WO2003101434A2

WO2003101434A2 - Intranasal pharmaceutical compositions comprising an antihistamine and a leukotriene inhibitor

Info

Publication number: WO2003101434A2
Application number: PCT/IN2003/000205
Authority: WO
Inventors: Sampad Bhattacharya; Kiran Lagu; Sangeeta Chhabada
Original assignee: Sampad Bhattacharya; Kiran Lagu; Sangeeta Chhabada
Priority date: 2001-12-21
Filing date: 2003-05-30
Publication date: 2003-12-11
Also published as: AU2003264859A8; AU2003264859A1; WO2003101434A3

Abstract

A pharmaceutical composition in the intranasal delivery to the nasal mucosa for prevention and treatment of symptoms of allergic rhiities and problems like nasal polyps comprising of Loratadine or Desloratadine which are potent antihistamine and solubilised at pharmaceutically acceptable pH of 4 to 8 which does not cause any irritation in the nose and permits the application of potent antihistamine at the site of action the nasal mucosa in lesser doses and without any side effect with immediate onset of action. Montelukast Sodium in combination with Loratadine would be very effective and gives some effect as intranasal steroids that without any side effects. Addition of pharmaceutical acceptable delivery vehicle help in forming intranasal application dosage units for applying the composition at nasal mucosa.

Description

INTRANASAL PHARMACEUTICAL COMPOSITIONS COMPRISING AN ANTIHISTAMINE AND A LEUKOTRIENE INHIBITOR

FIELD OF THE INVENTION: The invention relates to pharmaceutical compositions comprising an antihistamine with or without a leukotriene inhibitor,alongwith pharmaceutically acceptable solubilisers, thickening agents, dispersing agents, buffers, surfactants, stabilizers, propellants, cosolvents and preservatives for intra nasal delivery to the nasal mucosa, for prevention and treatment of symptoms of allergic rhinitis and problems like nasal polyps and a process of preparing the said composition.

BACKGROUND OF THE INVENTION:

Allergic rhinitis is a prevalent chronic illness affecting approximately 25% of the population, and causes appreciable discomfort and morbidity.

Antihistamines are considered first line therapy for the prevention and treatment of symptoms of allergic rhinitis, as histamine produces itching and sneezing by direct stimulation of HI receptors, which results in rhrnorrhea due to histamine induced vaso hlatation and increased permeability of the nasal vasculature. Leukotriene inhibitors inhibit the cysteinyl leukotriene receptors (CysLT), and help improve nasal allergy symptoms. The efficacy of therapy in combination is enhanced due to the additive effect. Patients suffering from perennial allergic rhinitis may require chronic therapy.

Loratadine also known as, ethyl 4-18-chloro-5,6-dihydro-l 1 H benzo [5,6| cyclohepta [1,2- b]pyridin-l l-ylidene)-l-piperidinecarboxylate is a second generation antihistamine and ,desloratadine is a metabolite of loratadine also known as 8-chloro-6,l l-dihydro-l l-(4- piperdinylidene)-5Hbenzo[5,6]cyclohepta [l,2-b]pyridine.

The significant attributes of oral loratadine and desloratadine are short onset of action, long duration of effect, low sedation, and though reasonably free from drug interactions and serious cardiovascular events, it has not been sufficiently studied to allow it to be certified 'free' of any serious adverse effects or interactions. Until more information is available on specific cytochrome P450 enzyme as is the case with other second generation antihistarnmes, it would be ill advised to orally co-administer drugs metabolized by this system.

Existing Intranasal therapy for Allergic rhinitis includes :

(1) Azelastine, the only anti-histamine available as intra-nasal preparation,

(2) decongestants, (3) mast cell stabilizer cromolyn, (4) anticholinergic ipratropium bromide and (5) corticosteroids.

In selecting an ideal agent, based on existing therapy it would be only appropriate to strike a balance between the advantages and the drawbacks associated with each type of preparation.

The drawbacks associated with existing intranasal therapy can be listed as

a) In case of azelastine, drowsiness, fatigue, headache, taste disorders, and nasal burning. b) In case of decongestants burning, stinging, sneezing, dryness of the nasal mucosa and more importantly the risk of rhinitis medicamentosa or severe nasal odema, decreased receptor sensiti ity and rebound congestion on withdrawal of therapy. c) Cromolyn though devoid of any side effects, has no immediate effect, is less effective than topical corticosteriods and should be given four times a day. d) Intranasal corticosteroids should be taken continuously for maximum benefit. Improvements begin to occur only after two doses and may take as long as 2 weeks in some patients. Adverse effects include local burning, throat irritation, bad taste, and superficial candidal infections, and epistaxis.

