FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
PHARMACEUTICAL COMPOSITION CONTAINING ANTI¬INFLAMMATORY, ANTIHITAMINIC AND DECONGESTANT (SUSTAINED RELEASE) FOR TREATING ALLERGIC RHINITIS
2. APPLICANT (S)
(a) NAME : Lincoln Pharmaceuticals Limited.
(b) NATIONALITY: an Indian Company
(c) ADDRESS : Nirav Complex, Opp. Navrang High School
Naranpura, Ahmedabad-380014 Gujarat, India.
3. PREMABLE TO THE DESCRIPTION

PROVISIONAL
The following specification describes the invention.

0 COMPLETE
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 novel pharmaceutical composition for the treatment of allergic rhinitis. More particularly, the present invention relates to a novel pharmaceutical composition containing anti-inflammatory, anti-histaminic and decongestant ingredients for sustained release in the treatment of allergic rhinitis.
The present invention also relates to a process for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis. Background of the invention
Allergic rhinitis is a common disorder observed all over the world especially during change of seasons. The disease is believed to occur due to the high pollen content in air, due to dust and other viral or bacterial infections. This common symptoms of this disorder are sneezing, headache, running nose, congestion, body ache and infections of upper respiratory system.
Various pharmaceutical compositions are available with one or more active ingredients for treating the symptoms of allergic rhinitis also known as common cold and patient has to be administered with multiple does of anti-inflammatory, decongestants and antihistamines or in combination of any two. Most of the times number of doses per day goes as high as 6 to 9 tablets.
It is known in the art to provide a composition of Nimesulide and slats thereof and Cetirizine possessing antileukotriene, antihistamine, antiallergic and anti-infiamatory action. The composition is useful in the cure of allergic disorders. Ref: CA2253061, US6258816, AU729581, EP1005865]
A pharmaceutical compositions and methods of using non-steroidal anti¬inflammatory analgesic Naproxen and decongestant Pseudoephedrine in a time release tablet form to cure sinusitis are also known [Ref. AU758880, EP1107740].
Pharmaceutical compositions have been developed for treatment of cough and cold symptoms comprising loratidine, ibuprofen and pseudoephedrine. [Ref US5100675].
Tablet comprising of Cetirizine and Pseudoephedrine was developed for curing allergic and decongestant disorders. [Ref: SKI5502003, EE200400005, WO03002098].
2

A process was developed for the preparation of controlled release delivery system containing Pseudoephedrine and a long acting antihistamine from the group consisting of loratadine, azatidine, fexofenadine, terfemadine, cetirizine, astemizole, and levocabastine. [Ref. EP1217997, WO0121168, US6267986J. A tablet comprising of Cetirizine and Pseudoephedrine was developed for anrihistaminic and decongestant activity [Ref. EP1404304].
Oral pharmaceutical composition have been developed comprising leukotriene inhibitor and Pseudoephedrine for the treatment of allergies, asthma and associated signs and symptoms. [Ref: US2004048890].
Pharmaceutical composition containing epinastine and Pseudoephedrine have been developed for anrihistaminic and decongestant activity. [Reft CN1468094TJ.
Composition containing loratadine and Pseudoephedrine was developed for treating the patients suffering from asthma and allergic rhinitis. [Ref: CA2268546, WO9818470, EP0941091, TR9901003T, AU731756].
Reports show the efficacy of Nimesulide and combination with Cetirizine in acute allergic rhinitis. Reports relying on clinical trials show that Cetirizine in combination with Nimesulide exerts synergistic action in reducing symptoms in-patients of allergic rhinitis (Ref: JAPI, 2001 ;49;518-522 and JAPI, 1999; VOL 47(4):389-392).
Efficacy and safety relative to placebo of an oral formulation of Cetirizine and sustained release Pseudoephedrine in the management of nasal condition has been studied and found that Cetirizine / PSE relieved nasal congestion and other subjective and objective symptoms to a significandy greater extent than Placebo. No serious adverse events occurred [REF: PMID:9788685].
However, at present no single pharmaceutical combination is available which can relieve all the signs and symptoms of allergic rhinitis. In conventional and known treatment, the patient is administered anti-inflammatory formulations, decongestants and antihistamines separately or in a combination of any two. The number of doses per day are also quite high and can be as much as 9 tablets per day.
It is therefore important to provide a novel pharmaceutical composition containing a combination of potent anti-inflammatory formulation, antihistamine formulation and a decongestant together in a single dosage form and reduce the number of doses to two per day.
3


