PSEUDOEPHEDRINE

Field of invention

The present invention relates to the preparation of stable pharmaceutical compositions comprising levocetirizine and pseudoephedrine.

Background of the invention

Levocetirizine which is an R-enantiomer of cetirizine is a piperazine derivative, potent and selective H1 receptor antagonist. Levocetirizine, chemical name is (2-{4~[(R)-(4-Chlorophenyl) (phenyl)methyl]-1-piperazinyl}ethoxy)acetic acid.

Formula 1 : Levocetirizine

Levocetirizine is an antihistaminic agent. It works by blocking a substance in the body called histamine. This helps to decrease allergy symptoms and hives. Levocetirizine is used to relieve runny nose; sneezing; and redness, itching, and tearing of the eyes caused by hay iever, urticaria, seasonal allergies, and allergies to other substances such as dust mites, animal dander, and mold. It is also used to treat symptoms of hives, including itching and rash.

Pseudoephedrine is a member of decongestant drugs. Pseudoephedrine and its pharmaceutically acceptable salts are well recognized by those skilled in the art as safe and effective nasa! and ocular decongestants.

Pseudoephedrine, chemical name is (1S,2S)-2-( ethylamino)-1-phenyl-1-propanol.

Formula 2: Pseudoephedrine

Pseudoephedrine is a well known for shrinking swollen nasal mucous membranes. It reduces tissue hyperemia, edema, and nasal congestion commonly associated with colds or allergies. Other beneficial effects may include increasing the drainage of sinus secretions, and opening of obstructed Eustachian tubes. It is also indicated for vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis.

Pseudoephedrine can be used either as oral or topical decongestant. The advantage of oral pseudoephedrine over topical nasal preparations is that it does not cause rebound congestion (rhinitis medicamentosa).

WO2011/146032 discloses effervescent composition of levocetirizine.

EP0811374 disclose a pharmaceutical composition comprising cetirizine and pseudoephedrine; US Patent 6,171 ,618 discloses a dosage form containing cetirizine as an immediate release component and pseudoephedrine as a controlled release component, a portion of the pseudoephedrine can be incorporated as an immediate release component.

EP 1404304 A1 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.

WO2010/078541 describes a pharmaceutical composition comprising drug layer comprising drug particles comprising naproxen and cetirizine and another drug layer comprising pseudoephedrine, for treating symptoms of upper respiratory allergies, nasal congestion, and headache.

Summary of the invention

An effervescent pharmaceutical composition, characterized in that it comprises:

a) pseudoephedrine or pharmaceutically acceptable salt thereof,

b) levocetirizine or pharmaceutically acceptable salt thereof,

in combination with at least one pharmaceutically acceptable excipient.

In a most preferred embodiment, present invention relates to an effervescent composition comprising:

a) 5-10 mg of levocetirizine,

b) 30-60 mg of pseudoephedrine,

c) citric acid,

d) sodium bicarbonate, and

e) at least one flavor. As used herein the term "levocetirizine" means levocetirizine or pharmaceutically acceptable salt thereof. As used herein the term "pseudoephedrine" means pseudoephedrine or pharmaceutically acceptable salt thereof.

Effervescent formulation of the present invention can be in powder, granule or tablet form. Effervescent formulation of the present invention is preferably in tablet form.

In a preferred embodiment, the composition of the present invention is in the form of an effervescent tablet intended to be dissolved or dispersed in water before administration and generally contains acid substances and carbonates or bicarbonates, which react rapidly in the presence of water releasing carbon dioxide. The effervescent tablets comprise effervescent couples selected from, but not limited to, thermolabile gas generating agents such as sodium bicarbonate, sodium glycine carbonate, potassium bicarbonate, ammonium bicarbonate, sodium bisulfite, sodium metabisulfite, and an acid source such as citric acid, maleic acid or tartaric acid.

Different carbonates, acids and buffers are used to attain good effervescence in short time and to obtain a clear solution, and to give maximum therapeutic effect in short time.

In one embodiment, in the compositions of the present invention, acid and base components are in the separate compartments.

Compositions of this invention may be used in the treatment of vasomotor rhinitis. It can be reduced rhinitis and asthma symptoms and improved overall quality of life. It is indicated for the relief of nasal and non-nasal symptoms associated with seasonal or perennial allergic rhinitis in adults and children 12 years of age and older.

This invention can be used for the treatment of allergies, hay fever, pollen, dust, mold and tree allergies. In addition, this invention is used to relieve allergy symptoms such as watery eyes, runny/stuffy nose, itching eyes/nose, and sneezing.

This invention may be used for the treatment of nasal congestion, sinus congestion, Eustachian tube congestion, and vasomotor rhinitis, and as an adjunct to other agents in the optimum treatment of allergic rhinitis, croup, sinusitis, otitis media, and tracheobronchitis.

In this present invention, it shows quick affect and efficiency.

This invention can include production method which is for increasing solubility. This method can be used in wet granulation.

An important subject of the present invention is to provide a formulation which has resistant against physical and enviromental conditions and also have a high bioavailability. The present invention provides pharmaceutical formulations comprising active ingredients combination characterized by 1) good stability properties, 2} controfiing the release of the active ingredient according to desired therapeutical needs, and finally 3) simple and also competitive manufacturing process.

We have now surprisingly found that levocetirizine may be effectively combined with pseudoephedrine, comparing with single activity of each of these and with an enhancement of the activity of pseudoephedrine and other compounds.

Pharmaceutical composition of the present invention may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, fillers, disintegrants, solvents, acid substance, base substance, binders, lubricants, glidants, sweeteners, aromatic agents, flavouring agents, preservatives, coloring agents, and the mixtures thereof.