The second generation antihistamines have adverse effects as well. Most of the adverse effects occur due to the systemic effects, and include headache, fatigue, nervousness, dyspepsia, and though cause considerably less sedation, CNS impaiπnent can still occur, resulting in sleep latency, reaction time, and visual motor co-ordination problems. In case of oral loratadine, somnolence, tachycardia, and in chirdrcn extrapyramidal signs and palpitations have been reported in case of over dosage.

Intranasal preparations of loratadine or desloratadine score very heavily when compared to oral systemic therapy in all the aspects discussed above and the advantages are :

Montelukast sodium also known as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethynyl]phenyl]-3-[2-(l- hydroxy-l-methylethyl)phenyl]propyl]thio]mcthyl]cyclopropaneacetic acid, monosodium salt is a selective leukotriene receptor antagonist and significant reductions in the common symptoms associated with allergic rhinitis have been reported. In combination with an antihistamine a synergistic or additive effect is seen due to inhibition of both the histaminic HI receptor and the leukotriene CysLT receptors, that arc stimulated in patients suffering from allergic rhinitis. Thus the combination acts on two different receptors helping improve nasal allergic symptoms.

In asthmatic patients oral montelukast sodium has proved to be a better choice over steroids. In trials conducted over a 12 week treatment period, oral montelukast sodium vs inhaled beclomethasone dipropionate, change in day time symptoms scores was -0.49 for montelukast as compared to -0.7 for beclomethasone on a scale of 0 - 6 (very much better through very much worse respectively). The same would be the case with intranasal administration as well and adverse effects associated with steroids could be avoided. Topical steroids have been used in patients suffering from nasal polyposis. Nasal polyps are the common end point of a number of conditions characterized by inflammation consisting of inflitration of the respiratory epithelium covering stroma by a number of inflammatory cells such as eosinophils, mast cells and lymphocytes. They are normally managed by combination of medical and surgical interventions. Post surgically the combination of loratadine or desloratadine alongwith montelukast sodium would have a multifactorial effect on the aspects of the inflammatory reaction, the effect being initiated by their binding to the hista inic and the leukotriene receptors, re-establish nasal airway and breathing; restore the sense of smell, and help prevent recurrence of nasal polyps. It is therefore in the maintenance therapy of nasal polyps where the combination of loratadine or desloratadine alongwith montelukast sodium would have a role to play.

These preparations thus achieve the goals of pharmacotherapy for allergic rhinitis namely, to prevent or minimize symptoms, improve lifestyle of patients by allowing them to indulge in regular activities, and avoid adverse drug reactions.

SUMMARY OF THE INVENTION:

The present invention relates to pharmaceutical compositions to provide a method for safely and conveniently administering loratadine or desloratadine with or without montelukast sodium in patients for prevention and treatment of symptoms of allergic rhinitis and problems like nasal polyps.

• The method comprises intranasal administration of an effective amount of loratadine or desloratadine to prevent or minimize symptoms of allergic rhinitis.

• In another embodiment the method comprises intranasal administration of an effective amount of loratadine or desloratadine in a mixture with an effective amount of montelukast sodium.

• Another embodiment is pharmaceutical compositions which include a therapeutically effective amount of loratadine or desloratadine with or without montelukast sodium alongwith pharmaceutically acceptable solubilisers, thickening agents, dispersing agents, buffers, surfactants, propellants, cosolvents, stabilizers and preservatives. In further embodiment, there is provided a method of treating allergic rhinitis. This method includes administration to the nasal mucosa a therapeutically effective dosage of loratadine or desloratadine with or without montelukast sodium in combination with an intranasal delivery vehicle that includes solubilisers, thickening agents propellants, buffers, surfactants, stabilizers and preservatives.

• Preferred formulations for intranasal use herein are drops or sprays, and in solution, gel, ointment, lotion, suspension or emulsion dosage forms.

• In another embodiment single dose and multidose devices for intranasal application of dosage units for delivery to the nasal mucosa are provided for treating allergic rhinitis, and include metered dose pumps, pressurised metered dose nasal aerosol and droppers. The dosage units include an effective amount of HI receptor antagonist loratadine or desloratadine with or without a leukotrine inhibitor montelukast sodium in combination with an intranasal formulation. These formulations contain pharmaceutically acceptable solubilisers, surfactants, propellants, thickening agents, buffers, emulsifiers, dispersing agents, stabilizers and preservatives.