Objects of the invention
The main object of the present invention is to develop a pharmaceutical composition containing anti-inflammatory, antihistamines and decongestants (sustained release) in a single dosage form.
It is another object of the invention to provide a novel pharmaceutical
formulation for the treatment of allergic rhinitis wherein the dosage is reduce^ to a
maximum of two per day.
Summary of the invention ,„- -
Accordingly, the present myentJon provides a phamacetical compostion for the treatment of allergic rhinitis comprising an^nti-mflammatoryC ail anti-histamine and a decongestant in a single dosage form, the amount of the anti-inflammatory being in the range of 50 mg to 200 mg, the amount of the anti-histamine being in the range of 2.5 to l0 mg and the amount of the decongestant being in the range of 30mg to 120 mg, all amounts being expressed in terms of weight per dose of the composition, the balance if any comprising one or more conventional additives and pharmaceutically acceptable excipients.
In one embodiment of the invention, the anti-inflammatory is nimesulide.
In another embodiment, the anti-histamine is cetirmne.
In another embodiment, the anti-histamine is levocetirizine.
In yet another embodiment of the invention, the decongestant is pseudoephedrine.
In yet another embodiment of the invention, the conventional ingredients are selected from the group consisting of diluents, binders, lubricants, disintegrants and other conventional excipients.
In yet another embodiment of the invention, the binder is selected from the group consisting of starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gum acacia, carbopol and other acrylic resins, and polyethylene glycols.
In yet another embodiment of the invention, the diluent is selected from the group consisting of starch and modified starches, microcrystalline cellulose, lactose,
4

sorbitol, dicalcium phosphate, calcium carbonate, hydroxy propyl cellulose, aluminium magnesium silicate and cyclodextrins.
In another embodiment of the invention, the lubricant and disintegrants are selected from the group consisting of starch, sodium starch glycolate, colloidal silicondioxide, guar gum, sodium carboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica.
In yet another embodiment of the invention, the composition is in the form of a tablet, hard gelatin capsule or oral liquid suspension.
In yet another embodiment of the invention, the conventional additives comprise sweetening agents, suspending agents, and preservatives.
In another embodiment of the invention, the diluent for a oral liquid suspension comprises purified water, glycerin, propylene glycol, polyethylene glycol-200 and polyethylene glycol-400.
In yet another embodiment of the invention, the sweetening agent is selected from the group consisting of tnannitol, sugar, invert sugar, liquid glucose, sorbitol, malt extract, aspartame, saccharine and salt thereof.
In yet another embodiment of the invention, the suspending agent for the oral liquid suspension is selected from the group consisting of carboxymethyl cellulose and salt thereof, cellulose dilutes, guar gum, xantham gum, precipitated silicone, colloidal silicone dioxide, alginic acid and salt thereof.
In another embodiment of the invention, the preservative is selected from the group consisting of benzoic acid, and salt thereof, sorbic acid and salt thereof, methyl paraben and salt thereof, propyl paraben and salt thereof, and bronopol.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of cetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of levocetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
The present invention also relates to a process for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis comprising an anti¬inflammatory, an anti-histamine and a decongestant in a single dosage form, the amount of the anti-inflammatory being in the range of 50 mg to 200 mg, the amount of the anti¬histamine being in the range of Z5 to lOmg and the amount of the decongestant being in
5

the range of 30mg to 120 mg, all amounts being expressed in terms of weight per dose of the composition, the balance if any comprising one or more conventional additives and pharmaceutically acceptable excipients, the process comprising mixing in any conventional manner the above referred ingredients.
In one embodiment of the invention, the anti-inflammatory is nimesulide.
In another embodiment, the anti-histamine is cetirizine.
In another embodiment, the anti-histamine is levoln yet another embodiment of the invention, the decongestant is pseudoephedrine.
In yet another embodiment of the invention, die conventional ingredients are selected from the group consisting of diluents, binders, lubricants, disiritegrants and other conventional excipients.
In yet another embodiment of the invention, the binder is selected from the group consisting of starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium catboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gum acacia, carbopol and other acrylic resins, and polyethylene glycols.
In yet another embodiment of the invention, the diluent is selected from the group consisting of starch and modified starches, rnicrocrystalline cellulose, lactose, sorbitol, dicalrium phosphate, calcium carbonate, hydroxy propyl cellulose, aluminium magnesium silicate and cyclodextrins.
In another embodiment of the invention, the lubricant and disintegrants are selected from the group consisting of starch, sodium starch glycolate, colloidal silicon dioxide, guar gum, sodium catboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica.
In yet another embodiment of the invention, the composition is in the form of a tablet, hard gelatin capsule or oral liquid suspension.
In yet anomer embodiment of the invention, the conventional additives comprise sweetening agents, suspending agents, and preservatives.
In another embodiment of the invention, the diluent for a oral liquid suspension comprises purified water, glycerin, propylene glycol, polyethylene glycol - 200 and polyethylene glycol 400.
6

