FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rulel3)
1. TITLE OF THE INVENTION:
"NOVEL CONCENTRATED LIQUID ORAL SPRAY DOSAGE FORM
CONTAINING ANTI-ALLERGIC, COUGH SUPPRESSANT AND NASAL
DECONGESTANT COMBINATIONS"
2. APPLICANT:
(a) NAME: Lincoln Pharmaceuticals Limited
(b) NATIONALITY: Indian Company incorporated under the Companies
Act, 1956
(c) ADDRESS: Lincoln House, Science City Road, Sola, Ahmedabad-38060,
Gujarat, India.
3. PREAMBLE TO THE DESCRIPTION:
The following specification particularly describes the invention and the manner in which it is to be performed.

TECHNICAL FIELD OF INVENTION
The present invention relates to a liquid oral spray dosage form comprising combination of anti-allergic, cough suppressant and nasal decongestant useful for management of dry or non-productive cough, cough associated with viral or bacterial inflammation of upper respiratory tract, sinusitis, laryngitis, tracheitis and pharyngitis.
BACKGROUND OF THE INVENTION
A cough medicine (or linctus, when in syrup form) is a medicinal drug used in an attempt to treat coughing and related conditions. For dry coughs, treatment with cough suppressants (antitussives) may be attempted to suppress the body's urge to cough, while in productive coughs (coughs that produce phlegm), treatment is attempted with expectorants (typically guaifenesin, in most commercial medications) in an attempt to loosen mucus from the respiratory tract.
Topical decongestants are decongestants applied directly to the nasal cavity. By applying them directly to the site of action, topical decongestants relieve nasal congestion while reducing the side effects associated with systemically-acting decongestants such as high blood pressure. Topical decongestants should only be used by patients for a maximum of 3 days in a row, because rebound congestion may occur in the form of rhinitis medicamentosa. Topical decongestants are a common form of nasal relief, due to their quick effects which can clear the sinus in as little as ten seconds.
In recent times, there have been enormous improvements in the medical practices used to treat allergic conditions. With respect to anaphylaxis and hypersensitivity reactions to foods, drugs and insects and in allergic skin diseases, advances have included the identification of food proteins to which IgE binding is associated with severe reactions and development of low-allergen foods, improvements in skin prick test predictions; evaluation of the atopy patch test; in wasp sting outcomes predictions and a rapidly disintegrating epinephrine tablet and anti-IL-5 for eosinophilic diseases.

Traditional treatment and management of allergies consisted simply of avoiding the allergen in question or otherwise reducing exposure. For instance, people with cat allergies were encouraged to avoid them. However, while avoidance of allergens may reduce symptoms and avoid life-threatening anaphylaxis, it is difficult to achieve for those with pollen or similar air-borne allergies. Nonetheless, strict avoidance of allergens is still considered a useful treatment method and is often used in managing food allergies.
Tracheitis is an inflammation of the trachea. Although the trachea is usually considered part of the lower respiratory tract, in ICD-10 tracheitis is classified under "Acute upper respiratory infections".
A cough is a sudden and often repetitively occurring reflex which helps to clear the large breathing passages from secretions, irritants, foreign particles and microbes. The cough reflex consists of three phases: an inhalation, a forced exhalation against a closed glottis and a violent release of air from the lungs following opening of the glottis usually accompanied by a distinctive sound. Coughing can happen voluntarily as well as involuntarily. A cough can be dry or productive, depending on whether sputum is coughed up. It may occur only at night (then called nocturnal cough), during both night and day or just during the day.
The treatment of a cough in children is based on the underlying cause with the use of cough medicine supported by little evidence and thus not recommended by the American Academy of Pediatrics. A trial of antibiotics or inhaled corticosteroids may be tried in children with a chronic cough in an attempt to treat protracted bacterial bronchitis or asthma respectively.
Various cough syrups both herbal and allopathic are available in the market such as Corex by Pfizer, Phensedyl Linctus, Delsym, Robitussin DM and Mucinex.
There are various compositions of liquid syrup dosage form such as Triprolidine (antiallergic), Dextromethorphan (cough suppressant), menthol and Pseadoephedrine (cough suppressant) marketed under brand name Biotryl AT and Dextromethorphan hydrobromide (cough suppressant), phenylephrine hydrochloride (nasal decongestant),