• The solubilisers, propellants, buffers, surfactants, dispersants are selected to facilitate effective concentration of loratadine or desloratadine with or without montelukast sodium at the site of action, the nasal mucosa.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention is directed to pharmaceutical composition and method for therapy of allergic rhinitis and problems like nasal polyps in patients. The composition includes loratadine or desloratadine, a long acting antihistamine with selective peripheral histamine HI receptor antagonistic activity, with or without montelukast sodium a leukotriene inhibitor for prevention and treatment of symptoms of allergic rhinitis and inproblems like nasal polyps in combination with an intranasal delivery vehicle. The term "allergic rhinitis" is indicated to involve medically related symptoms which might be seasonal or perennial resulting in nasal congestion, watery rhinnorhea, postnasal drip, nasal pruritus, lacrimation, paroxysmal sneezing, which can further lead to frontal or sinus headaches, dry mouth and halitosis. Clinical presentation of allergic rhinitis includes itching of the throat or soft palate, mucous membranes of the eyes, eustachian tube, middle ear, and paranasal sinuses which can lead to redness, tearing and conjunctival irritation of the eyes; popping, aching and fullness of the ears and severe sinus headaches. The term "Nasal polyps" includes common end points of a number of conditions characterized by inflammation due to infiltration of the respiratory epithelium covering the stroma by mast cells, eosinophils, and lymphocytes. Psychological effects can include frequent absences from work or school, poor performance, poor appetite, malaise, and chronic fatigue.

The term "antihistamine" used herein is intended to mean an agent that is capable of preventing the binding of histamine from the histamine type HI -receptors. Desirably the antihistamine is loratadine or desloratadine and salts thereof. Loratadine is also known as ethyl 4-18-chloro-5,6- dihydro-11 H benzo [5,6] cyclohepta | l,2-bJpyridin-l l-ylidene)-l-piperidinecarboxylate.

Desloratadine is also known as 8-chloro-6,l l-dihydro-ll-(4-piperdinylidene)-

5Hbenzo[5,6]cyclohepta [ 1 ,2-bJpyridine.

The term "leukotriene inhibitor" is intended to mean an agent that inhibits the cysteinyl leukotriene receptors (CysLT) .

Desirably the leukotriene inhibitor is montelukast sodium or other salts of montelukast.

Montelukast sodium is also known as [R-(E)]-l-[[[l-[3-|2-(7-chloro-2- quinolinyl)ethynyl]phenyl]-3-[2-(l-hydroxy-l- me ylethyl)phenyl|propyl]thio]methyl]cyclopropaneacetic acid, monosodium salt. The term "effective" amount used herein is intended to mean a sufficient amount of the long acting tricyclic antihistamine loratadine or desloratadine with or without a sufficient amount of leukotriene inhibitor montelukast sodium to provide the desired effect that is : prevention and treatment of symptoms of allergic rhinitis and in problems like nasal polyps.

The term "delivery vehicle" used herein refers to carrier materials suitable for intranasal application. Carriers or vehicles used herein include any such material known in the art which arc non toxic, and do not interact with other components of the composition and also do not interact with components of the dosage units in a deleterious manner.

The term "Intranasal" is used to mean application to the nasal mucosa of the composition to deliver the long acting antihistamine loratadine or desloratadine with or without the leukotriene inhibitor montelukast sodium.

The term "devices" is used herein to mean devices available for nasal delivery and includes metered dose-pump driven nasal sprays, propellant driven metered dose nasal sprays, droppers, along with the containers, which may be glass bottles, plastic bottles, metal containers, tubes. It has been found that long acting tricyclic antiliistamine loratadine or desloratadine with or without montelukast sodium in a delivery vehicle which when applied to nasal mucosa, the intended effect is achieved within 10 minutes or less as compared to 1 hour or longer by the oral route.

The delivery vehicles can take various forms including for example solutions, suspensions, gels, ointments, emulsions, or lotions.

The various forms of the delivery vehicle are made by solubilising or dispersing loratadine or desloratadine with or without montelukast sodium in pharmaceutically acceptable solubilisers, dispersing agents, thickening agents, emulsifiers, surfactants, stabilizers and perservatives.

