FORM 2

THE PATENTS ACT, 1970 (39 OF 1970)
COMPLETE SPECIFICATION
(See Section 10)
A PROCESS OF PREPARING LORATIDINE AND MONTELUKAST SODIUM
NASAL SPRAY
M/s. ALEMBIC LIMITED, ALEMBIC ROAD, VADODARA- 390 003, GUJARAT, an Indian Company incorporated under the Companies Act, 1956.
The following specification particularly describes the nature of this invention, and the
manner in which it is to be performed.

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This invention relates to a process for preparing nasal spray composition containing
loratidine and montelukast sodium as active ingredients.
More particularly this invention relates to a process of preparing a pharmaceutical
composition of nasal spray comprising an antihistamine such as Loratadine and
Leukotriene inhibition such as Montelukast sodium along with pharmaceutical acceptable
delivery vehicle for intra nasal delivery to the nasal mucosa for preventing and treatment
of symptoms of allergic rhinitis and problems like nasal polyps.
Oral therapy with antihistamine drugs is well known in Allergic rhinitis the release of
stimulatory mediators like histamines and leukotrienes are responsible for many of the
immediate symptoms.
Oral therapy with leukotriene receptor antagonist like Montelukast Sodium is reported. A
combination of the antihistamine Loratadine and Montelukast Sodium in the oral therapy
of allergic rhinitis is also reported.
Allergic rhinitis is a prevalent chronic illness affecting approximately 25% of the
population, and causes appreciable discomfort and mobility.
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 Rhinorrhea due to histamine induced
vasodilatation and increased permeability of the nasal vasculature. Leukotriene inhibitors
inhibit the cysteinyl leukotriene receptors (CysLT), and help improve nasal allergy
symptoms.
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The efficacy of therapy in combination is enhanced due to the additive effect. Loratadine
also known as, ethyl 4-18-chloro-5, 6-dihydro-l 1 H benzo [5,6] cyclohepta [1,2-
b]pyridine-ll-ylidene)-l-piperdinecarboxylate is a second generation antihistamine.
Patients suffering from perennial allergic rhinitis may require chronic therapy.
The significant attributes of 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 enzume as is the case
with other second generation antihistamines, it would be ill advised to 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 pratropium bromide and (5) corticosteroids.
In choosing an ideal agent, it is but natural to weigh the plus and minus points. The drawbacks associated with existing Intranasal therapies can be listed as
a) In case of Azelastine, drowsiness, fatigue, headache, taste disorders and nasal burning.
b) In case of decogestants burning, stinging, sneezing, dryness of the nasal mucosa and more importantly the risk of rhinitis medicamentosa or severe nasal odema, decreased receptors sensitivity and rebound congestion on withdrawal of therapy.
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c) Cromolyn though devoid of any side effects, has no immediate effect, is less effective than topical corticosteroids 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 impairment can still occur, resulting in sleep latency, reaction time and visual motor co-ordination problems. In case of Loratadine, somnolence, tachycardia and in children 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:

Sr. No. Aspect Loratadine Oral Desloratadine Oral Loratadine Nasal Desloratadine Nasal
1. Onset of Action 1-3 hours 3 hours 10-15 minutes 10-15 minutes
2. Dosage 10 mg daily 5 mg daily Up to 2:4 mg daily Up to 2:4 mg daily
3. Overdosage Possible -4- Possible Unlikely Unlikely