Binders can be selected from the group, but are not limited to, methylcellulose, sodium carboxymethycellulose, calcium carboxymethycellulose, ethylcellulose, hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, silicified microcrystalline cellulose(SMCC), polyvinylpyrrolidone, gelatine, polyvinyl alcohol, acacia, tragacanth, guar, pectin, starch paste, potato starch, corn starch, wheat starch, pre-gelatinized starch, alginic acid, compressible sugar, liquid glucose, dextrates, dextrin, dextrose, ma!todextrin, guar gum, magnesium aluminium silicate, polymethacrylates, sorbitol, natural-synthetic gums and other materials known to one of ordinary skill in the art. A mixture of binders may also be used.

Diluents may be water-soluble or water insoluble. Diluents can be selected from the group, but are not limited to, spray-dried or anhydrous lactose, sucrose, dextrose, starch, pre-geiatinized starch, mannitol, maltitol, sorbitol, xylitol, dextrin, cellulose derivatives including powdered cellulose, microcrystalline cellulose, dibasic calcium phosphate, tribasic calcium phosphate and calcium sulphate, kaolin, precipitated calcium carbonate, maltodextrin and other materials known to one of ordinary skill in the art. A mixture of diluents may also be used.

Lubricants can be selected from the group, but are not limited to, vegetable oils, such as hydrogenated vegetable oil or hydrogenated castor oil; polyethylene glycols, such as polyethylene glycol (PEG)-4000 and PEG-6000; stearic acid; derivatives of stearic acid, such as magnesium stearate, sodium stearate, calcium stearate, zinc stearate, glyceryl monostearate, glyceryl palmitostearate and sodium stearyl fumarate; mineral salts, such as talc; inorganic salts; organic salts, such as sodium benzoate, sodium acetate, sodium chloride and sodium oleate; and polyvinyl alcohols, microcrystalline cellulose, sodium lauryl sulphate, silica, colloidal silica, cornstarch, calcium silicate, magnesium silicate, silicon hydrogel and other materials known to one of ordinary skill in the art.A mixture of lubricants may also be used. Gtidants can be selected from the group, but are not limited to, colloidal silicon dioxide, colloidal silica, cornstarch, talc, calcium silicate, magnesium silicate, magnesium trisiiicate, amorphous silica, colloidal silicon, silicon hydrogel, powdered cellulose, silicon dioxide, talc, tribasic calcium phosphate and other materials known to one of ordinary skill in the art. A mixture of glidants may also be used.

Flavoring agents, including, but not limited to, black current, sodium chloride, strawberry, peppermint, menthol, artificial vanilla, cinnamon, various fruit flavors, natural aroma oils (such as peppermint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthane, anethole, methyl salicylate, eucalyptol, methyl acetate, sage, 1-eugenol, oxanon, alpha-irisone, marjoram, lemon, orange, blackberry, propenyl guaetol acetyl, vanilla, timole, linalol, cinnamaldehyde glycerol acetal, N-substituted p-menthane-3-carboxamide and other materials known to one of ordinary skill in the art. A mixture of flavoring agents may also be used.

Sweeteners, including, but not limited to, sugars such as sucrose, glucose (corn syrup), invert sugar, fructose, and mixtures thereof; saccharin and its various salts such as sodium or calcium salt; cyclamic acid and its various salts such as sodium salt; the dipeptide sweeteners such as aspartame; dihydrochalcone; glycyrrhizin; Stevia rebaudiana (Stevioside); and sugar alcohols such as sorbitol, sorbitol syrup, D- tryptophan, monoammonium glycyrrhizinate, neohesperidin, dihydrochalcone, thaumatin, neotam, alitam, cyclamates,mannitol, xylitol, and the like. A combination of sweeteners and flavoring agents can also be used.

Buffering agents can be selected from the group, but not limited to, potassium bicarbonate, citric acid, glycine, arginine, sodium acetate and sodium citrateand other materials known to one of ordinary skill in the art, and the mixtures thereof.

Acid substance can be selected from the group, but not limited to, ascorbic acid, citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, lactic acid, oxalic acid, formic acid, benzene sulfonic add, benzoic acid, maleic acid, glutamic acid, succinic acid, aspartic acid, diatrizoic acid, acetic acid and acid anhydrides and acid salts thereof, and mixtures thereof. The acidifying agent may also be an inorganic acid, such as hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid.

Base substance can be selected from the group, but not limited to, aluminum salts such as magnesium aluminum silicate; magnesium salts such as magnesium carbonate, magnesium trisiiicate, magnesium stearate; calcium salts such as calcium carbonate; bicarbonates such as calcium bicarbonate and sodium bicarbonate; phosphates such as monobasic calcium phosphate, dibasic calcium phosphate, dibasic sodium phosphate, tribasic sodium phosphate (TSP), dibasic potassium phosphate, tribasic potassium phosphate; metal hydroxides such as aluminum hydroxide, sodium hydroxide and magnesium hydroxide; metal oxides such as magnesium oxide; N-methyl glucami ^' ne; arginine and salts thereof; amines such as monoethanolamine, diethanolamine, triethanolamine, and tris(hydroxymethyl)aminomethane (TRIS) and other materials known to one of ordinary skill in the art, and the mixtures thereof. The pharmaceutical formulation are produced by one of the dry granulation, dry blending, direct compression, wet granulation methods.

The method proposed for production of the formulations of the present invention is preferably wet granulation method and it basically comprises the following steps;

a. Preparation of the granulation solution,

b. Granulation,

c. Drying and sieving,

d. Tablet compression.

The granulation solution to be used in the production of the formulations of the present invention comprise a pharmaceutically acceptable solvent in an effective amount and at least one binder.

Example 1

Example 2