triprolidine hydrochloride (anti-allergic) marketed under brand name Deletus. However, these compositions are in liquid syrup form. There is less accuracy in dose measurement in case of oral syrup administration and there is also a chance of crystallization in syrup formulation. Large volume is to be administered in syrup and suspension whereas accurate volume is administrated in spray formulation.
US 4619934 by Abraham Sunshine et al. discloses pharmaceutical composition comprising a non-steroidal anti-inflammatory drug in combination with atleast one other active component selected from an antihistamine, decongestant, cough suppressant (antitussive) or expectorant for the relief of cough, cold and cold-like symptoms wherein dosage forms are in the form of tablets, capsules or elixir.
US 6709676 by Wing-Kee Philip Cho et al. provides a bilayer solid composition comprising (a) an immediate release first layer comprising an anti-allergic effective amount of desloratadine and at least one pharmaceutically acceptable excipient and (b) a sustained release second layer comprising an effective amount of a nasal decongestant, e.g. pseudoephedrine sulfate and a pharmaceutically acceptable sustained release agent.
US 4783465 by Abraham Sunshine et al. teaches pharmaceutical compositions and methods of using same comprising a non-steroidal anti-inflammatory drug in combination with a non-sedating antihistamine and optionally one or more other active components selected from a decongestant, cough suppressant (antitussive) or expectorant for the relief of cough, cold, cold-like and/or flu symptoms and the discomfort, pain, headache, fever and general malaise associated therewith wherein the dosage forms are in the form of tablet, capsule or suspension.
US 7863287 by Roger G. Berlin is directed to a pharmaceutical composition and method for the treatment of rhinitis and cold-like symptoms which includes a non-steroidal antiinflammatory drug (NSAID), a decongestant, and an antihistamine wherein the dosage form is in the form of a tablet, trochet, dispersion, suspension, solution, elixir, capsule or patch.

US 2010/0280059 by James Joseph McDermot et al. discloses extended release solid dosage composition comprising an antihistamine, an antitussive and/or a decongestant.
In view of the above state of art, the present inventors have come up with a composition in a liquid oral spray dosage form comprising combination of anti-allergic, cough suppressant and nasal decongestant at their effective doses to provide relatively better effect than other dosage forms like tablets or capsules and messy application of gel and creams. Further, the novel mode of delivery is useful for the management of dry or nonproductive cough, cough associated with viral or bacterial inflammation of upper respiratory tract, sinusitis, laryngitis, tracheitis and pharyngitis.
The spray formulation of the present invention gives relatively uniform dose dispensing than other oral liquid formulation and no crystallization takes place at very low temperature. Unique formulation of spray provides good taste inspite of large drug concentration. Validated spray delivers unit dosing for potent drug delivery directly to oral cavity that ensures uniform dose dispensing,
The formulation is dispensed in mist form that covers large area of oral cavity and very small amount of dispensed volume will be ingested thereby leading to minimum chances of hepatic metabolism. Transmucosal absorption leads to direct availability of drug to systemic circulation thereby providing faster onset of action as compared to syrup/suspension. Transmucosal absorption also avoids the metabolism, degradation and excretion by gastrointestinal tract, water is not required in administration process for better patient compliance. It can be carried in a tiny pocket and can be used whenever required.
SUMMARY OF THE INVENTION:
In accordance with the above, the present invention provides a liquid oral spray dosage form comprising combination of anti-allergic, cough suppressant and nasal decongestant useful for the management of dry or non-productive cough, cough associated with viral or bacterial inflammation of upper respiratory tract, sinusitis, laryngitis, tracheitis and pharyngitis.

