve.
Extragranular part:
Step 6: Microcrystalline cellulose, croscarmellose sodium, stearic acid and colloidal silicon dioxide were co-sifted through a sieve.
Step 7: Step-7 load the granules in blender and add stearic acid and lubricate for appropriate time.
Tablet:
Step 8: Fexofenadine Hydrochloride blend of step 7 and Pseudoephedrine Hydrochloride blend of step 2 was compressed into bilayered tablets.
Step 9: The compressed core tablets of Step-8 were coated with coating solution.

Example 2
Ingredients Qty/tablet (mg) % w/w
(mg)
Pseudoephedrine HCl core tablet
Pseudoephedrine HCl 240.000 30.977
Hypromellose (Methocel K100 M Premium DC2) 185.500 24.07
Lactose monohydrate 3.500 0.45
Microcrystalline cellulose 20.000 2.59
Colloidal silicon dioxide 3.000 0.38
Stearic acid 8.000 1.03
Seal coating
Opadry AMB II white 88A 180040 17.240 2.23
Purified water@ 64.960 -
Extended release coating
Cellulose acetate 15.904 2.06
Polyethylene glycol 5.471 0.71
Di butyl sebacate 2.236 0.29
Acetone@ 509.000 -
Purified water@ 10.000 -
Co povidone seal coating
Talc 7.600 0.98
Copovidone 3.900 0.50
Titanium dioxide 3.500 0.45
Purified water@ 45.00 -
Fexofenadine drug loading
Fexofenadine HCl 180.00 23.23
Hypromellose (Methocel E3 Premium LV) 9.250 1.20
Polyethylene glycol (Polyglycol 400) 13.000 1.68
Croscarmellose sodium 27.000 3.50
Acetone@ 1017.771 -
Isopropyl alcohol@ 661.551 -
Purified water@ 16.962 -
Core tablet 745.10
Opadry® AMB II white 88A 180040 29.629 3.84
Purified water@ 118.516 -
Opacode Black S-1-17823 0.043 0.005
Coated tablet 770.421
@: Processing solvent will be removed during manufacturing process.

Manufacturing Procedure:
Pseudoephedrine HCl core tablet:
Step 1: Pseudoephedrine hydrochloride and hypromellose (Methocel K100 M Premium DC2) were co sifted through sieve.
Step 2: Material of Step-1 was loaded into blender for appropriate time.
Step 3: Colloidal silicon dioxide, microcrystalline cellulose and lactose monohydrate were co-sifted through sieve and loaded into Step-2 blender for appropriate time.
Step 4: Stearic acid was sifted through sieve and added into Step-3 material and blend for appropriate time.
Step 5: Lubricated blend was compressed into tablets.
Seal coating:
Step 6: Opadry AMB II white 88A 180040 was dispersed into purified water.
Step 7: Core tablets of Step-5 were loaded in the coating pan and coated using Step-6 solution.
Step 8: The coated tablets were dried at appropriate temperature.
Extended release coating:
Step 9: Cellulose acetate was dissolved in the purified water and acetone under continuous stirring and then polyethylene glycol and di butyl sebacate were added.
Step 10: Seal coated tablet of Step-8 were loaded in the coating pan and coating solution of Step-9 were sprayed.
Seal coating:
Step 11: Copovidone was dissolved in purified water under continuous stirring and then talc and titanium dioxide were disperse with continuous stirring.
Step 12: The core tablets of Step-10 were coated with Step-11 coating solution.
Fexofenadine drug loading:
Step 13: Dissolved polyethylene glycol (poly glycol 400) in isopropyl alcohol under stirring and dispersed the Croscarmellose sodium followed by fexofenadine HCl.
Step 14: Dispersed the hypromellose (Methocel E3 Premium LV) to hot water under stirring, cooled the dispersion and then added acetone under stirring to get clear solution.
Step 15: Step-14 was transferred to Step-13 and stirred for appropriate time.
Step 16: Seal coated tablets of Step-12 were loaded in the coating pan and coating suspension of Step-15 was sprayed.
Step 17: Dried the coated tablet of Step-16 at appropriate temperature.
Tablet:
Step 18: The core tablets of Step-17 were coated with coating solution by dissolving Opadry AMB II white in purified water under stirring. ,CLAIMS:We Claim:

1. A layered composition of fexofenadine hydrochloride and pseudoephedrine hydrochloride comprising: (i) a fexofenadine hydrochloride layer coated over the pseudoephedrine hydrochloride layer comprising a therapeutically effective amount of fexofenadine hydrochloride and one or more pharmaceutically acceptable excipients; (ii) a pseudoephedrine hydrochloride layer comprising: (a) a rate-controlling core comprising an effective amount of pseudoephedrine hydrochloride and one or more pharmaceutically acceptable excipients; (b) a seal coat; (c) a coating comprising one or more rate-controlling polymers and one or more other pharmaceutically acceptable excipients; (d) a seal coat.

2. A layered composition of claim 1, wherein the fexofenadine hydrochloride layer comprising one or more pharmaceutically acceptable excipients selected from the group comprising of film former, plasticizer, disintegrant and one or more pharmaceutically acceptable solvents.

3. A layered composition of claim 1, wherein the fexofenadine hydrochloride layer comprising hypromellose, polyethylene glycol, croscarmellose sodium, acetone, isopropyl alcohol and purified water.

4. A layered composition of claim 1, wherein the pseudoephedrine hydrochloride layer comprising: (a) a rate-controlling core comprising an effective amount of pseudoephedrine hydrochloride and one or more pharmaceutically acceptable excipients selected from rate-controlling polymers, diluents, glidants and lubricants.

5. A layered composition of claim 1, wherein the pseudoephedrine hydrochloride layer comprising: (a) a rate-controlling core comprising an effective amount of pseudoephedrine hydrochloride and hypromellose, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide and stearic acid; (b) a seal coat; (c) a coating comprising cellulose acetate, polyethylene glycol, dibutyl sebacate, acetone and purified water; (d) a seal coat.

6. A layered composition of claim 1, wherein 180 mg fexofenadine hydrochloride for immediate release and 240 mg pseudoephedrine hydrochloride for extended release.

7. A layered composition of claim 1, further comprising a film coat over (d) seal coat.

8. A layered composition of fexofenadine hydrochloride and pseudoephedrine hydrochloride of claim 1 comprising: (i) a fexofenadine hydrochloride layer coated over the pseudoephedrine hydrochloride layer comprising a therapeutically effective amount of fexofenadine hydrochloride, hypromellose, polyethylene glycol, croscarmellose sodium, acetone, isopropyl alcohol and purified water; (ii) a pseudoephedrine hydrochloride layer comprising: (a) a rate-controlling core comprising an effective amount of pseudoephedrine hydrochloride and hypromellose, lactose monohydrate, microcrystalline cellulose, colloidal silicon dioxide and stearic acid; (b) a seal coat; (c) a coating comprising cellulose acetate, polyethylene glycol, dibutyl sebacate, acetone and purified water; (d) a seal coat.

9. A layered composition of fexofenadine hydrochloride and pseudoephedrine hydrochloride of claim 1, indicated for the relief of symptoms associated with seasonal allergic rhinitis in adults and children 12 years of age and older.

10. A layered composition of fexofenadine hydrochloride and pseudoephedrine hydrochloride of claim 1 is one tablet once daily administered on an empty stomach for adults and children 12 years of age and older.