ORAL PHARMACEUTICAL FORMULATIONS

INTRODUCTION

Aspects of the present invention provide formulations for oral administration, comprising a combination of at least two active agents. In aspects, the present invention provides formulations comprising at least one active agent selected from a non-opioid antitussive class of compounds, combined with at least one active agent selected from a class of antihistamines, in the form syrups. Aspects of the present invention also include processes for the preparation of such formulations and methods of using them.

Formulations of the present invention are intended to be used as a prophylactic and/or a therapeutic, particularly in the management of cough such as non-productive cough and associated conditions.

Cough is mainly caused by excessive secretion from the mucous membranes of respiratory tract, by chemical stimuli such as smoke and gas, by foreign substances, by inflammation of respiratory tract, by allergic reactions, by the compression of bronchi by tumor in the thoracic cavity, or by psychogenic factors. The worsening and chronicity of cough consumes energy of the respiratory muscles and physical strength to thereby prevent recovery of the underlying disease.

Apart from the above reasons there can be a combination of causes for cough. For example, non productive cough may be a result of a simple viral upper respiratory infection, of short duration, lasting for a few weeks (acute non productive cough). However, non productive cough can be persistent, lasting for several weeks, months, or even years (chronic cough). Chronic cough may be caused by continuous mucus drainage down the throat, asthma, gastro esophageal reflux, a variety of pulmonary disorders, and even as a side effect of certain medications. Cough is the most common symptom of different respiratory illnesses including asthma, rhinitis, and chronic bronchitis. Cough is also present in cases of lung infections like pneumonia and it is also a resultant of lung cancer. In severe cases it can lead to insomnia, exhaustion, vomiting and headache.

A cough can be of two types, either useful or useless. A useful or productive cough is one that effectively expels out the sputum, thereby clearing the breathing passages. In such a situation, suppressing the cough can actually do more harm because the sputum that is retained may block the smaller airways, promoting infection and delaying recovery. Rationally, a productive cough should only be stopped if it is dangerous for the patient (such as someone who has just undergone an eye operation) or when it is causing sleep disturbances and is exhausting to the patient. A useless, non-productive or dry cough which is distressing to the patient, if not suppressed, can further increase the irritation of the air passages. It can have an allergic or neurotic origin or can be caused by other severe diseases.

Several classes of drug compounds have been approved and marketed for the treatment of productive cough such as expectorants, decongestants, demulcents, etc. Demulcents relieve coughing by coating irritated passageways. They form a protective coating over the irritated pharyngeal mucosa. Local anesthetics such as lidocaine, benzocaine, hexylcaine hydrochloride, and tetracaine are used to inhibit the cough reflex under special circumstances, for example, before bronchoscopy or bronchography. Expectorants are drugs that make mucus easier to cough up by thinning it. Guaifenesin and terpin hydrate are the primary ingredients in most over-the-counter expectorants. These drugs are intended to help expel bronchial secretions from the respiratory tract by decreasing their viscosity, thus facilitating removal of mucus. Mucolytics are the class of compounds which break the mucus by reducing the surface tension of mucus and helps in easy expulsion of mucus. Examples from this class are the cromolyn compounds, like cromolyn sodium. Decongestants, like pseudoephedrine and phenylephrine, can be used to clear a runny nose and postnasal drip.

Antihistaminics and antitussives are among the most commonly used medications for non-productive cough woridwide. Antitussives are the active agents which suppress cough by interfering with the cough reflex. Antitussive agents are classified as centrally-acting antitussive agents (which block the cough center) and peripherally-acting antitussive agents (which reduce the stimuli to peripheral receptors). Antitussives may work at one or at a combination of sites along the cough reflex arc. The centrally-acting antitussive agents like morphine and codeine and their analogues like dihydrocodeine and dextromethorphan are considered to be effective antitussives in non-productive cough, but induce adverse actions such as respiratory depression, constipation, nausea, emesis, headache, sleepiness, and loss of alertness. They also give rise to tolerance and/or addiction when used repeatedly. The peripherally-acting antitussive agents, for example non-opioid antitussives act peripherally and do not cross blood-brain-barrier to exert central side effects. Peripherally acting antitussives like methylephedrine exhibit only mild antitussive actions. Recently, the opioid (delta) receptor antagonists have been developed as antitussive agents. However, because the delta receptor is deeply involved in mental and emotional behaviors, these antagonists should induce adverse actions (Nat. Genet. 25, 2, 195, 2000). Also, most currently available cough suppressants have not demonstrated antitussive efficacy in adequately performed clinical trials of acute cough. This includes non-prescription (OTC) products (K. Schroeder and T. Fahey, Systematic review of randomized controlled trials of over- the-counter medicines for acute cough in adults, {Br Med J 324 (2002), pp. 329-331) as well as central cough suppressants such as codeine (D.C. Bolser, Cough suppressant and pharmacologic protussive therapy. In: Diagnosis and management of cough: ACCP evidence-based clinical practice guidelines. Chest 129 (2006), pp. 238S-249). Accordingly, there is a demand for antitussive agents having higher efficacy and less adverse actions. This has increased the need for peripherally acting antitussives which are devoid of central side effects but have same efficacy as that of the centrally acting antitussives.