The composition of the present invention affords a better patient compliance and better bioavailability as the present formulation is in solution form that can be administered by spraying method.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
In one embodiment, the present invention provides a liquid oral spray dosage form comprising combination of anti-allergic, cough suppressant and nasal decongestant along with pharmaceutically acceptable ingredients useful for management of dry or nonproductive cough, cough associated with viral or bacterial inflammation of upper respiratory tract, sinusitis, laryngitis, tracheitis and pharyngitis.
Anti-allergic drug is selected from a group consisting of but not limited to triprolodine hydrochloride, cetrizine, levocetrizine, fexofenadine, chlorpheniramine maleate, diphenhydramine, preferably triprolodine hydrochloride or their pharmaceutically acceptable salts thereof used alone or in combination. The anti-allergic is present in an amount of their pharmacologically active amount ranging from 1-50 mg/spray.
Cough suppressant drug used in present invention is selected from a group consisting of but not limited to codeine, pseudoephedrine, dextromethorphan hydrobromide, hydromorphone, hydrocodone preferably dextromethorphan hydrobromide or their pharmaceutically acceptable salts thereof used alone or in combination. The cough suppressant is present in an amount of their pharmacologically active amount ranging from 1-10 mg/spray.
Nasal decongestant drug used in the present invention is selected from a group consisting of but not limited to phenylpherine hydrochloride, levomethamphetamine, ephedrine, naphazoline, synephrine, tetrahydrozoline, propyl hexedrine preferably phenylpherine hydrochloride or their pharmaceutically acceptable salts thereof used alone or in

combination. The nasal decongestant is present in an amount of their pharmacologically active amount ranging from 1-10 mg/spray.
The ratio of the drugs used in the composition of present invention is an amount of their pharmacologically active amount.
The abovementioned drugs are present in their therapeutic doses. In the present invention unique concentrated anti-cold/cough combination is in 0.1ml to 0.5ml of volume for management of various diseases.
One or more pharmaceutically acceptable excipients of the present invention is selected from group consisting of but not limited to cosolvents like P.E.G 400, propylene glycol monocaprylate, sorbitol 70% solution, liquid glucose and glycerine; preservatives like sodium methyl paraben, sodium propyl paraben, methyl paraben, propyl paraben and sodium benzoate; taste modifier like menthol; sweetening agents like neotame, sucrose, acesulfame, aspartame, sodium saccharine and sucralose and buffering agents like citric acid anhydrous, sodium citrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid, sodium chloride and hydrochloric acid.
Validated spray delivers unit dosing for potent drug delivery directly to oral cavity that ensures uniform dose dispensing. The formulation is dispensed in mist form that covers large area of oral cavity and very small amount of dispensed volume will be ingested, so there will be minimum chances of hepatic metabolism. For better patient compliance, it can be carried in a tiny pocket and can be used whenever required. Water is not required for administration and no assistance is required for administration to pediatrics.
Due to above said reason, the absorption of drug substances will be greater by transmucosal route as compared to gastrointestinal route. Transmucosal absorption leads to direct availability of drug to systemic circulation, this will provide faster onset of action as compared to syrup/suspension. Transmucosal absorption also avoids the metabolism, degradation and excretion by gastrointestinal tract.

In another embodiment, the invention provides a spray dispenser comprising therapeutically effective combination of anti-allergic, cough suppressant and nasal decongestant. The composition is filled in a convenient container that can give the formulation in form of fine droplets. Hence, it is easy to deliver even to the pediatrics. The formulation is palatable eventhough the drug concentration is relatively large.
The invention provides a composition which is in a liquid oral spray dosage form comprising therapeutically effective combination of anti-allergic, cough suppressant and nasal decongestant wherein the said composition does not crystallize at very low temperature during storage.
A pilot clinical study was conducted to evaluate the efficacy and safety of the liquid oral spray composition comprising dextromethorphan hydrobromide, phenylephrine hydrochloride and triprolidine hydrochloride in patients with cough and cold.
Name of Test Drug/lnvestigational Product: Each 0.2 ml test drug/investigational product which is liquid oral spray contains
Dextromethorphan hydrobromide 5% w/v
Phenylephrine hydrochloride 2.5% w/v
Triprolidine hydrochloride 0.625% w/v
Indication Studied:
Cough and Cold
Dose:
One spray of test drug thrice daily for three consecutive days
Methodology:
The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. This open labelled study was conducted at Ahmedabad. The patients received oral information about the intentions and nature of the study. Patients who met all the inclusion criteria and none of the exclusion criteria, based on history and clinical examination recruited in this study. Patients were recruited into study after the