The solubilisers in the delivery vehicle of the present invention that can be used may include dimethyl isosorbide, diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol, polyoxyl-35 -castor oil, polyoxyl-40-hydrogenated castor oil, tocopheryl polyethylene glycol 1000 succinate, glycofurol, glycerol, ethanol, mixture of polyethylene glycol 660 12-hydroxy 70%, and polyethylene glycol 30%, polysorbate 80, and mixtures thereof. The concentration of the solutions will depend upon the type of delivery vehicle selected, and may be present in concentration ranging from 0.1 - 50%

The viscosity of the delivery vehicle of the present invention can be maintained at a desired level using pharmaceutically acceptable thickening and dispersing agents. Thickening or dispersing agents which can be used in accordance with the present invention may include carbomer, carboxymethyl cellulose sodium, poloxamers, povidone, microcrystalline cellulose, polyvinyl alcohol, methylhydroxy ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, hydroxypropylcellulose, polycarbophils, xanthan gum, guar gum, and mixtures thereof. The concentration of the thickening or dispersing agent will depend upon the type of delivery vehicle desired and may be present in a concentration ranging from 0.1 - 50%.

The emulsifiers or surfactants that can be used may include polyoxyl-35 -castor oil, glycerine stearate and polyethyleneglycol 75 stearate, polyoxyl-40-hydrogenated castor oil, polyethylene glycol-6-32-stearate and glycol stearate, sorbitan trioleate, olcic acid, phospholipids such as phosphatidylethanolamine, phosphatidylchloline, phophatidylinositol, , and mixtures thereof. The concentration of the emulsifiers will depend upon the type of delivery vehicle selected and may be present in a concentration ranging from 0.001 - 30%.

In the present invention, the propellant that might be used in pressurised metered dose nasal sprays include for example di-chloro-difluoro methane or trichloro monofluoro ethane CFC 11, dicholorotetrafluoro ethane or CFC 114, tetrafluoroethane or HFA-134a, heptafluoropropane or HFA-227 and mixtures thereof.

The stabilizers in the delivery vehicle of the present invention that can be used includes complexing agents and antioxidants. The complexing agents which may be used but are not limited to include for example hydroxypropyl beta cyclodextrin or gamma cyclodextrin. The antioxidants which may be used but are not limited to include for example sodium metabisulphite, sodium sulphite, sodium bisulphite, acetyl cysteine, butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, tocopheryl compounds, d-alpha tocopheryl polyethylene glycol 1000 succinate or mixtures thereof. In the present invention, other optional ingredients may also be included in the delivery vehicle provided they do not interfere with the action or decrease the potency of the antihistamine or the leukotriene inhibitor. Such pharmaceutically acceptable excipients may be preservatives, and buffers. Preservatives that can be used with the present delivery vehicles include potassium sorbate, benzalkonium chloride, phenylethylalcohol, methylparaben, propylparaben, ethylparaben, butylparaben, disodium edetate, sorbic acid, phenoxyethanol and mixtures thereof. The preservatives may be used in a concentration upto about 1% by weight. Buffering agents that may be used in the present preparation include for example citric acid, dibasic potassium phosphate, sodium citrate, hydrochloric acid, sodium hydroxide, tromethamine, acetate buffers and mixtures thereof.

In another embodiment of the present invention, the composition as described above are applied intranasally to the nasal mucosa for the prevention and treatment of symptoms of allergic rhinitis and in problems like nasal polyps.

For purpose of the present invention intranasal administration is intended to mean that the long acting antihistamine with or without a leukotriene inhibitor is combined with a suitable delivery vehicle for intranasal aαitiinistration or application to the nasal mucosa.

Another embodiment of the present invention is composition for intranasal administration which may include a thcrapeutically significant amount of the antihistamine with or without a leukotriene inhibitor solubilised or dispersed in pharmaceutically acceptable solubilisers, thickening agents, and pharmaceutically acceptable emulsifiers and surfactants.

"Therapeutically significant" amount as used herein means dosage of the present antihistamine with or without a leukotriene inhibitor in combination with a pharmaceutically acceptable delivery vehicle to be administered to the nasal mucosa to render the intended pharmacotherapcutic effect i.e. to prevent or minimize symptoms of allergic rhinitis and problems like nasal polyps.