4. Adverse Effects Head ache, eye pain etc Less,compare to Loratadine Remote Remote
Montelukast sodium also known as [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethynyl]phenyl]-3 - [2-( 1 -hydroxy-1 -
methylethyl)phenyl]propylthio]methyl]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 the synergistic or additive effect is due to inhibition of both the histamine HI receptor and the leukotriene CysLt receptors, that are stimulated in patients suffering from allergic rhinitis. Thus the combination acts on two different receptors helping improve nasal allergic symptoms.
In asthmatic patients oral montlukast 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 therapy as the mechanism action is same in case of allergic rhinitis as well and adverse effects associated with nasal steroids can 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
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consisting of infiltration 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 combinations of loratadine or desloratadine along with montelukast sodium would have a multifactorial effect on the aspects of the inflammatory reaction, the effect being initiated by their binding to the histaminic 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 along with 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. 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 not permit its use in the nasal mucosa which could cause high irritation. In the present invention loratadine 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.
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Montelukast sodium in combination with loratadine or desloratadine:
Montelukast is an unstable drug and its aueous solutions degrade rapidly on storage. In
the present invention the aqueous solutions have been stabilized with the optimum choice
of pH, stabilizes 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 these 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 provides a process of preparing a pharmaceutical composition
where by the drugs Loratadine and Montelukst Sodium in combination can be mkade
available at the site of action, the nasal mucosa. In the present invention Loratadine may
be substituted with the active metabolite Desloratadine, which is also very effective in the
treatment of allergenic rhinitis.
Accordingly this invention provides a process of preparing an Antihistamine and a
Leukotriene inhibitor nasal spray comprising the following steps:
a. Mixing Antihistamine (0.05-5% w/v) in Purified water to make a slurry.
b. Adding 1M Hydrochloric acid under stirring to the slurry of step (a), and stirring
till a clear solution of Antihistamine is obtained.
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c. Dissolving Butylated hydroxyl anisole (0.005 - 0.5% w/v) and Butylated
hydroxy! toluene (0.005 - 0.5%w/v) in Propylene glycol (2-25% w/v) at 50-
60°C.
d. Mixing solution of step (c) with solution of step (b)
e. Adding Polyoxyl -3 5-castor oil (2-3 0% w/v) with solution of step (d).
f. Dissolving Disodium eda\etate (0.01 - 0.5% w/v) in Purified water and adding
to it Phenyl ethyl alcohol (0.05 - 0.5% w/v), and Benzalkonium chloride 50%
w/v solution (0.01 - 0.04% w/v) under stirring to oObtain a solution and
transferring the solution to the solution of step (e).
g. Dissolving Leukotriene inhibitor (0.05 - 5% w/v) in Purified water.
h. Adding the solution of step (g) to the solution of step (f) under stirring.
i. Preparing 20% w/v solution of Tromethamine in Purified water.
j. Adjusting the pH of the solution of step (h) with 20% w/v Tromethamine
solution of step (i) in the range pH 4.0 - pH 7.0.
k. Making up the volume of solution of solution of Step (j) with Purified water. The main advantages of the invention are:
- A combination of Loratadine or Desloratadine and Motelukast Sodium will give a synergistic effect in that it will be able to block two different mediators involved in allergic rhinitis : (I) histamine and (II) leukotriene thus, allowing more effective control of symptoms of allergic rhinitis.
- Rapid relief from symptoms
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- Lesser quantity of drug is required to elicit a pharmaceutical response and thus reduced dosage as compared to oral therapy.
- Freedom from side effects like headache and eye pain associated with oral therapy.
- Return to normalcy from the time symptoms appear is very fast thus increases work efficiency and reduces days away from work.
EXAMPLE: 1

Process / Procedure
1. Transfer 20 kg of Polyoxyl-35-castor oil and 25 kg of Propylene Glycol to a s.s vessel filter with a mechanical stirrer.
2. Heat the mixture of step (1) to 65 C and under stirring add Butylated hydroxyl anisole and Butylated hydroxyl toluene and 0.5 kg Loratadine and stir till a clear solution is formed.
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Sr. No. Ingredients % w/v
1. Loratadine 0.5
2. Montelukast Sodium 0.5
3. Butylated hydroxyl anisole 0.025
4. Butylated hydroxyl toluene 0.015
5. Propylene Glycol 25.0
6. Polyoxyl-35-castor oil 20.0
7. Phenyl ethyl alcohol 0.25
8. Benzalkonium Chloride solution (50%) 0.04
9. Disodium edetate 0.1

3. Dissolve 0.1 kg of Disodium edentate and Montelukast Sodium 0.5 kg in 2.5 litres. Purified water and transfer the solution to the solution of step (2).
4. Transfer 0.25 kg of Phenyl ethyl alcohol and Benzalkonium chloride solution (50%) to a s.s vessel. Add 10 litres Purified water under stirring and stir till a homogenous mixture is formed.
5. Transfer the mixture of step 4 to the solution of step 3 and stir till a clear solution is formed.
6. Prepare a 5% w/v solution of Sodium hydroxide in purified water.
7. Check the pH of the solution of step 5 and adjust the pH in the range of 4 to 7 using the 5% w/v solution of Sodium hydroxide solution.
8. Make up the volume to 100-L with Purified water and stir.
9. Filter the solution and fill it in containers.
Example 2:

Sr. No. Ingredients %w/v
1. Desloratadine 0.5
2. Montelukast Sodium 0.5
3. Propylene Glycol 35.0
4. Propyl Gallate 0.10
5. Polyoxyl-35-castor oil 20.0
6. Phenyl ethyl alcohol 0.25
7. Glycerin 10.0
8 Benzalkonium Chloride solution (50%) 0.04
9. Sodium Hydroxide q.s.
10. Purified water q.s.
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Process / Procedure:
1. Transfer 20kg of Polyoxyl-35-castor oil and 35 kg of Propylene Glycol to a s.s. vessel filter with a mechanical stirrer.
2. Heat the mixture of step (1) to 650C and under stirring add Propyl gallate and 0.5kg Loratadine and stir till a clear solution is formed.
3. Under stirring allow the solution of step 2 to cool to ambient temperature.
4. Dissolve 0.5kg Montelukast Sodium in Purified water under stirring and add the solution to the solution of step (3)
5. Transfer 10 kg of Glycerin to the solution of step 3 and stir.
6. Transfer Phenyl ethyl alcohol 0.25 kg and Benzalkonium chloride solution (50% 0.04 kg to a s.s vessel. Add 10 litres of purified water and mix.
7. Transfer a solution of step 5 to the solution of step 4 and stir.
8. Prepare a 5% w/v solution of Sodium Hydroxide in purified water.
9. Check the pH of the step 5 and adjust the pH in the range of 4 to 7 using the 5°/ w/v solution of Sodium hydroxide solution.
10. Make up the volume to 100-L with Purified Water and stir.
11. Filter the solution and fill it in containers.
Example 3 :

Sr. No. Ingredients %w/v
1. Loratadine 0.4
2. Montelukast Sodium 0.4
3. Hydrochlorc Acid 1M q.s.
4. Propylene Glycol-11- 15.0

5. dl-a-tocopheryl polyethylene glycol 1000 succinate 0.3
6. Polyoxyl-35-castor oil 15.0
7. Phenyl ethyl alcohol 0.25
8 Benzalkonium Chloride solution (50%) 0.04
9. Tromethamine q.s.
10. Disodium edetate 0.1
11. Purified water q.s.

Process / Procedure
1. Transfer 20 litres of Purified water to a s.s vessel filter with a mechanical
stirrer.
2. Add 0.4 kg of Loratadine to the water to step (1) and stir to make a slurry.
3. Under stirring slowly add Hydrochloric acid 1M solution to dissolve
Loratadine.
4. Transfer 15 Kg of Propylene glycol and 15 kg of Polyoxyl-3 5-castor oil to the
Loratadine solution and stir.
5. Dissolve Disodium edetate in 20-L of Purified water and add 0.25 kg Phenyl
ethyl alcohol and 0.04 litres of Benzalkonium chloride solution (50%) dl-a-
tocopheryl polyethylene glycol 1000 succinate 0.3 kg and transfer the solution
to the solution of step 4.
6. Dissolve Montelukast Sodium 0.4 Kg in purified water and transfer it to the
solution of step 5.
7. Prepare a 20% solution of Tromethamine in Purified water.
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8. Check the pH of the solution of step 6 and adjust the pH in the range of 4 to 7 using the 20% w/v solution of Tromethamine of step 7.
9. Make up the volume to 100-L with Purified water and stir.
10. Filter the solution and fill it in containers.
Example 4 :

Sr. No. Ingredients %w/v
1. Loratadine 0.5
2. Montelukast Sodium 0.5
3. Butylated hydroxy anisole 0.025
4. Butylated hydroxy toluene 0.025
5. Hydrochlorc Acid 1M q.s.
6. Propylene Glycol 10.0
7. Polyoxyl-35-castor oil 20.0
8. Phenyl ethyl alcohol 0.25
9. Benzalkonium Chloride solution (50%) 0.04
10. Tromethamine q.s.
11. Disodium edatate 0.1
12. Purified Water q.s.
Process / Procedure:
1. Transfer 20-L of Purified water to a s.s vessel filter with a mechanical stirrer.
2. Add Loratadine to the water to step (1) and stir to make a slurry.
3. Under stirring slowly add Hydrochloric acid 1M solution to dissolve Loratadine.
4. Dissolve Butylated hydroxy anisole and Butylated hydroxy toluene in Propylene glycol in 50° - 60° C and mix the solution of Loratadine.
5. Tranfer Polyoxyl-3 5 -castor oil to the Loratadine solution and stir.
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6. Dissolve Disodium edatate in 40-L of Purified water and add Phenyl ethyl ala and Benzalkonium chloride solution (50%) and transfer the solution to the solution of step 4.
7. Dissolve Montelukast sodium 0.5kg in purified water and transfer the solution to the solution of step (6).
8. Prepare a 20% w/v solution of Tromethamine in purified water.
9. Check the pH of the solution of step 5 and adjust the pH in the range of 4 to ' using eth 20% w/v solution of Tromethamine of step 6.
10. Make up the volume to 100-L with purified water and stir.
11. Filter the solution and fill it in containers.
Range of Various Excipients used in forming the pharmaceutical Composition of this invention.