assessment of eligibility criteria and taking verbal consent from the patient. Eligible patient received one spray of test drug thrice daily for three days.
Patient's baseline medical history, physical examination, vital signs and the common cold symptom score was taken and recorded. The study medication was dispensed to the enrolled patients and instructed to take one spray of test drug thrice daily for three days and he/she has to visit the site on the 4th day of drug administration for the follow up visit. On the 4th day of drug administration, patient's vitals, physical examination, clinical examination and the common cold symptom score were taken and recorded. Moreover Investigators were asked patients about any adverse drug reaction experienced by them during the study drug administration period.
Diagnosis and main criteria for inclusion:
Cough and Cold
Inclusion Criteria:
Patient with either sex having the age of 6 years or above suffering from cough and cold, acute cough/bronchitis, acute sore throat, acute sinusitis and common cold and willing to take study medication.
Exclusion Criteria:
Pregnant women or nursing mothers, patients with hypersensitivity to components of the formula of anti-flu drug, patients using alcohol, illicit drug monoamine oxidase inhibitors or barbiturates, patients suffering from seasonal or perennial allergic rhinitis, acute or chronic disease or patient with any condition which in the opinion of the investigator makes the patient unsuitable for inclusion.
Criteria for evaluation:
The efficacy evaluation parameter of this study was the common cold symptom score which was obtained at the baseline and at the end of the treatment. The safety evaluation was done with the number of adverse drug reactions reported by the patient taking test drug.

Result:
Total of 10 screened patients, all the patients met eligibility criteria and hence enrolled into the study. Among all 10 patients of cold and cough, none were reported any kind of adverse drug reaction. Average common cold symptom score was reduced from 15.3 to 2.6 after three days of treatment with test drug.
Conclusion:
Study concluded that test drug viz., liquid oral spray composition comprising Dextromethorphan hydrobromide, Phenylephrine hydrochloride and Triprolidine hydrochloride is safe and efficacious for the management of cough and cold. Moreover patients find it compliant for the oral administration.
The following example, which includes preferred embodiments, will serve to illustrate the practice of this invention, is being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention. It will be appreciated by any person skilled in this art that the present invention includes following examples and further can be modified and altered within the technical scope of the present invention.
EXAMPLES: Example 1:

SR.NO INGREDIENTS LABEL CLAIM
(mg/spray)
1 Dextromethorphan hydrobromide 10.00
2 Phenylpherine hydrochloride 5.00
3 Triprolidine hydrochloride 1.25
4 Propylene glycol 100.00
5 Sorbitol 70% solution 40.00
6 Menthol 0.20
7 Sodium methyl paraben 0.40
8 Sodium propyl paraben 0.10

9 Neotame 0.10
10 Sucralose 2.00
11 Colour Brilliant Blue Supra 0.006
12 Ess. Peppermint 0.30
13 Ess. Vanilla 0.30
14 Citric acid anhydrous 0.24
MANUFACTURING PROCEDURE:
Step: 1 Dissolve Dextromethorphan Hydrobromide in hot propylene glycol, after cooling add Sorbitol 70%.
Step: 2 Dissolve Phenylpherine Hydrochloride and Triprolidine Hydrochloride in 20% of purified water
Step: 3 Dissolve Neotame and Sucralose in 20% of purified water
Step: 4 Dissolve Sodium methyl paraben and Sodium propyl paraben in little amount of water.
Step: 5 Mix step 4, 3,2 and 1 in manufacturing tank
Step: 6 Add colour in manufacturing tank
Step: 7 Dissolve Menthol then add in manufacturing tank
Step: 8 Adjust the pH 5 with citric acid
Step: 9 Make up the final volume with purified water.
Example 2:
SR.NO INGREDIENTS LABEL CLAIM
(mg/spray)
1 Pseudoephedrine 5.00
2 Ephedrine 2.00
3 Cetrizine 1.25
4 Propylene Glycol 95.00
5 Sorbitol 70% solution 35.00
6 Menthol 0.15

7 Sodium methyl paraben 0.30
8 Sodium propyl paraben 0.10
9 Neotame 0.05
10 Sucralose 1.00
11 Colour brilliant blue 0.006
12 Ess. Black currant 0.50
14 Citric acid anhydrous 0.30
Example 3:
SR.NO INGREDIENTS LABEL CLAIM
(mg/spray)
1 Hydrocodone 2.00
2 Phenylpherine Hydrochloride 5.00
3 Levo-cetrizine 2.50
4 Propylene Glycol 90.00
5 Sorbitol 70% solution 30.00
6 Menthol 0.10
7 Sodium methyl paraben 0.20
8 Sodium propyl paraben 0.10
9 Neotame 0.02
10 Sucralose 1.50
11 Colour sunset yellow 0.005
12 Ess. orange 0.70
14 Citric acid anhydrous 0.25
Example 4:
SR.NO INGREDIENTS LABEL CLAIM
(mg/spray)
1 Codeine 2.00
2 Phenylepherine hydrochloride 5.00
3 Fexofenadine 30.00