In yet another embodiment of the invention, the sweetening agent is selected from the group consisting of mannitol, sugar, invert sugar, liquid glucose, sorbitol, malt extract, aspartame, saccharine and salt thereof.
In yet another embodiment of the invention, the suspending agent for the oral liquid suspension is selected from the group consisting of carboxymethyl cellulose and salt thereof, cellulose dilutes, guar gum, xantham gum, precipitated silicone, colloidal silicone dioxide, alginic acid and salt thereof.
In another embodiment of the invention, the preservative is selected from the group consisting of benzoic acid, and salt thereof, sorbic acid and salt thereof, methyl paraben and salt thereof, propyl paraben and salt thereof, and bronopol.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of cetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of levocetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
The composition of the invention is a synergistic admixture showing improved properties of being administrable in a single dose form and with reduced per diem dosage and not a mere aggregate of the properties of the individual ingredients. Detailed description of the invention
As explained in the background of the invention, allergic rhinitis is a common disorder occurring normally during change of seasons. The patient normally shows symptoms like sneezing, headache, running nose, congestion, body ache and infection of upper respiratory system. The symptomatic cure to provide relief from these symptoms normally comprises administering antihistamines, anti-inflammatories and decongestant drugs to the patient, either alone or in a combination of any two thereof. It has been observed that the time taken for the patient to obtain relief can be quite long and the dosage can be quite high - as much as 9 tablets per day. Missing a single dose in a regimen of treatment can result in slowing down of the efficacy of the treatment process.
The present invention provides a novel pharmaceutical composition containing Nimesulide as an anti-inflammatory, Cetirizine or Levocetirizine as antihistamine and Pseudoephedrine as a decongestant in a single dose. The composition can be in the form of tablet, capsule or oral liquid suspension. The maximum dose per day of the dosage form is two.
7

Symptoms of allergic rhinitis occur as a result of direct and indirect action of histamine acting largely on the HI receptors in target tissues. Along with histamine a range of other vasoactive mediators such as kinins cause vasodilation resulting in congestion. Nimesulide apart from its analgesic, antipyretic and anti-inflammatory activity it is a mast cell inhibitor i.e. in turn inhibits the release of histamines. Cetirizine or Levocetirizine in combination with Nimesulide as a synergistic effect and acts as an antihistamine by selective HI histamine receptor antagonistic. Combination of Nimesulide and Cetirizine however does not relieve nasal congestion. Therefore, the
present invention relies on the addition of pseudoephedrine as a decongestant
Pseudoephedrine acts as predominantly on alfa receptors without central nervous system
Tn"mulationrT!ombination of Nimesulide, Cetirizine and Pseudoephedrine in a single
'formulation helps in relieving the signs and symptoms of allergic rhinitis within three
days
The composition has been clinically studied at multiple locations. Clinical studies have shown that the combination of Nimesulide Cetirizine or Levocetirizine and Pseudoephedrine in a single dosage form gives much better results in terms of relieving J of signs of symptoms of allergic rhinitis. Patients administered with above combinations have shown faster recovery from allergic rhinitis than the patients administered with drugs with individual dosage forms.
50 to 200mg 2.5 to lOmg 30 to 120mg
Q.S.
50to200mg 2.5 to 5mg
It has been also observed that failure by a patient to take the dosage is reduced since the number of doses per day is less (with sustained release Pseudoephedrine). This has also helped in maintaining the drug-serum level in the body. (A) Pharmaceutical combination has been developed in tablet from containing: ©Each tablet contains:
1. Nimesulide
2. Cetirizine Dihydrochloride
3. Pseudoephedrine Hydrochloride (Sustained Release Form)
4. Excipients
©Each tablet contains:
1. Nimesulide
2. Levocetirizine Dihydrochloride

3. Pseudoephedrine Hydrochloride 30 to 120mg (Sustained Release Form)
4. Excipients Q-S.
Tablet form was developed widi different combinations of diluents (Le. starch and modified starches, microcrystalline cellulose, lactose, sorbitol, dicalcium phosphate, calcium carbonate, hydroxypropyl cellulose, aluminium magnesium silicate), Binders (i.e. starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ediyi cellulose, hydroxyethyl cellulose> hydroxypropyl methyl cellulose* gum acacia, carbopol and other acrylic resins, polyethylene glycols) and lubricants and disintegrants (i.e. starch, sodium starch glycolate, colloidal silicondioxide, guar gum, sodium carboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica).



10


Hard gelatin capsule form was developed with different combinations of Diluents & Excipients (Le. starch and modified starches, microcrystalline cellulose , lactose, sorbitol,
11


V-i
dicalcium phosphate, calcium carbonate, starch, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydoixypropyl methyl cellulose and other acrylic resins, polyethylene glycols ) and Lubricants (Le. stearic acid and its salts , purified talc and modified silica).