The long acting antihistamine is ethyl 4-18-chloro-5,6-dihydro-l l H benzo [5,6] cyclohepta | l,2-bjpyridin-l l-ylidene)-l-piperidinecarboxylate also known as loratadine and salts thereof or 8-chloro-6,l l-dihydro-l l-(4-piperdinylidene)-5Hbenzo[5,6]cyclohepta [1,2- bjpyridinc. also known as desloratadine and salts thereof. The leukotriene inhibitor is desirably |R-(E)|-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethynyl]phenyl]-3-[2-(l-hydroxy-l- methylethyl) phenyl]propyljthio]methyl]cyclopropaneacetic acid, monosodium salt also known as montelukast sodium or other salts of montelukast. In a further embodiment of the present invention a method for preventing and treating symptoms of allergic rhinitis includes intranasal administration to the nasal mucosa a therapeutically effective dosage of a long acting antihistamine with or without a therapeutically effective dosage of a leukotriene inhibitor. The antihistamine used here in is loratadine or desloratadine. The leukotriene inhibitor used herein is montelukast sodium.

A further embodiment of the present invention includes an intranasal delivery dosage unit for preventing or treating symptoms of allergic rhinitis and problems like nasal polyps. This intranasal dosage unit includes an effective amount of long acting antihistamine loratadine or desloratadine with or without a leukotriene inhibitor montelukast sodium in combination with pharmaceutically acceptable delivery vehicle. This delivery vehicle includes pharmaceutically acceptable solubilisers, dispersing agents, thickening agents, surfactants, emulsifying agents, stabilizers, preservatives, propellants and buffers. The pH of the delivery vehicle is selected so as to minimize irritation to the nasal mucosa, enhance the stability of the composition and is adjusted by selecting the concentration of the buffers and mixtures thereof.

Depending upon the exact nature of the dosage form required the pharmaceutically acceptable carrier will be different. Suitable dosage forms developed with the present compositions for intranasal administration are found in pharmaceutical literature and includes solutions, suspensions, gels, ointments, lotions and emulsions.

Range of Excipients

The following examples illustrates the process of preparing the pharmaceutical composition comprising an antihistamine with or without a leukotriene inhibitor for intranasal delivery to the nasal mucosa for prevention and treatment of symptoms of Allegic Rhinitis and in problems like nasal polyps:

EXAMPLES: EXAMPLE - 1

Transfer 0.1 gm loratadine to a container. Add dimethyl isosorbide 12.5 ml, propylene glycol 10 ml, and sufficient quantity of 20% citric acid solution under stirring till a clear solution is obtained. Separately dissolve benzalkonium chloride 0.02 gm and 0.2 gm of phenyl ethyl alcohol in purified water and add it to the drug solution. Adjust the pH with Sodium acetate to 5.2 and make up the volume with purified water.

EXAMPLE - 2

Transfer 0.1 gm loratadine to a container. Add 6.5 gm d-alpha tocopheryl polyethylene glycol 1000 succinate and 15 ml purified water, warm till a solution is obtained. Add 18 ml of diethylene glycol monoethyl ether and 0.1 gm methyl paraben, 0.01 gm propyl paraben and adjust the pH to 5.6 and make up the volume with purified water.

EXAMPLE - 3

Transfer 0.1 gm loratadine to a container. Add 20 ml purified water and stir to make a slurry. Add sufficient quantity of hydrochloric acid of suitable strength under stirring till a clear solution is obtained. Separately dissolve polyvinyl alcohol 2.0 gm in 30 ml hot purified water and transfer it to the drug solution under stirring. Dissolve butylated hydroxy anisole 0.02 gm in 5 gm of propylene glycol and add it to the above solution. Dissolve disodium edetate 0.05 gm in purified water and add it to the above solution. Adjust the pH to 6.8 with 5% tromethamine solution. Separately dissolve 0.1 gm montelukast sodium in purified water along with 10 gm hydroxypropyl betacyclodextrin and stir for 30 minutes and transfer the solution to the main solution. Add 0.02 gm benzalkonium chloride and make up the volume with purified water. EXAMPLE - 4

Transfer 0.1 gm loratadine to a container. Add 5 gm of polyoxyl-35 castor oil and 20 ml propylene glycol. Stir to dissolve. Dissolve 0.1 gm sodium metabisulphite and 0.1 gm disodium edetate in purified water and transfer it to the drug solution. Separately dissolve montelukast sodium in purified water and add it to the above solution. Prepare a solution of 5.0 gm povidone in water and add it to the above solution. Dissolve 0.1 gm methyl paraben and 0.01 gm of propyl paraben and 0.01 gm benzalkonium chloride in purified water and add it to the above solution. Adjust the pH with 5% sodium hydroxide solution to 6.6. Make up the volume with purified water.