Levodropropizine, a phenylpiperazinopropane derivative, is a non-opioid antitussive agent. Chemically levodropropizine is 3-(4-phenyl-1-piperazinyl)-1,2- propanediol and is the 'levo'-isomer of dropropizine. The chemical structure of levodropropizine is given below:

International Application Publication No WO/2002/010150 contains a discussion about levodropropizine and its analogues and has given evidence of the antitussive action of Levodropropizine. Levodropropizine has been proven to be an effective antitussive against non-productive cough associated to different lung pathologies (E.Catena, L. Daffonchio, Efficacy and Tolerability of Levodropropizine in Adult Patients with Non-productive Cough. Comparison with Dextromethorphan, Pulmonary Pharmacology and Therapeutics, 1997, 10, 89-96.) Randomized, double- blind trials have demonstrated levodropropizine to be superior to placebo against bronchitic cough, comparable to dextromethorphan in non-productive cough, and comparable to dihydrocodeine against cough associated with lung cancer. Levodropropizine works by inhibiting vagally conducted cough by activating the reflex mediated by capsaicin sensitive afferents and not by central mechanisms of action. In addition, it interferes with the sensory neuropeptide system.

Another class of drugs used for treating cough is antihistaminics. Antihistaminics are used for allergic cough and in addition to relieving cough they also relieve other symptoms of allergy like running nose, watery eyes, sneezing etc. Antihistamines are the class of compounds which are so named because they block Hi histamine receptors located on respiratory tissues. Histamine is typically released from airway mast cells following some allergic and infectious challenge, and histamine irritates the upper airway tissue leading to coughing and other symptoms.

Antihistamines in general can be classified as belonging to first, second or third generation. First generation antihistamine includes chlorpheniramine. Second generation antihistamines include terfenadine and astemizole. Third generation antihistamines include loratadine, fexofenadine, mizolastine, ebastine, azelastine, and cetirizine.
Chlorpheniramine maleate is a first generation antihistamine belonging to the class of alkylamines. It is used in the prevention of the symptoms of allergic conditions such as rhinitis and utricaria. Its sedative effects are relatively weak compared to other first-generation antihistamines. It is used for not only the treatment of cough but also other related symptoms of allergy such as sneezing, itchy and/or watery eyes, itchy nose or throat, and runny nose caused by hay fever (allergic rhinitis), or other respiratory allergies. The lUPAC name of chlorpheniramine is 3-(4-chlorophenyl)-A/,A/-dimethyl-3-pyridin-2-yl-propan-1-amine and its molecular formula is C16H19CIN2. The molecular structure is as follows:

Second generation antihistamines include terfenadine and astemizole. Third generation antihistamines include loratadine, fexofenadine, mizolastine, ebastine, azelastine, and cetirizine.

International Publication No. WO 2006/113485 describes a combination product containing a non-adrenergic aminergic compound in combination with a complement agent. The complement agent mentioned can be selected from the class of ascorbates, opioids, polycarboxylic acid chelators, resveratrol family members, cysteine family members, analogs and substituted derivatives thereof, and mixtures thereof.
U.S. Patent No. 5,648,358 relates to compositions and methods for providing improved treatment, management or mitigation of cold, cold-like symptoms, allergy, sinus and/or flu symptoms by administering a safe and effective amount of composition comprising caffeine and certain pyrrolidine and piperidine ether antihistaminic agents.
International Publication No. WO 99/62516 claims an antihistaminic syrup formulation containing about 0.05 to about 5 mg/ml of an aminopolycarboxylic acid, including its salts.

International Publication No WO 2007/087344 relates to a stabilized pharmaceutical liquid formulation comprising an antihistamine and having a purity equal to or greater than about 99% by weight, based on HPLC assay, residual solvents of less than about 0.5%, and a total impurity of less than about 0.2%. The said formulation contains a storage stabilizing agent for improving the stability of the said pharmaceutical liquid formulation.

There exists an unmet medical need for pharmaceutical formulations that are easy to formulate and stable, and are effective not only in the management of cough but also for alleviating/minimizing the other associated symptoms/conditions such as one or more of watery eyes, itchy eyes/nose/throat, runny nose, sneezing and the like.

SUMMARY

Aspects of the present invention provide formulations for oral administration comprising a combination of at least two active agents, wherein at least one active agent is selected from a non-opioid antitussive class of compounds and the other active agent is selected from a class of antihistamines, optionally together with one or more pharmaceutical excipients.