13

Sugar 35.0 gm
Sorbitol Solution 70% 10.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Aspartame 0.05 gm
Propyl Paraben sodium 0.05 gm
Bronopol 0.02 gm
Citric Acid 0.04 gm
Xantham Gum 0.15 gm
Colour Q.S.
Purified Water Q.S.
Example 14:
INGREDIENT EACH 100 ML CONTAINS
Nimesulide 2.0 gm
Levocetirizine dihydrochloride 0.1 gm
Pseudoephedrine Hydrochloride 1.2 gm
Liquid Glucose 20.0 gm
Sugar 45.0 gm
Sorbitol Solution 70% 10.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Propyl Paraben sodium 0.05 gm
Bronopol 0.02 gm
Citric Acid 0.04 gm
Sodium Carboxymethyl Cellulose 2.0 gm
Colour Q.S.
Purified Water Q.S.
Example 15:
INGREDIENT EACH 100 ML CONTAINS
Nimesulide 1.0 gm •
Cetirizine Hydrochloride 0.2 gm
Pseudoephedrine Hydrochloride 1.2 gm
15


16

Liquid Glucose 30.0 gm
Sugar 45.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Aspartame 0.05 gm
Propyl Paraben sodium 0.05 gm
Methyl Paraben Sodium 0.2 gm
Citric Acid 0.04 gm
XanthamGum 0.15 gm
Colour Q.S.
Purified Water Q.S.
Example 18:
INGREDIENT EACH 100 ML CONTAINS
Nimesulide 0.5 gm
Cetirizine dihydrochloride 0.05 gm
Pseudoephedrine Hydrochloride 0.3 gm
Liquid Glucose 30.0 gm
Sugar 45.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Aspartame 0.05 gm
Propyl Paraben sodium 0.05 gm
Bronopol 0.02 gm
Citric Acid 0.04 gm
Sodium Carboxymethyl Cellulose 2.0 gm
Colour Q.S.
Purified Water Q.S.
The above examples are flon-limiting and are illustrative of the composition of the invention. Modifications and variations therefrom are possible without departing from the spirit of the invention.
17

Claim:
1. A pharmaceutical composition for the treatment of allergic rhinitis comprising the amount of nimesulide as an anti-inflammatory being in the range of 50 mg to 200 mg, the amount of cetirizine or levocetirizine as an anti-histamine being in the range of 2.5 to lOmg and the amount of pseudoephedrine as a decongestant in sustained release form being in the range of 30mg to 120 mg and one or more conventional additives and pharmaceutically acceptable excipients.
2. A composition as claimed in claim 1 wherein the conventional ingredients are selected from the group consisting of diluents, binders, lubricants, disintegrants and other conventional excipients.
3. A composition as claimed in claim 2 wherein the binder is selected from the group consisting of starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gum acacia, carbopol and other acrylic resins, and polyethylene glycols.
4. A composition as claimed in claim 2 wherein the diluent is selected from the group consisting of starch and modified starches, microcrystalline cellulose, lactose, sorbitol, dicalcium phosphate, calcium carbonate, hydroxypropyl cellulose, aluminium magnesium silicate and cyclodextrins.
-2 JUN 2008

5. A composition as claimed in claim 2 wherein the lubricant and disintegrants are selected from the group consisting of starch, sodium starch glycolate, colloidal silicon dioxide, guar gum, sodium carboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica.
6. A composition as claimed in any preceding claim wherein the composition is in the form of a tablet, hard gelatin capsule or oral liquid suspension.
7. A composition as claimed in claim 2 wherein the conventional additives comprise sweetening agents, suspending agents, and preservatives.
8. A composition as claimed in claim 7 wherein the diluent for a oral liquid suspension comprises purified water, glycerin, propylene glycol, polyethylene glycol - 200 and polyethylene glycol 400.
9. A composition as claimed in claim 7 wherein the sweetening agent is selected from the group consisting of mannitol, sugar, invert sugar, liquid glucose, sorbitol, malt extract, aspartame, saccharine and salt thereof.
10. A composition as claimed in claim 7 wherein the suspending agent for the oral liquid suspension is selected from the group consisting of carboxymethyl cellulose and salt thereof, cellulose dilutes, guar gum, xantham gum, precipitated silicone, colloidal silicone dioxide, alginic acid and salt thereof.
11. A composition as claimed in claim 7 wherein the preservative is selected from the group consisting of benzoic acid, and salt thereof, asorbic acid and salt thereof, methyl paraben and salt thereof, propyl paraben and salt thereof, and bronopol.


12. A composition as claimed in claim 1 wherein the amount of nimesulide is 100 mg, the amount of cetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
13. A composition as claimed in claim 1 wherein the amount of nimesulide is 100 mg, the amount of levocetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
14. A composition as claimed in claim 1 wherein the amount of nimesulide is 100 mg, the amount of levocetirizine is 2.5 mg and the amount of pseudoephedrine is 120 mg.
15. A pharmaceutical composition for the treatment of allergic rhinitis substantially as described herein and with reference to the foregoing examples.

Dated this on 16th day of July, 2004.


Dr. Rajeshkumar H. Acharya.
Advocate & Patent agent
For and on behalf of the applicant.

FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION
PHARMACEUTICAL COMPOSITION CONTAINING ANTI¬INFLAMMATORY, ANTIHITAMINIC AND DECONGESTANT (SUSTAINED RELEASE) FOR TREATING ALLERGIC RHINITIS
2. APPLICANT (S)
(a) NAME : Lincoln Pharmaceuticals Limited.
(b) NATIONALITY: an Indian Company
(c) ADDRESS : Nirav Complex, Opp. Navrang High School
Naranpura, Ahmedabad-380014 Gujarat, India.
3. PREMABLE TO THE DESCRIPTION

PROVISIONAL
The following specification describes the invention.

0 COMPLETE
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 novel pharmaceutical composition for the treatment of allergic rhinitis. More particularly, the present invention relates to a novel pharmaceutical composition containing anti-inflammatory, anti-histaminic and decongestant ingredients for sustained release in the treatment of allergic rhinitis.
The present invention also relates to a process for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis. Background of the invention
Allergic rhinitis is a common disorder observed all over the world especially during change of seasons. The disease is believed to occur due to the high pollen content in air, due to dust and other viral or bacterial infections. This common symptoms of this disorder are sneezing, headache, running nose, congestion, body ache and infections of upper respiratory system.
Various pharmaceutical compositions are available with one or more active ingredients for treating the symptoms of allergic rhinitis also known as common cold and patient has to be administered with multiple does of anti-inflammatory, decongestants and antihistamines or in combination of any two. Most of the times number of doses per day goes as high as 6 to 9 tablets.
It is known in the art to provide a composition of Nimesulide and slats thereof and Cetirizine possessing antileukotriene, antihistamine, antiallergic and anti-infiamatory action. The composition is useful in the cure of allergic disorders. Ref: CA2253061, US6258816, AU729581, EP1005865]
A pharmaceutical compositions and methods of using non-steroidal anti¬inflammatory analgesic Naproxen and decongestant Pseudoephedrine in a time release tablet form to cure sinusitis are also known [Ref. AU758880, EP1107740].
Pharmaceutical compositions have been developed for treatment of cough and cold symptoms comprising loratidine, ibuprofen and pseudoephedrine. [Ref US5100675].
Tablet comprising of Cetirizine and Pseudoephedrine was developed for curing allergic and decongestant disorders. [Ref: SKI5502003, EE200400005, WO03002098].
2

A process was developed for the preparation of controlled release delivery system containing Pseudoephedrine and a long acting antihistamine from the group consisting of loratadine, azatidine, fexofenadine, terfemadine, cetirizine, astemizole, and levocabastine. [Ref. EP1217997, WO0121168, US6267986J. A tablet comprising of Cetirizine and Pseudoephedrine was developed for anrihistaminic and decongestant activity [Ref. EP1404304].
Oral pharmaceutical composition have been developed comprising leukotriene inhibitor and Pseudoephedrine for the treatment of allergies, asthma and associated signs and symptoms. [Ref: US2004048890].
Pharmaceutical composition containing epinastine and Pseudoephedrine have been developed for anrihistaminic and decongestant activity. [Reft CN1468094TJ.
Composition containing loratadine and Pseudoephedrine was developed for treating the patients suffering from asthma and allergic rhinitis. [Ref: CA2268546, WO9818470, EP0941091, TR9901003T, AU731756].
Reports show the efficacy of Nimesulide and combination with Cetirizine in acute allergic rhinitis. Reports relying on clinical trials show that Cetirizine in combination with Nimesulide exerts synergistic action in reducing symptoms in-patients of allergic rhinitis (Ref: JAPI, 2001 ;49;518-522 and JAPI, 1999; VOL 47(4):389-392).
Efficacy and safety relative to placebo of an oral formulation of Cetirizine and sustained release Pseudoephedrine in the management of nasal condition has been studied and found that Cetirizine / PSE relieved nasal congestion and other subjective and objective symptoms to a significandy greater extent than Placebo. No serious adverse events occurred [REF: PMID:9788685].
However, at present no single pharmaceutical combination is available which can relieve all the signs and symptoms of allergic rhinitis. In conventional and known treatment, the patient is administered anti-inflammatory formulations, decongestants and antihistamines separately or in a combination of any two. The number of doses per day are also quite high and can be as much as 9 tablets per day.
It is therefore important to provide a novel pharmaceutical composition containing a combination of potent anti-inflammatory formulation, antihistamine formulation and a decongestant together in a single dosage form and reduce the number of doses to two per day.
3