EXAMPLE - 5

Transfer 0.1 gm micronised desloratadine to a container. Add 30 ml purified water and 0.02 gm polysorbatc 80 and stir for 40 minutes. Disperse 0.1 gm sodium carboxymethylcellulose and 1 gm microcrystalline cellulose in 10 gm glycerin. Dissolve Benzalkonium chloride 0.02 gm and phenylethylalcohol 0.2 gm in purified water and add it to the above solution. Mix for 20 minutes. Adjust the pH with 5% hydrochloride acid to 4.5 and make up the volume with purified water.

EXAMPLE - 6

Transfer 0.1 gm desloratadine to a container. Add 10 ml purified water and sufficient hydrochloric acid to obtain a clear solution. Dissolve 0.025 gm butalyated hydroxy anisole and 0.025 gm of butylated hydroxy toluene in propylene glycol and stir. Separately dissolve montelukast sodium 0.1 gm in purified water containing 0.05% disodium edetate and add it to the above solution. Dissolve methyl paraben and propyl paraben in purified water and add it to the above solution. Adjust the pH with 5% sodium citrate solution to 6.8. Make up the volume with purified water. INNOVATION:

Loratadine or desloratadine are potent antihistamines. These drugs are soluble normally at an acidic pH, especially loratadine which is soluble at pH below 3.1. This pH would be highly acidic and does not permit its use in the nasal mucosa which could cause high irritation. In the present invention the antihistamine has been solubilised at a physiologically acceptable pH of 4- 8 and preferably 6.6 which does not cause any irritation in the nose. This permits the application of a potent antihistamine at the site of action the nasal mucosa at less than 25% of the daily oral dose. There would be no side effects like eye-pain or sedation that are associated with oral therapy. The onset of action is immediate and would provide relief within 10 minutes of application.

Montelukast sodium in combination with loratadine or desloratadine :

Montelukast sodium is an unstable drug and its aqueous solutions degrade rapidly on storage. In the present invention the aqueous solutions have been stabilised with the optimum choice of pH, stabilizers, and process. This combination would be very effective and give the same effect that is seen with intra-nasal steroids without causing any side effects associated with intra-nasal steroids like local burning, superficial infections, throat irritation.

Thus in combination also the present invention would achieve the goals of pharmacotherapy for allergic rhinitis and in nasal polyps with fast onset of action at a lower dose and negligible side effects, associated with oral or existing intranasal therapies.

The present invention described in conjunction with the preferred embodiment and also the examples that follow arc intended to illustrate and not limit the scope of the invention. The invention may be varied in many ways and all such modifications are intended to be included within the scope of the following claims.

Claims

What is claimed is:

1. A pharmaceutical composition for intranasal delivery to the nasal mucosa for prevention and treatment of symptoms of allergic rhinitis and problems like nasal polyps comprising an antihistamine with or without a leukotriene inhibitor in combination with a pharmaceutically acceptable delivery vehicle.

2. The pharmaceutical composition as claimed in claim 1, wherein the said antihistamine comprises an effective amount of long acting antihistamine present in a concentration ranging from 0.005 % to 5 % and is selected from (a) loratadine (ethyl 4-18-chloro-5,6- dihydro-1 1 H benzo [5,6] cyclohepta [l,2-b]pyridin-l l-ylidene)-l- piperidinecarboxylate) or salts thereof (b) desloratadine (8-chloro-6,l l-dihydro-l l-(4- piperdinylidcne)-5Hbenzo[5,6]cyclohepta [l,2-b]pyridine) or salts thereof.

3. The pharmaceutical composition as claimed in claim 1, wherein the said leukotriene inhibitor comprises of an effective amount of montelukast Sodium or otlier salts of montelukast present in a concentration ranging from 0.005 to 5 % .

4. The pharmaceutical composition as claimed in claim 1, wherein the said delivery vehicle for intranasal administration comprises pharmaceutically acceptable solubilisers, thickening agents, stabilizers, dispersing agents, emulsifiers, surfactants and water.