Aspects of the present invention provide a stable liquid composition comprising levodropropizine and chlorpheniramine for the prophylaxis, amelioration and/or treatment of cough and associated conditions.

In embodiments, the pharmaceutical formulations of the present invention comprise chlorpheniramine or salts, polymorphs, solvates, esters, hydrates, enantiomers, racemates, and mixtures thereof as the antihistamine active agent, and levodropropizine or salts, polymorphs, solvates, esters, hydrates, enantiomers, racemates, and mixtures thereof as the non-opioid antitussive active agent, optionally together with one or more pharmaceutical excipients.

In embodiments, the pharmaceutical formulations of the present invention comprise chlorpheniramine maleate and levodropropizine, optionally together with one or more pharmaceutically acceptable excipients.

In embodiments, the oral formulations of the present invention are in the form of syrup.
Aspects of the present invention also provide processes for preparing the formulations, intended for oral administration.

The novel pharmaceutical formulations of the present invention are highly effective in the treatment of non-productive cough, and exhibit reduced intolerable side effects like drowsiness, loss of alertness, etc.

In an aspect, the formulations of the present invention comprising a combination of a first generation antihistaminic and non-opioid antitussive are highly stable and are capable of eliciting and sustaining desirable pharmacokinetic responses in a subject in need thereof.
In another aspect, the present invention provides methods of using such pharmaceutical formulations for the prophylaxis, amelioration and/or treatment of cough such as non-productive cough and associated conditions.

The formulations of the present invention are effective not only in the management of cough but also for alleviating and minimizing the other associated symptoms/conditions such as one or more of watery eyes, itchy eyes/nose/throat, runny nose, sneezing and the like.

DETAILED DESCRIPTION

Aspects of the present invention provide stable pharmaceutical formulations for oral administration, comprising a combination of at least two active agents. The formulations comprise at least one active agent from a non-opioid antitussive class of compounds combined with at least one active agent from a class of antihistamines. The 'Antihistamine' active agent according to the present invention may belong to the first, second or third generation. First generation antihistamine includes chlorpheniramine. Second generation antihistamines include terfenadine and astemizole. Third generation antihistamines include loratadine, fexofenadine, mizolastine, ebastine, azelastine, and cetirizine.
Aspects of the present invention also provide processes for the preparation of the formulations and methods of using them.

The terms "drug" or "active agent" or "API" are used interchangeably and refer to substances having pharmacologic activity and being present in a formulation in a quantity that is sufficient to elicit an intended pharmacological response.

The term "levodropropizine" or "chlorpheniramine" as used herein includes the compounds and any one or more of salts, polymorphs, solvates, esters, hydrates, enantiomers, racemates, and mixtures thereof.
The term "stable pharmaceutical composition" refers to a pharmaceutical system which maintains its physico-chemical integrity initially and during commercially relevant storage (e.g., throughout the normal product shelf life) and is not easily decomposed or othen lies modified physically or chemically.

The terms "excipient" or "pharmaceutically acceptable excipienf refer to non- API substances such as vehicles, cosolvents, sweetners, preservatives, buffering agents, antioxidants, flavours, colours, etc., used in formulating pharmaceutical products. They are generally safe for administering to humans according to established governmental standards.

In embodiments, the pharmaceutical formulations of the present invention provide an effective management of non-productive cough due to allergy, flu symptoms, allergic rhinitis, breathing illnesses, e.g., sinusitis, hay fever, chronic obstructive pulmonary disease, lung infections, asthma and any combination thereof.
In an embodiment, the present invention provides novel compositions for oral administration comprising a combination of at least two active agents wherein at least one active agent is selected from a non-opioid antitussive class of compounds and the other active agent is selected from a class of antihistamines optionally alongwith one or more excipients.

In an embodiment, one of the active agents belonging to the class of antihistaminics comprises chlorpheniramine, pheniramine, hydroxyzine, diphenhydramine, promethazine, or any mixtures thereof.

The term "antitussive" refers to drugs that suppress a cough. Non-opioid antitussives are the drugs which do not cross blood brain barrier and do not follow the central mechanism of non productive cough relief.

In an embodiment, one of the active agents belonging to the class of antitussives comprises of a non-opioid antitussive such as levodropropizine, benzonatate, guaifensin, moguisteine, a GABA agonist, theobromine, levoclorperastine, a vanilliod receptor antagonist, an endogenous cannabinoid, a tachykinin receptor antagonist, a potassium channel opener, a bradykinin receptor antagonist, and any mixtures thereof.
In embodiments, a pharmaceutical formulation of the present invention comprises chlorpheniramine or salts, polymorphs, solvates, esters, hydrates, enantiomers, racemates, and mixtures thereof as an antihistamine active agent, and levodropropizine or salts, polymorphs, solvates, esters, hydrates, enantiomers, racemates, and mixtures thereof as a non-opioid antitussive active agent, optionally together with one or more excipients.
In embodiments, a pharmaceutical formulation of the present invention comprises chlorpheniramine maleate and levodropropizine optionally alongwith one or more excipients.