Objects of the invention
The main object of the present invention is to develop a pharmaceutical composition containing anti-inflammatory, antihistamines and decongestants (sustained release) in a single dosage form.
It is another object of the invention to provide a novel pharmaceutical
formulation for the treatment of allergic rhinitis wherein the dosage is reduce^ to a
maximum of two per day.
Summary of the invention ,„- -
Accordingly, the present myentJon provides a phamacetical compostion for the treatment of allergic rhinitis comprising an^nti-mflammatoryC ail anti-histamine and a decongestant in a single dosage form, the amount of the anti-inflammatory being in the range of 50 mg to 200 mg, the amount of the anti-histamine being in the range of 2.5 to l0 mg and the amount of the decongestant being in the range of 30mg to 120 mg, all amounts being expressed in terms of weight per dose of the composition, the balance if any comprising one or more conventional additives and pharmaceutically acceptable excipients.
In one embodiment of the invention, the anti-inflammatory is nimesulide.
In another embodiment, the anti-histamine is cetirmne.
In another embodiment, the anti-histamine is levocetirizine.
In yet another embodiment of the invention, the decongestant is pseudoephedrine.
In yet another embodiment of the invention, the conventional ingredients are selected from the group consisting of diluents, binders, lubricants, disintegrants and other conventional excipients.
In yet another embodiment of the invention, the binder is selected from the group consisting of starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gum acacia, carbopol and other acrylic resins, and polyethylene glycols.
In yet another embodiment of the invention, the diluent is selected from the group consisting of starch and modified starches, microcrystalline cellulose, lactose,
4

sorbitol, dicalcium phosphate, calcium carbonate, hydroxy propyl cellulose, aluminium magnesium silicate and cyclodextrins.
In another embodiment of the invention, the lubricant and disintegrants are selected from the group consisting of starch, sodium starch glycolate, colloidal silicondioxide, guar gum, sodium carboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica.
In yet another embodiment of the invention, the composition is in the form of a tablet, hard gelatin capsule or oral liquid suspension.
In yet another embodiment of the invention, the conventional additives comprise sweetening agents, suspending agents, and preservatives.
In another embodiment of the invention, the diluent for a oral liquid suspension comprises purified water, glycerin, propylene glycol, polyethylene glycol-200 and polyethylene glycol-400.
In yet another embodiment of the invention, the sweetening agent is selected from the group consisting of tnannitol, sugar, invert sugar, liquid glucose, sorbitol, malt extract, aspartame, saccharine and salt thereof.
In yet another embodiment of the invention, the suspending agent for the oral liquid suspension is selected from the group consisting of carboxymethyl cellulose and salt thereof, cellulose dilutes, guar gum, xantham gum, precipitated silicone, colloidal silicone dioxide, alginic acid and salt thereof.
In another embodiment of the invention, the preservative is selected from the group consisting of benzoic acid, and salt thereof, sorbic acid and salt thereof, methyl paraben and salt thereof, propyl paraben and salt thereof, and bronopol.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of cetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of levocetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
The present invention also relates to a process for the preparation of a pharmaceutical composition for the treatment of allergic rhinitis comprising an anti¬inflammatory, an anti-histamine and a decongestant in a single dosage form, the amount of the anti-inflammatory being in the range of 50 mg to 200 mg, the amount of the anti¬histamine being in the range of Z5 to lOmg and the amount of the decongestant being in
5

the range of 30mg to 120 mg, all amounts being expressed in terms of weight per dose of the composition, the balance if any comprising one or more conventional additives and pharmaceutically acceptable excipients, the process comprising mixing in any conventional manner the above referred ingredients.
In one embodiment of the invention, the anti-inflammatory is nimesulide.
In another embodiment, the anti-histamine is cetirizine.
In another embodiment, the anti-histamine is levoln yet another embodiment of the invention, the decongestant is pseudoephedrine.
In yet another embodiment of the invention, die conventional ingredients are selected from the group consisting of diluents, binders, lubricants, disiritegrants and other conventional excipients.
In yet another embodiment of the invention, the binder is selected from the group consisting of starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium catboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gum acacia, carbopol and other acrylic resins, and polyethylene glycols.
In yet another embodiment of the invention, the diluent is selected from the group consisting of starch and modified starches, rnicrocrystalline cellulose, lactose, sorbitol, dicalrium phosphate, calcium carbonate, hydroxy propyl cellulose, aluminium magnesium silicate and cyclodextrins.
In another embodiment of the invention, the lubricant and disintegrants are selected from the group consisting of starch, sodium starch glycolate, colloidal silicon dioxide, guar gum, sodium catboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica.
In yet another embodiment of the invention, the composition is in the form of a tablet, hard gelatin capsule or oral liquid suspension.
In yet anomer embodiment of the invention, the conventional additives comprise sweetening agents, suspending agents, and preservatives.
In another embodiment of the invention, the diluent for a oral liquid suspension comprises purified water, glycerin, propylene glycol, polyethylene glycol - 200 and polyethylene glycol 400.
6