5. The pharmaceutical composition as claimed in claim 4, further comprising one or more pharmaceutical excipients.

6. The pharmaceutical composition as claimed in claim 5 further comprising buffer to maintain the pH.

7. The pharmaceutical composition as claimed in claim 5 further comprising pharmaceutically acceptable preservatives.

8. The pharmaceutical composition as claimed in claim 5 may further contain pharmaceutically acceptable propellants.

9. The pharmaceutical composition as claimed in claim 4 wherein the said solubilisers are present in a concentration ranging from 0.1 to 50% and comprises solubilisers selected from the group consisting of dimethyl isosorbide, diethylene glycol monoethyl ether, propylene glycol, polyethylene glycol, polyoxyl-35 -castor oil, polyoxyl-40- hydrogenated castor oil, tocopheryl polyethylene glycol 1000 succinate, glycofurol, glycerol, ethanol, mixture of polyethylene glycol 660 12-hydroxy 70%, and polyethylene glycol 30%, polysorbate 80, and mixtures thereof.

10. The pharmaceutical composition as claimed in claim 4 wherein the said thickening and dispersing agents maybe present in a concentration ranging from 0.1 to 50% and comprises thickemng and dispersing agents selected from the group consisting of carbomer, carboxymethyl cellulose sodium, poloxamers, povidone, microcrystalline cellulose, polyvinyl alcohol, methylhydroxy ethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, polycarbophils, xanthan gum, guar gum, and mixtures thereof.

11. The pharmaceutical composition as claimed in claim 4 wherein the said stabilizers comprises complexing agents or antioxidants. The complexing agents comprise of hydroxypropyl betacyclodextrin and gammacyclodextrin used singly or in combination or mixtures thereof.

12. The antioxidants are selected from the group comprising sodium metabisulphitc, sodium sulphite, sodium bisulphite, acetyl cysteine, butylated hydroxyanisole, butylated hydroxy toluene, propyl gallatc, tocopheryl compounds, d-alpha tocopheryl polyethylene glycol 1000 succinate used singly or in combination and mixtures thereof.

13. The pharmaceutical composition as claimed in claim 4 wherein the said emulsifiers and surfactants are present in a concentration ranging from 0.001 to 50 % and comprises emulsifiers and surfactants selected from the group consisting poiyoxyl-35 -castor oil, glycerine stearate and polyethylencglycol 75 stearate, polyoxyl-40-hydrogenated castor oil, polyethylene glycol-6-32-stearate and glycol stearate, sorbitan trioleate, oleic acid, phospholipids such as phosphatidylethanolamine, phosphatidylchloline and phosphatidylinositol and mixtures thereof.

14. The pharmaceutical composition as claimed in claim 7 wherein the preservatives comprises preservatives selected from the group consisting of potassium sorbate, benzalkonium chloride, phenylethylalcohol, methylparaben, propylparaben, ethylparaben, butylparaben, disodium edetate, sorbic acid, phenoxyethanol and mixtures thereof.

15. The pharmaceutical composition as claimed in claim 8 wherein the propellants comprises propellants selected from the group consisting of di-chloro-difluoro methane or trichloro monofluoro ethane CFC 11, dicholorotetrafluoro ethane or CFC 114, tetrafluoroethane or HFA-134a, heptafluoropropane or HFA-227 and mixtures thereof.

16. The pharmaceutical composition as claimed in claim 6 wherein the buffers comprises buffers selected from the group consisting of citric acid, dibasic potassium phosphate, sodium citrate, hydrochloric acid, sodium hydroxide, tromethamine, acetate buffers and mixtures thereof.

17. The pharmaceutical composition as claimed in claim 6 wherein the pH of the composition is maintained from about 4 - 8.

18. An intranasal pharmaceutical composition comprising a therapeutically effective amount of the antihistamine with or without leukotriene inhibitor solubiliscd or dispersed in pharmaceutically acceptable solubilisers, thickening agents, dispersing agents, buffers, surfactants, propellants, cosolvents and preservatives.

19. A process for preparing the pharmaceutical composition as claimed in claim 1 comprising the following steps. i. Loratadine or desloratadine is solubilised by using acidifying agents or solubilisers or dispersed in a mixture of solvents, emulsifiers, or surfactants, ii. The thickening agents where used are incorporated by melting or dispersed in purified water as the case may be. iii. The solution of step i is mixed with thickening agent as herein described properly to obtain homogenous mixture, iv. The preservative is solubilised and incorporated. v. Where the composition comprises an antihistamine along with the leukotriene inhibitor, montelukast sodium is added slowly to the solution or dispersion of step iv and stirred till montelukast sodium dissolves completely, vi. Antioxidants, complexing agents may be added as stabilisers to the solution of step v. vii. Adequate buffering agents and/or pH adjusting agents as herein described are added slowly to the above and mixed properly. viii. The weight or volume as the case may be is made up with purified water or the delivery vehicle as may be applicable, ix. Where the preparation comprises of pressured metered dose nasal spray, the solution or dispersion is filled into cans along with the propellants. x. Where the preparation comprises ointment, cream or gel the congealed mass may be homogenised or passed through a colloidal mill and again mixed properly and filled in containers, xi. Where the preparation comprises of pump driven nasal spray, the formulation is filled into containers and fitted with a metered dose pump with suitable actuators.