In an embodiment, the oral formulation of the present invention is in the form of syrup. The dose of the active agents administered particularly depends on the severity of the pathological condition, such as non-productive cough and history of the subject. Typically, a therapeutically effective amount of chlorpheniramine maleate per dose or per 5 mL of the pharmaceutical formulation in the form of syrup can range from about 0.5 mg to about 6 mg, with a maximum dose of about 24 mg/day administered t.i.d. An effective amount of levodropropizine per dose or per 5 mL of a syrup composition can range from about 1 mg to about 50 mg, or from about 10 mg to about 30 mg, with a maximum dose of about 360 mg/day administered t.i.d., wherein t.i.d. is a medical abbreviation meaning 'three times daily'.

Suitable pharmaceutically acceptable excipients, include but are not limited to, one or more of cosolvents, preservatives, sweeteners, buffering agents, cooling agents, colourants, flavours, antioxidants, vehicles, tonicity modifiers, surfactants, wetting agents, and the like.

Some of the excipients that are useful in the pharmaceutical formulations of the present invention can serve more than one purpose, such as, for example a flavouring agent can also act as a coolant, and a buffering agent can also act as an antioxidant.
In embodiments of the present invention, the pharmaceutical formulations herein comprise at least one active agent from the class of antihistamines, and another active agent is from the class of non-opioid antitussives, together with excipients such as one or more sweeteners, one or more preservatives, one or more buffering agents, optionally at least one coolant, one flavouring agent, one colourant, and a vehicle.

The term "cosolvent" refers to a second solvent present with a first solvent, generally in smaller concentrations, to form a mixture that has enhanced solvent powers due to synergism. The cosolvent frequently comprises one or more monohydric or polyhydric alcohols. Examples of specific cosolvents that can be used in formulations of this invention include propylene glycol, polyethylene glycol, glycerol, ethanol, and any mixtures thereof. The amount of cosolvents in a pharmaceutical formulation can range from about 10 mg to about 900 mg, per 5 mL of the pharmaceutical formulation in the form of syrup.

"Sweetners" according to the present invention are added to make syrup and also to enhance pharmaceutical formulation palatability. Sweetners can be natural sweetners or artificial sweetners. Suitable sweetners include, but are not limited to, methyl", ethyl- and carboxy-ethyl celluloses and -methyl celluloses, pectins, carraghenates, alginates, sodium and calcium saccharinates, saccharine, glucose, fructose, sucrose, xylitol, tagarose, sucralose, maltitol, isomaltulose, hydrogenated isomaltulose, lactitol, sorbitol, mannitol, trehalose, polydextrose, glycerin, erythritol, acesulfame, neohesperidin dihydrochalcone, stevioside, thaumatin, hydrogenated starch hydrolysates, steviosides, cyclamates, and combinations thereof. The amount of sweetners in a pharmaceutical formulation can range from about 0.0001% to about 10%, by weight of the formulation.

In embodiments the present invention includes a buffering agent. A "buffering agent" is one wliicli maintains the pH of the system in a defined limit during the shelf life of the pharmaceutical formulation. Buffering agents which can be used in the pharmaceutical composition include, but not limited to, alkali metal hydroxides, carbonates, sesquicarbonates, borates, silicates, phosphates, imidazole, and mixtures thereof.

Examples of specific buffering agents include monosodium phosphate, trisodium phosphate, sodium benzoate, benzoic acid, sodium hydroxide, potassium hydroxide, alkali metal carbonate salts, sodium carbonate, imidazole, pyrophosphate salts, citric acid, and sodium citrate. Buffering agents are typically used in the formulations at levels of from about 0.1% to about 3%, by weight of the composition.

Any acid which will provide the proper pH can be used to formulate syrups, such as citric, malic, ascorbic, acetic, lactic, phosphoric, hydrochloric, sulfuric and erythorbic acids. The amount of acid in the buffering agent combination in the pharmaceutical formulation can be in the range of about 0.5 mg to about 80 mg, per 5 mL of syrup, and that of a salt in the buffering agent combination can range from about 0.1 mg to about 75 mg, per 5 mL of syrup.

In embodiments, a pH of a liquid pharmaceutical formulation of the present invention is in the range of about 3 to about 8, or about 5 to about 6.5. This is because at higher or lower pH values, there is a chance of increasing the amount of impurities or drug-related substances in the product.