In yet another embodiment of the invention, the sweetening agent is selected from the group consisting of mannitol, sugar, invert sugar, liquid glucose, sorbitol, malt extract, aspartame, saccharine and salt thereof.
In yet another embodiment of the invention, the suspending agent for the oral liquid suspension is selected from the group consisting of carboxymethyl cellulose and salt thereof, cellulose dilutes, guar gum, xantham gum, precipitated silicone, colloidal silicone dioxide, alginic acid and salt thereof.
In another embodiment of the invention, the preservative is selected from the group consisting of benzoic acid, and salt thereof, sorbic acid and salt thereof, methyl paraben and salt thereof, propyl paraben and salt thereof, and bronopol.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of cetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
In another embodiment of the invention, the amount of nimesulide is 100 mg, the amount of levocetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
The composition of the invention is a synergistic admixture showing improved properties of being administrable in a single dose form and with reduced per diem dosage and not a mere aggregate of the properties of the individual ingredients. Detailed description of the invention
As explained in the background of the invention, allergic rhinitis is a common disorder occurring normally during change of seasons. The patient normally shows symptoms like sneezing, headache, running nose, congestion, body ache and infection of upper respiratory system. The symptomatic cure to provide relief from these symptoms normally comprises administering antihistamines, anti-inflammatories and decongestant drugs to the patient, either alone or in a combination of any two thereof. It has been observed that the time taken for the patient to obtain relief can be quite long and the dosage can be quite high - as much as 9 tablets per day. Missing a single dose in a regimen of treatment can result in slowing down of the efficacy of the treatment process.
The present invention provides a novel pharmaceutical composition containing Nimesulide as an anti-inflammatory, Cetirizine or Levocetirizine as antihistamine and Pseudoephedrine as a decongestant in a single dose. The composition can be in the form of tablet, capsule or oral liquid suspension. The maximum dose per day of the dosage form is two.
7

Symptoms of allergic rhinitis occur as a result of direct and indirect action of histamine acting largely on the HI receptors in target tissues. Along with histamine a range of other vasoactive mediators such as kinins cause vasodilation resulting in congestion. Nimesulide apart from its analgesic, antipyretic and anti-inflammatory activity it is a mast cell inhibitor i.e. in turn inhibits the release of histamines. Cetirizine or Levocetirizine in combination with Nimesulide as a synergistic effect and acts as an antihistamine by selective HI histamine receptor antagonistic. Combination of Nimesulide and Cetirizine however does not relieve nasal congestion. Therefore, the
present invention relies on the addition of pseudoephedrine as a decongestant
Pseudoephedrine acts as predominantly on alfa receptors without central nervous system
Tn"mulationrT!ombination of Nimesulide, Cetirizine and Pseudoephedrine in a single
'formulation helps in relieving the signs and symptoms of allergic rhinitis within three
days
The composition has been clinically studied at multiple locations. Clinical studies have shown that the combination of Nimesulide Cetirizine or Levocetirizine and Pseudoephedrine in a single dosage form gives much better results in terms of relieving J of signs of symptoms of allergic rhinitis. Patients administered with above combinations have shown faster recovery from allergic rhinitis than the patients administered with drugs with individual dosage forms.
50 to 200mg 2.5 to lOmg 30 to 120mg
Q.S.
50to200mg 2.5 to 5mg
It has been also observed that failure by a patient to take the dosage is reduced since the number of doses per day is less (with sustained release Pseudoephedrine). This has also helped in maintaining the drug-serum level in the body. (A) Pharmaceutical combination has been developed in tablet from containing: ©Each tablet contains:
1. Nimesulide
2. Cetirizine Dihydrochloride
3. Pseudoephedrine Hydrochloride (Sustained Release Form)
4. Excipients
©Each tablet contains:
1. Nimesulide
2. Levocetirizine Dihydrochloride

3. Pseudoephedrine Hydrochloride 30 to 120mg (Sustained Release Form)
4. Excipients Q-S.
Tablet form was developed widi different combinations of diluents (Le. starch and modified starches, microcrystalline cellulose, lactose, sorbitol, dicalcium phosphate, calcium carbonate, hydroxypropyl cellulose, aluminium magnesium silicate), Binders (i.e. starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ediyi cellulose, hydroxyethyl cellulose> hydroxypropyl methyl cellulose* gum acacia, carbopol and other acrylic resins, polyethylene glycols) and lubricants and disintegrants (i.e. starch, sodium starch glycolate, colloidal silicondioxide, guar gum, sodium carboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica).



10


Hard gelatin capsule form was developed with different combinations of Diluents & Excipients (Le. starch and modified starches, microcrystalline cellulose , lactose, sorbitol,
11


V-i
dicalcium phosphate, calcium carbonate, starch, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydoixypropyl methyl cellulose and other acrylic resins, polyethylene glycols ) and Lubricants (Le. stearic acid and its salts , purified talc and modified silica).