Sr. No. Ingredients %w/v
1. Hydrochloric Acid 1M q.s.
2. Butylated hydroxy anisole 0.005-0.5%
3. Butylated hydroxy toluene 0.005-0.5%
4. Propyl gallate 0.01-0.5%
5. dl-a-tocopheryl polyethylene glycol 1000 succinate 0.01-2%
6. Tocopheryl acetate 0.01-1%
7. Polyoxyl-3 5-castor oil 2-30%
8. Propylene Glycol 2-25%
9. Phenyl ethyl alcohol 0.05-0.5%
10. Benzalkonium Chloride solution (50%) 0.001-0.04%
11. Tromethamine q.s.
12 Sodium Hydroxide q.s.
13. Disodium edatate 0.01-0.5%
14. Purified Water q.s.
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Test Reports
Sr.No Parameter Test Results
Ex.1 Ex.2. Ex.3 Ex.4
1. Appearance Pale Yellow Coloured Solution StrawColouredSolution Pale Yellow Coloured Solution Pale yellowColouredsolution
2. PH 5.50 5.75 6.60 6.35
3. Clarity Clear Clear Clear Clear
4. Assay
Loratadine 98.6% - 99.87% 100.7%
Desloraradine - 97.75% - -
Montelukast Sodium 100.1 98.66 99.58 100.73

We claim
1. A process for preparing nasal spray composition of loratidine and montelukast
sodium comprises the following steps:
a. mixing 0.05-5% w/v loratidine in purified water to make a slurry;
b. adding 1M Hydrochloric acid under stirring to the slurry of step (a)
and continuing stirring until clear solution is obtained;
c. dissolving either 0.005-0.5% w/v butylated hydroxy anisole or
butylated hydroxy toulene in 2-25% w/v in propylene glycol at 50°C to
60°C temperature;
d. mixing solution of step (c) with solution of step (b);
e. adding 2-30% w/v polyoxyl-35-castor oil in solution of step (d);
f. dissolving 0.5-10% w/v glycerin and 0.01-0.5% w/v disodium edetate
in purified water and adding to it under stirring 0.05-5% w/v phenyl
ethyl alcohol and 0.01-0.04% v/v 50% solution of Benyalkonium
chloride, thereafter transferring the whole to solution of step (e);
g. dissolving 0.05-5% w/w montelukast sodium in purified water;
h. adding solution of step (g) to the solution of step (f) under continues
stirring;
i. adjusting pH of solution of step (h) either with 20% w/v solution of
tromethamine or 5% w/v solution of sodium hydroxide in the range of
4.0 to 7.0; and
j. finally making the volume of solution of step (i) with purified water.
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2. A process as claimed in claim 1, wherein Loratadine {ethyl 4-18-chloro-5,6-dihydro-1 l-H-benzo-[5,6]-cyclohepta-[ 1,2-b]-pyridine-11-ylidene)-1-piperidinecarboxylate}is used as antihistaminic drug.
3. A process as claimed in claim 1, wherein montelukast sodium [R-(E)]-l-[[[l-[3-[2-(7-chloro-2-quinolinyl)ethynyl]phenyl]-3-2-(l-hydroxy-l-methylethyl)phenyl]propyl]thio]methyl]cyclopropaneacetic acid is used as leukotriene inhibitor.
4. A process for preparing nasal spray composition of loratidine and montelukast sodium as substantially described and illustrated in examples 1 to 4 of complete specification.
Dated this 14th day of May, 2003
(V RAMU)
Agent of the Applicant
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ABSTRACT OF THE INVENTION
A process for preparing nasal spray composition of loratidine and montelukast sodium comprises the following steps:
a. mixing 0.05-5% w/v loratidine in purified water to make a slurry;
b. adding 1M Hydrochloric acid under stirring to the slurry of step (a)
and continuing stirring until clear solution is obtained;
c. dissolving either 0.005-0.5% w/v butylated hydroxy anisole or
butylated hydroxy toulene in 2-25% w/v in propylene glycol at 50°C to
60°C temperature;
d. mixing solution of step (c) with solution of step (b);
e. adding 2-30% w/v polyoxyl-35-castor oil in solution of step (d);
f. dissolving 0.5-10% w/v glycerin and 0.01-0.5% w/v disodium edetate
in purified water and adding to it under stirring 0.05-5% w/v phenyl
ethyl alcohol and 0.01-0.04% v/v 50% solution of Benyalkonium
chloride, thereafter transferring the whole to solution of step (e);
g. dissolving 0.05-5% w/w montelukast sodium in purified water;
h. adding solution of step (g) to the solution of step (f) under continues
stirring;
i. adjusting pH of solution of step (h) either with 20% w/v solution of
tromethamine or 5% w/v solution of sodium hydroxide in the range of
4.0 to 7.0; and
j. finally making the volume of solution of step (i) with purified water.
Dated this 14th day of May, 2003

(VRAMU) Agent of the Applicant