The term "preservative" refers to any natural or synthetic chemical that is added to products such as pharmaceuticals to prevent decomposition by microbial growth or by undesired chemical changes. Preservatives can desirably be incorporated into the composition for protecting against the growth of potentially harmful microorganisms. Microorganisms tend to proliferate in an aqueous phase and, to prevent that, a preservative has to be added to the pharmaceutical composition. Suitable preservatives for formulations of the present invention include, but are not limited to, methyl paraben, propyl paraben and their sodium salts, hydroxyparabenzoate, sodium metabisulphite, sodium benzoate, cetrimonium chloride, and any mixtures thereof. Other useful antimicrobial agents can include quaternary ammonium salts, bis-biquanide salts, triclosan monophosphate, dodecyltrimethyl ammonium bromide, tetradecylpyridinium chloride, domiphen bromide, N-tetradecyl-4-ethyl pyridinium chloride, dodecyldimethyl(2-phenoxyethyl) ammonium bromide, benzyldimethylstearyl ammonium chloride, cetylpyridinium chloride, quaternized 5-amino-1,3-bis(2-ethyl-hexyl)-5-methylhexahydropyrimidine, benzalkonium chloride, benzethonium chloride, and methyl benzethonium chloride. The amount of preservative may be about 0.05% to about 25% w/w, with regard to the total weight of the formulation.

Embodiments of formulations of the present invention include one or more flavouring agents. These ingredients are used to enhance the flavor of medications and to make them palatable. "Flavouring agents" suitable for use in the present invention include natural, natural-identical, and/or artificial flavouring substances, and mixtures thereof, added in their solid and/or liquid states. Suitable flavoring components include menthol, lemon supreme flavour, ginger supreme flavour, oxanone, alpha-irisone, marjoram, lemon, orange, propenyl guaethol, cinnamon, vanillin, ethyl vanillin, or mixtures thereof. Flavours may also comprise common flavours such as orange, banana, raspberry and golden syrup, or mixtures thereof. Other flavours that can be used are heliotropine, 4-cis-heptenal, diacetyl, methyl- para-t-butyl phenyl acetate, or mixtures thereof. A flavor system is typically used in the formulations at levels of from about 0.0001% to about 10%, by weight.

In embodiments, a flavouring agent used in the pharmaceutical formulation of the present invention can be in the range of about 0.01 mg to about 150 mg, per 5 mL of the pharmaceutical formulation.

A cooling agent can optionally be present in the pharmaceutical formulations of the present invention, such as menthol, thymol, methyl salicylate or mixtures thereof; the amount of which can vary from about 0.1 mg to about 25 mg, per 5 mL. A cooling agent is typically used in the formulations at levels of from about 0.005% to about 0.02%, by weight of the composition.

Antioxidants are substances that inhibit oxidation or suppress reactions promoted by oxygen or peroxides. Suitable antioxidants for formulations of the present invention include, but are not limited to, ascorbic acid (vitamin C), EDTA and its salts, glutathione, lipoic acid, uric acid, carotenes, a-tocopherol (vitamin E), ubiquinol, butylated hydroxyanisole, butylated hydroxytoluene, sodium benzoate, malic acid, sodium thiosulphate, sodium metabisulphite, propyl gallate (PG, E310), t- butylhydroquinone (TBHQ), and any mixtures thereof. The amount of antioxidant may be about 0.001% to about 30% w/w, with regard to the total weight of the formulation.

Colorants are the substances that are added in small quantities to increase the aesthetic appearance of the pharmaceutical formulations and they do not have any substantial therapeutic significance. Non-limiting examples of colorants that can be used in the pharmaceutical formulations are quinoline yellow, Red #40, Ponceau 4R Red, Bordeaux S Red, erythrosine, iron oxide, FD&C green #3, erythrosine, Allura red AC, tartrazine. Sunset yellow, D&C yellow #10, and any mixtures thereof.

In embodiments, proportions of organic solvent such as propylene glycol to water in pharmaceutical formulations are in the range of about 1:100 to about 100:1.

In embodiments, densities of the pharmaceutical formulations are in the range of about 0.85 to about 2.5 g/mL.

In embodiments, pharmaceutical formulations of the present invention contain not less than about 90%, and not more than about 120%, of the label amount of each of the active agents chlorpheniramine maleate and levodroproplzine.

In aspects of the present invention, pharmaceutical formulations may be substantially free of any buffering agent, and/or antioxidant, and/or preservative, and/or alcohol, and/or glycol.

In aspects of the present invention, the stable liquid composition comprises 0.001% to about 30% w/w of antioxidant, 0.05% to about 25% w/w of preservative, 0.0001% to about 10% w/w of flavouring agent and/or sweetner, 0.005% to about 0.02% w/w of cooling agent and 0.1% to about 3% w/w of buffering agent, along with one or more other pharmaceutically acceptable excipients.

In embodiments, pharmaceutical formulations of the present invention containing chlorpheniramine maleate and levodroproplzine, together with one or more pharmaceutically acceptable excipients, either after manufacture or upon storage (e.g., during the normal shelf life), contain less than about 3% of impurity A, and/or 2% of impurity B, and/or 3% of impurity C; a highest individual unidentified impurity of the said pharmaceutical composition is not more than about 3%, and the total impurities are less than about 5%, by weight of the chemically related active agents.