13

Sugar 35.0 gm
Sorbitol Solution 70% 10.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Aspartame 0.05 gm
Propyl Paraben sodium 0.05 gm
Bronopol 0.02 gm
Citric Acid 0.04 gm
Xantham Gum 0.15 gm
Colour Q.S.
Purified Water Q.S.
Example 14:
INGREDIENT EACH 100 ML CONTAINS
Nimesulide 2.0 gm
Levocetirizine dihydrochloride 0.1 gm
Pseudoephedrine Hydrochloride 1.2 gm
Liquid Glucose 20.0 gm
Sugar 45.0 gm
Sorbitol Solution 70% 10.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Propyl Paraben sodium 0.05 gm
Bronopol 0.02 gm
Citric Acid 0.04 gm
Sodium Carboxymethyl Cellulose 2.0 gm
Colour Q.S.
Purified Water Q.S.
Example 15:
INGREDIENT EACH 100 ML CONTAINS
Nimesulide 1.0 gm •
Cetirizine Hydrochloride 0.2 gm
Pseudoephedrine Hydrochloride 1.2 gm
15


16

Liquid Glucose 30.0 gm
Sugar 45.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Aspartame 0.05 gm
Propyl Paraben sodium 0.05 gm
Methyl Paraben Sodium 0.2 gm
Citric Acid 0.04 gm
XanthamGum 0.15 gm
Colour Q.S.
Purified Water Q.S.
Example 18:
INGREDIENT EACH 100 ML CONTAINS
Nimesulide 0.5 gm
Cetirizine dihydrochloride 0.05 gm
Pseudoephedrine Hydrochloride 0.3 gm
Liquid Glucose 30.0 gm
Sugar 45.0 gm
Glycerin 5.0 gm
Propylene Glycol 5.0 gm
Aspartame 0.05 gm
Propyl Paraben sodium 0.05 gm
Bronopol 0.02 gm
Citric Acid 0.04 gm
Sodium Carboxymethyl Cellulose 2.0 gm
Colour Q.S.
Purified Water Q.S.
The above examples are flon-limiting and are illustrative of the composition of the invention. Modifications and variations therefrom are possible without departing from the spirit of the invention.
17

Claim:
1. A pharmaceutical composition for the treatment of allergic rhinitis comprising the amount of nimesulide as an anti-inflammatory being in the range of 50 mg to 200 mg, the amount of cetirizine or levocetirizine as an anti-histamine being in the range of 2.5 to lOmg and the amount of pseudoephedrine as a decongestant in sustained release form being in the range of 30mg to 120 mg and one or more conventional additives and pharmaceutically acceptable excipients.
2. A composition as claimed in claim 1 wherein the conventional ingredients are selected from the group consisting of diluents, binders, lubricants, disintegrants and other conventional excipients.
3. A composition as claimed in claim 2 wherein the binder is selected from the group consisting of starch paste, gelatin, pregelatinised starch, polyvinyl pyrrolidone - various grades like K-30, K-90, VA-64, etc., sodium carboxymethyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, gum acacia, carbopol and other acrylic resins, and polyethylene glycols.
4. A composition as claimed in claim 2 wherein the diluent is selected from the group consisting of starch and modified starches, microcrystalline cellulose, lactose, sorbitol, dicalcium phosphate, calcium carbonate, hydroxypropyl cellulose, aluminium magnesium silicate and cyclodextrins.
-2 JUN 2008

5. A composition as claimed in claim 2 wherein the lubricant and disintegrants are selected from the group consisting of starch, sodium starch glycolate, colloidal silicon dioxide, guar gum, sodium carboxymethyl cellulose, stearic acid and its salts, purified talc and modified silica.
6. A composition as claimed in any preceding claim wherein the composition is in the form of a tablet, hard gelatin capsule or oral liquid suspension.
7. A composition as claimed in claim 2 wherein the conventional additives comprise sweetening agents, suspending agents, and preservatives.
8. A composition as claimed in claim 7 wherein the diluent for a oral liquid suspension comprises purified water, glycerin, propylene glycol, polyethylene glycol - 200 and polyethylene glycol 400.
9. A composition as claimed in claim 7 wherein the sweetening agent is selected from the group consisting of mannitol, sugar, invert sugar, liquid glucose, sorbitol, malt extract, aspartame, saccharine and salt thereof.
10. A composition as claimed in claim 7 wherein the suspending agent for the oral liquid suspension is selected from the group consisting of carboxymethyl cellulose and salt thereof, cellulose dilutes, guar gum, xantham gum, precipitated silicone, colloidal silicone dioxide, alginic acid and salt thereof.
11. A composition as claimed in claim 7 wherein the preservative is selected from the group consisting of benzoic acid, and salt thereof, asorbic acid and salt thereof, methyl paraben and salt thereof, propyl paraben and salt thereof, and bronopol.


12. A composition as claimed in claim 1 wherein the amount of nimesulide is 100 mg, the amount of cetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
13. A composition as claimed in claim 1 wherein the amount of nimesulide is 100 mg, the amount of levocetirizine is 5 mg and the amount of pseudoephedrine is 120 mg.
14. A composition as claimed in claim 1 wherein the amount of nimesulide is 100 mg, the amount of levocetirizine is 2.5 mg and the amount of pseudoephedrine is 120 mg.
15. A pharmaceutical composition for the treatment of allergic rhinitis substantially as described herein and with reference to the foregoing examples.

Dated this on 16th day of July, 2004.


Dr. Rajeshkumar H. Acharya.
Advocate & Patent agent
For and on behalf of the applicant.