4 Propylene Glycol 110.00
5 Sorbitol 70% solution 45.00
6 Menthol 0.20
7 Sodium methyl paraben 0.40
8 Sodium propyl paraben 0.20
9 Neotame 0.03
10 Sucralose 2.00
11 Colour erythrosine supra 0.006
12 Ess. strawberry 0.80
13 Citric acid anhydrous 0.15
Example 5:
SR.NO INGREDIENTS LABEL CLAIM
(mg/spray)
1 Pseudoephedrine 6.00
2 Phenylepherine hydrochloride 5.00
3 Chlorpheniramine maleate 2.00
4 Propylene Glycol 95.00
5 Sorbitol 70% solution 40.00
6 Menthol 0.15
7 Sodium methyl paraben 0.30
8 Sodium propyl paraben 0.10
9 Neotame 0.02
10 Sucralose 1.00
11 Colour carmosine supra 0.004
12 Ess. Strawberry 0.80
14 Citric acid anhydrous 0.10

We claim,
1. A liquid oral spray composition comprising:-
a. at least one anti-allergic in an amount ranging from 1-50 mg/spray;
b. at least one cough suppressant in an amount ranging from 1-10 mg/spray;
and
c. at least one nasal decongestant in an amount ranging from 1-10 mg/spray
along with one or more pharmaceutically acceptable excipients.
2. The liquid oral spray composition according to claim 1, wherein anti-allergic drug is selected from a group consisting of but not limited to triprolodine hydrochloride, cetrizine, levocetrizine, fexofenadine, chlorpheniramine maleate, diphenhydramine or their pharmaceutically acceptable salts thereof used alone or in combination.
3. The liquid oral spray composition according to claim 1, wherein cough suppressant is selected from a group consisting of but not limited to codeine, pseudoephedrine, dextromethorphan hydrobromide, hydromorphone, hydrocodone or their pharmaceutically acceptable salts thereof used alone or in combination.
4. The liquid oral spray composition according to claim 1, wherein nasal decongestant is selected from a group consisting of but not limited to phenylpherine hydrochloride levomethamphetamine, ephedrine, naphazoline, synephrine, tetrahydrozoline, propylhexedrine or their pharmaceutically acceptable salts thereof used alone or in combination.
5. The liquid oral spray composition according to claim 1, wherein one or more pharmaceutically excipients are selected from a group consisting of cosolvents, preservatives, taste modifier, sweeting agents and buffering agents.
6. The liquid oral spray composition according to claims 1 and 5, wherein cosolvents are selected from a group consisting of but not limited to P.E.G 400,

propylene glycol monocaprylate, sorbitol 70% solution, liquid glucose and glycerine.
7. The liquid oral spray composition according to claims 1 and 5, wherein preservatives are selected from a group consisting of but not limited to sodium methyl paraben, sodium propyl paraben, methyl paraben, propyl paraben and sodium benzoate.
8. The liquid oral spray composition according to claims 1 and 5, wherein taste modifier is menthol.
9. The liquid oral spray composition according to claims 1 and 5, wherein sweetening agents are selected from a group consisting of but not limited to neotame, sucrose, acesulfame, aspartame, sodium saccharine and sucralose.
10. The liquid oral spray composition according to claims 1 and 5, wherein buffering agents are selected from a group consisting of but not limited to citric acid anhydrous, sodium citrate, potassium dihydrogen phosphate, sodium dihydrogen phosphate, phosphoric acid, sodium chloride and hydrochloric acid.
11. The liquid oral spray composition according to claim 1, wherein said composition leads to greater absorption; direct availability of drug to systemic circulation thereby providing speedy onset of action and avoids the metabolism, degradation and excretion by gastrointestinal tract due to its transmucosal route.
12. The liquid oral spray composition according to claim 1 wherein said composition is palatable inspite of large drug concentration.
13. The liquid oral spray composition according to claim 1 wherein said composition does not crystallize at very low temperature during storage.

14. A spray dispenser to deliver the composition of claim 1, wherein the said composition is filled in a convenient container that delivers the formulation in the form of fine droplets for easy delivery to the paediatrics.