In preferred embodiments, pharmaceutical formulations of the present invention containing chlorpheniramine maleate and levodroproplzine, together with one or more pharmaceutically acceptable excipients, either after manufacture or upon storage (e.g., during the normal shelf life), contain less than about 2% of impurity A, and/or 1% of impurity B, and/or 1% of impurity C; a highest individual unidentified impurity of the said pharmaceutical composition is not more than about 0.5%, and the total impurities are less than about 3%, by weight of the chemically related active agents. Impurities A, B and C have the following chemical names and structures:

Impurity A: (2R)-3-(4-phenylpiperazin-1-yl)propane-1,2-diol (dextropropizine).

Impurity B: 1-phenylpiperazine.

Impurity C: [(2RS)-oxiran-2-yl]methanol (glycidol).

In embodiments, pharmaceutical formulations of the present invention are packaged into suitable containers such as amber-coloured polyethylene terephthalate (PET) bottles, fitted with roll-on pilfer- proof (ROPP) caps.

The pharmaceutical formulations of the present invention are easy to formulate and stable, and are effective not only in the management of cough but also for alleviating/minimizing the other associated symptoms/conditions such as one or more of watery eyes, itchy eyes/nose/throat, runny nose, sneezing, and the like.

In aspects, the present invention provides methods of administering, to a subject in need thereof, pharmaceutical formulations by measuring an appropriate amount between 2 mL to 10 mL, such as 2.5 mL or 5 mL or 7.5 mL or 10 mL or any sub-multiples or multiples thereof, and administering it through the mouth.

Aspects of the present invention also provide processes for preparing stable liquid compositions intended for oral administration. In an embodiment, a process of preparation of a stable liquid composition comprises:

i) Dissolving levodropropizine in a mixture of propylene glycol and water and combining this with a solution of chlorpheniramine maleate in water.

ii) Optionally, dissolving a cooling agent in propylene glycol and combining with the solution of i).

iii) Optionally, adding one or more excipients such as antioxidants and preservatives, and mixing with the solution of i) or ii).

Aspects of the present invention also provide processes for preparing stable liquid compositions intended for oral administration. In an embodiment, a process of preparation of liquid composition comprises:

i) Dissolving levodropropizine in a mixture of propylene glycol and water and combining this with a solution of chlorpheniramine maleate in water.

ii) Optionally, dissolving one or more cooling agent in propylene glycol and combining with the solution of i).
iii) Optionally, adding one or more antioxidant and mixing with the solution of i) or
iv) ii).

iv) Optionally, adding one or more buffering agent and mixing with the solution of i) or ii).

v) Optionally, adding one or more flavouring agent and/or colorant and mixing with the solution of i) or ii).
The pharmaceutical formulations of the present invention are highly effective in the treatment of non-productive cough, and exhibit reduced intolerable side effects like drowsiness, loss of alertness, and the like.
In an aspect, the compositions of the present invention comprising a combination of a antihistamine and a non-opioid antitussive are appreciably stable and are capable of eliciting and sustaining desirable pharmacokinetic responses in a subject in need thereof.
In aspects, the present invention provides methods of using pharmaceutical formulations for the prophylaxis, amelioration and/or treatment of cough such as non-productive cough and associated conditions.
Formulations of the present invention are effective not only in the management of cough but also for alleviating/minimizing other associated symptoms/conditions such as one or more of watery eyes, itchy eyes/nose/throat, runny nose, sneezing and the like.
The following examples illustrate certain specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given for purposes of illustration only and are not intended to limit the scope of the invention in any manner.

EXAMPLES:

EXAMPLE 1: Syrup formulation.

Manufacturing procedure:

(a) Heat water and dissolve the required quantity of sucrose to make a 66.67% w/w syrup.

(b) Heat part of the propylene glycol to 40-50°C. Add methyl paraben and propyl paraben slowly with stirring and continue stirring to get a clear solution. Mix with the material of (a).

(c) Dissolve disodium edetate in water with stirring and add to material of
(b).

(d) Combine water and propylene glycol and add levodropropizine with stirring, and continue stirring until the drug dissolves completely. Combine this solution with the solution of (c).

(e) Dissolve chlorpheniramine maleate in water. Combine this solution with the solution of (d).

(f) Dissolve citric acid monohydrate in water, add sodium citrate and stir to dissolve completely. Combine this solution with the solution of (e).

(g) Dissolve menthol in the remaining quantity of propylene glycol with stirring and combine with the solution of (f).

(h) Dissolve quinoline yellow in water and mix the solution with the solution
of(g).

(i) Add ginger supreme flavour and lemon supreme flavour to the solution of (h) and stir.