20. A method for the prevention and treatment of symptoms of allergic rhinitis and nasal polyps, comprising intranasal administration of the composition according to claim 1.

21. The intranasally administered pharmaceutical composition of claim 20 wherein the said antihistamine is loratadine or desloratadine and salts thereof with or without leukotriene inhibitor montelukast Sodium and other salts of montelukast.

22. A method of preventing and treating symptoms of allergic rhinitis and in problems like nasal polyps comprising intranasally administering to the nasal mucosa a therapeutically effective dosage of the long acting antihistamine loratadine or desloratadine with or without leukotriene inhibitor such as montelukast sodium in a intranasal delivery vehicle comprising pharmaceutically acceptable solubilisers, thickening agents, dispersing agents, buffers, surfactants, stabilizers, propellants, cosolvents and preservatives.

23. The method as claimed in claim 22, wherein the said composition containing the long acting antihistamine with or without a leukotriene inhibitor is effective for the prevention and treatment of symptoms of allergic rhinitis and in problems like nasal polyps.

24. A method of administering a therapeutically effective amount of the long acting antihistamine loratadine or desloratadine with or without the leukotriene inhibitor montelukast sodium by intranasal administration of a delivery vehicle comprising pharmaceutically acceptable solubilisers, thickening agents, dispersing agents, buffers, surfactants, stabilizers, propellants, cosolvents and preservatives.

25. An intranasal application dosage unit for application to the nasal mucosa for preventing and treating symptoms of allergic rhinitis and problems like nasal polyps comprising an effective amount of the long acting antihistamine loratadine or desloratadine with or without the leukotriene inhinbitor montelukast sodium for intranasal application comprising pharmaceutically acceptable solubilisers, thickening agents, dispersing agents, buffers and surfactants whose concentration is selected to produce onset of action within 10 minutes of applying the said dosage units to the nasal mucosa.

26. The intranasal application dosage unit as claimed in claim 25 wherein the delivery vehicle may be in different dosage forms and comprises dosage forms from the group consisting of gels, ointments, lotions, solutions, suspensions, emulsions and administered by drops or as sprays.

27. The intranasal application dosage units as claimed in claim 26, further comprising one or more pharmaceutically acceptable excipients.

28. The intranasal application dosage units as claimed in claim 27, further comprising pharmaceutically acceptable preservatives.

29. The intranasal application dosage units as claimed in claim 27 wherein the pH of the said delivery vehicle is selected so as to facilitate effective concentration of loratadine or desloratadine with or without montelukast sodium at the site of action, the nasal mucosa, and is adjusted by selecting the concentration of the buffers and mixtures thereof, to produce the pharmaceutical effect within 10 minutes of applying the said dosage unit to the nasal mucosa.

30. The intranasal dosage units as claimed in claim 25 wherein the selected pH is from about 4.0 to 8.0 preferably 6.0 to 6.8.

31. An intranasal application dosage unit as claimed in claim 26 wherein the concentration of the solubilisers used in the delivery vehicle ranges from 0.1 to 50%.

32. An intranasal application dosage unit as claimed in claim 26 wherein the concentration of thickening agent or dispersing agent used in the delivery vehicle ranges from 0.1 to 50%.

33. An intranasal application dosage unit as claimed in claim 26 wherein the concentration of emulsifiers or sufactants used in the delivery vehicle ranges from 0.01 to 30%.

34. An intranasal application dosage unit as claimed in claim 26 wherein the therapetically effective amount of the composition is applied to the nasal mucosa by using single dose or multi dose devices for intranasal application of dosage unit for delivery to nasal mucosa.

35. A pharmaceutical composition according to any of the claims wherein the composition is applied to the nasal mucosa by using single dose or multidose devices for intranasal application of the dosage unit for delivery to the nasal mucosa.

36. A pharmaceutical composition according to any of the claims where in the application dosage unit is administered using devices wherein the devices comprise metered dose pumps, pressurized metered dose inhalers and droppers.