(j) Make up the volume of the syrup with remaining water and adjust the pH with sodium citrate if required such that the pH of the final solution is about 4.0- 6.0.
The composition prepared in Example 1 is prepared in a batch size of 200 L, 120 mL portions of which are packaged in individual amber coloured bottles with ROPP caps and stored at 40°C and 75% relative humidity for six months. Parameters such as pH, density, drug assay and drug-related impurities are measured before, during, and after storage, and the data are shown in Table 1.

Table 1

* Levo = Levodropropizine; ** CPM = Chlorpheniramine Maleate; HUl = Highest unidentified impurity; ND = Not detected; Imp = Impurity.

Based on the data, it is concluded that the formulations have excellent stability under accelerated stability testing conditions (40°C and 75% RH) even for a period of 6 months. The physical appearance of the solution remains unchanged during the stability study period. The pH, viscosity, density, drug assay and the amount of impurities are found to be within desired limits throughout the stability testing period.

EXAMPLE 2: Syrup formulation.

Manufacturing procedure:

(a) Levodropropizine is dissolved in a mixture of water, ethanol and propylene glycol, in the ratio of 1.1:2, and stirred.

(b) Sucrose is slowly added to water and heated. The solution is cooled.

(c) Chlorpheniramine maleate is dissolved in water with continuous stirring and added to (b).

(d) The solutions made in (a) and (b) are then mixed with continuous stirring.

(e) Menthol, sodium citrate and citric acid monohydrate are mixed with a small quantity of propylene glycol and combined with the solution prepared in (a).

(f) BHA is dispersed in water and mixed with the material of (d).

(g) Methyl paraben and propyl paraben are mixed with a small quantity of a mixture of propylene glycol and ethanol, and the solution is added to the material of step (d).

(h) Colour and flavour are mixed with a small quantity of propylene glycol and combined with material of (d).

(i) Water is added to make up the volume.

EXAMPLE 3: Syrup formulation.

Manufacturing procedure:

(a) Saccharin sodium is slowly added to water and heated. The solution is cooled.

(b) Chlorpheniramine maleate is slowly added to the solution of (a) with continuous stirring.

(c) Levodropropizine is dissolved in a mixture of water and ethanol in the ratio of 1:2 and stirred. The solution is added to (b).

(d) Menthol, sodium citrate and citric acid monohydrate are mixed with a small quantity of ethanol and combined with the solution prepared in (c).

(e) Methyl paraben and propyl paraben are added to water and small quantity of ethanol and mixed to (d).

(f) Malic acid is dissolved in water and mixed with the material of (e).

(g) Colour and flavour are dissolved in a small quantity of ethanol and mixed with material of (f).

(h) Water is added to make up the volume.

EXAMPLE 4: Syrup formulation.

Manufacturing procedure:

(a) Levodropropizine is dissolved in a mixture of water and propylene glycol in the ratio of 1.1:2 and stirred.

(b) Sucrose is slowly added to water and heated. The solution is cooled.

(c) Chlorpheniramine maleate is dissolved in water with continuous stirring and added to the material of (b).

(d) Levodropropizine solution from (a) is added to the mixture of (c).

(e) Menthol, methyl paraben gnd propyl paraben are mixed with a small quantity of propylene glycol and combined with the solution prepared in (d).

(f) Butylated Hydroxy Toluene is dissolved in water and mixed with the material of
(e).

(g) Colour and flavour are mixed with a small quantity of propylene glycol and combined with the material of (f).

(h) Water is added to make up the volume.

EXAMPLE 5: Syrup formulation.
Manufacturing procedure:

(a) Levodropropizine is dissolved in small a quantity of propylene glycol and water is added slowly to it and stirred.

(b) Sucrose is slowly added to water and heated until the sucrose dissolves. The solution is cooled to room temperature.

(c) Chlorpheniramine maleate is added to the solution of (b) with continuous stirring,

(d) Levodropropizine solution made in (a) is added to (c).

(e) Menthol is mixed with a small quantity of propylene glycol and combined with the solution of (d).

(f) Sodium citrate and citric acid monohydrate are mixed in small quantity of water and propylene glycol and added to above.

(g) Sodium EDTA, colour and flavours are mixed with a small quantity of propylene glycol and combined with the material of (e).

(h) Water is added to make up the volume.

EXAMPLE 6: Syrup formulation.
Manufacturing procedure:

(a) Sucrose is slowly added to water and heated until the sucrose dissolves. The solution is cooled to room temperature.

(b) Levodropropizine is dissolved in a small quantity of propylene glycol and water is added slowly to it and stirred.

(c) Chlorpheniramine maleate is added to the solution of (a) with continuous stirring,

(d) Levodropropizine solution made in (b) is combined with (c).

(e) Sodium acetate and acetic acid are mixed in small quantity of water and propylene glycol and added to (d).

(f) Benzyl alcohol is added to small quantity of propylene glycol and the mixture is added to (e).

(g) Menthol is mixed with a small quantity of propylene glycol and combined with the solution of (f).

(h) Colour and flavours are mixed with a small quantity of propylene glycol and combined with the material of (g).

(i) Water is added to make up the volume.

EXAMPLE 7: Syrup formulation.

Manufacturing procedure:

(a) Sucrose is slowly added to water and heated until the sucrose dissolves. The solution is cooled to room temperature.

(b) Levodropropizine is dissolved in a small quantity of propylene glycol and water is added slowly to it and stirred.

(c) Chlorpheniramine maleate is added to the solution of (a) with continuous stirring,

(d) Levodropropizine solution made in (b) is combined with (c).

(e) Sodium citrate and citric acid monohydrate are mixed in small quantity of water and propylene glycol and added to (d).

(f) Methyl paraben and propyl paraben are added to small quantity of propylene glycol and the solution is added to (e).

(g) Menthol is mixed with a small quantity of propylene glycol and combined with the solution of (f).

(h) Ascorbic acid is mixed with a small quantity of water and combined with the solution of (g).
(i) Colour and flavours are mixed with a small quantity of propylene glycol and combined with the material of (h).

(j) Water Is added to make up the volume.

EXAMPLE 8: Syrup formulation.

Manufacturing procedure:

(a) Sucrose is slowly added to water and heated until the sucrose dissolves. The solution is cooled to room temperature.

(b) Levodropropizine is dissolved in a small quantity of propylene glycol and water is
added slowly to it and stirred.

(c) Chlorpheniramine maleate is added to the solution of (a) with continuous stirring,

(d) Levodropropizine solution made in (b) is combined with (c).

(e) Sodium citrate and citric acid monohydrate are mixed in small quantity of water and propylene glycol and added to (d).

(f) Methyl paraben and propyl paraben are added to small quantity of propylene glycol and the solution is added to (e).

(g) Menthol is mixed with a small quantity of propylene glycol and combined with the solution of (f).

(h) Sodium thiosulphate and Sodium metabisulfite are mixed with a small quantity of water and combined with the solution of (g).

(i) Colour and flavours are mixed with a small quantity of propylene glycol and combined with the material of (h).

(j) Water is added to make up the volume.

We Claim:
1. A stable liquid composition for the prophylaxis, amelioration and/or treatment of cough and associated conditions comprising levodropropizine and chlorpheniramine along with one or more pharmaceutically acceptable excipients selected from the group comprising vehicles, cosolvents, sweetners, preservatives, buffering agents, antioxidants, flavouring agents and colorants.

2. The stable liquid composition according to claim 1, wherein the chlorpheniramine is chlorpheniramine maleate.

3. The stable liquid composition according to any of the claims 1 and 2, comprising 0.001% to about 30% w/w of antioxidant, 0.05% to about 25% w/w of preservative, 0.0001% to about 10% w/w of flavouring agent and/or sweetner, 0.005% to about 0.02% w/w of cooling agent and 0.1% to about 3% w/w of buffering agent, along with one or more other pharmaceutically acceptable excipients.

4. The stable liquid composition according to claim 3, wherein the antioxidant is Disodium EDTA.

5. The stable liquid composition according to any of the preceding claims 1-4, which is in the form of a syrup.

6. The stable syrup composition according to claim 5, wherein the pH of the syrup is in the range of about 3 to about 8.
7. The process of preparing the stable liquid composition according to any of the preceding claims 1 and 2, comprising:

i) Dissolving levodropropizine in a mixture of propylene glycol and water and combining this with a solution of chlorpheniramine maleate in water.

ii) Optionally, dissolving one or more cooling agent in propylene glycol and combining with the solution of i).

iii) Optionally, adding one or more antioxidant and mixing with the solution of i) or

ii).

iv) Optionally, adding one or more buffering agent and mixing with the solution of i) or ii).
v) Optionally, adding one or more flavouring agent and/or colorant and mixing with the solution of i) or ii).

8. The stable liquid composition comprising levodropropizine and chlorpheniramine according to any of the preceding claims 1-6, wherein the said composition contains less than about 2% of impurity A, and/or 1% of impurity B, and/or 1% of impurity C; a
highest individual unidentified impurity of not more than about 0.5%; and the total impurities of less than about 3%, by weight of the chemically related active agents.

9. Methods of administering, to a subject in need thereof, pharmaceutical formulations according to any of the preceding claims 1-6, which comprises measuring an appropriate amount of the formulation between 2 mL to 10 mL, such as 2.5 mL or 5 mL or 7.5 mL or 10 mL or any sub-multiples or multiples thereof, and administering it through the mouth.

10. Pharmaceutical formulations according to any of the preceding claims 1-6 which are packaged into amber-coloured polyethylene terephthalate (PET) bottles, fitted with roll-on pilfer-proof (ROPP) caps.