FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. Title of the invention:
"A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF RESPIRATORY DISORDERS"
2. Macleods Pharmaceuticals Ltd., an Indian Company, having its Registered Office at 304 - Atlanta Arcade, Opp. Leela Hotel, Marol Church Road, Andheri (East), Mumbai - 400 059, Maharashtra, India.
3. The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF THE INVENTION
The present invention relates to a novel pharmaceutical composition for the effective
treatment, prevention and/or reduction of symptoms of respiratory disorders; wherein
the pharmaceutical composition comprises a combination of therapeutically effective
amount of Eidosteinc and a Bronchodilator, or pharmaceutically acceptable salts
thereof.
BACKGROUND OF THE INVENTION
Increasing population and changing lifestyle has led to a global spread of wide range of disorders. Among these, respiratory disorders are prominently affecting population at large. Patients suffering from respiratory disorders like bronchial asthma, chronic obstructive pulmonary diseases (COPD), chronic bronchitis and related diseases are constantly increasing. Multiple drugs are available in various dosage forms for the treatment of such respiratory disorders; however there is always a need of new combinations and compositions comprising new combinations of drugs which can effectively treat the disorder or manage the symptoms.
Bronchodilators are widely used for treatment of respiratory disorders as they are safe^ easily administered to children and adults in variety of dosage forms. However bronchodilators as monotherapy give relief only for immediate symptoms of disease, not suitable for longer treatment. As a result the present inventors have combined effect of bronchodilator with other agent in order to give synergistic effects and improved treatment regimen. Bronchodilators like theophylline, acebrophylline, aminophylline, Ambroxol, Salbutamol and deriphylline are commonly used in treatment of respiratory disorders.
Acebrophylline is a theophylline analogue, obtained by salification of ambroxol base [trans-4(2-amino-3,5 dibromobenzylamino) cyclohexanol] and theophylline-7 acetic acid in a stoichiometric ratio. The Patent No. DE3425007C2 specifically discloses Acebrophylline, which is equimolar amounts of Ambroxol and Theophylline-7-acetic

acid and exhibits bronchodilator effects. Acebrophylline is commercially available and marketed in several oral dosage forms. Reportedly, several studies have suggested that Acebrophylline has multiple mechanisms, one being inhibiting phosphodiesterase enzyme and increasing cAMP causing bfonchodilation. It is chemically known as 4-[(2-amino-3,5-dibromophenyl)methylaminolcyclohexan-l-ol; 2-(l,3-dimethyl-2,6-dioxopurin-7-yl)acetic acid and represented by the structure of Formula-I as below;

Erdosteine is a mucolytic agent which helps in decreasing sputum viscoelectric
properties and bacterial adhesion to the cell membrane. The Patent No. US 4,411,909
and US 8,269,022 B2 discloses Erdosteine, its pharmaceutical composition and
polymorphs of Erdosteine, respectively. Erdosteine is commercially available and
marketed in several oral dosage forms. Reportedly, Erdosteine also endowed with
bronchial anti-inflammatory activity and a scavenging effect on free oxidant radicals.
Erdostein is a prodrug with active metabolites owing to its free thiol group.
Experimentation suggests that erdosteine metabolites can break the disulphide bonds
of mucin in bronchial secretion and hence change its rheological properties helping
to improve respiratory function. Erdosteine is chemically 2-[N-3-(2-
oxotetrahydrothienyl)]acetamido)-thioglycolic acid and structurally represented by
the structure of formula-II as below


The treatment, prevention and/or reduction of symptoms of respiratory disorders
often require monotherapy precisely using only one drug with single active
ingredient to treat an infection or disease or co-administration of two drugs with
supplemental mechanism of action. The drawbacks of multidrug therapy majorly
involves intake of greater number of pills, higher administration frequency, poor
tolerability; may lead to less significant clinical results.
The inventors of the present invention has found that the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator, wherein Erdosteine and the Bronchodilator or pharmaceutically acceptable salt thereof are present in a single dosage form, together with one or more pharmaceutically acceptable excipients. Evidently, the pharmaceutical composition provided the solution to the underlying problem, wherein the composition improves the medication compliance by reducing the pill burden of the patients and yet providing significant effect for the treatment, prevention and/or reduction of symptoms of respiratory disorders.
SUMMARY OF THE INVENTION
In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator.

In one aspect, the present invention relates to a pharmaceutical composition for the effective treatment, prevention and/or reduction of symptoms of respiratory disorders comprising therapeutically effective amount of Erdosteine and a Bronchodilator.
In another aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator; wherein Erdosteine and the Bronchodilator in the pharmaceutical composition are present in a weight ratio within the range of 1 :9-to 9:1; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients.
In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and a Bronchodilator is present in an amount of 1 to 500 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In one aspect, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 10 to 80 % w/w of total weight of composition and the Bronchodilator is present in an amount of 5 to 50 % w/w of total weight of composition; for treatment, prevention and/or reduction of symptoms of respiratory disorders.

In one aspect, the present invention relates to a pharmaceutical composition for
treatment, prevention and/or reduction of symptoms of respiratory disorders
comprising Erdosteine and Acebrophylline in a single dosage form; together with
one or more pharmaceutically acceptable excipients.
In one aspect, the present invention relates to a pharmaceutical composition
comprising a combination of therapeutically effective amount of Erdosteine and
Acebrophylline; wherein Erdosteine and Acebrophylline in the pharmaceutical
composition are present in a weight ratio within the range of 1:9 to 9:1 in a single
dosage form; for treatment, prevention and/or reduction of symptoms of respiratory
disorders.
BRIEF DESCRIPTION OF THE DRAWINGS OF THE INVENTION
Figure-1: represents dissolution profile of the formulation obtained according to
Example-1.
Figure-2: represents dissolution profile of the formulation obtained according to
Example-2.
DETAILED DESCRIPTION OF THE INVENTION
It should be understood that the following specific embodiments are to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever, in the detailed description and examples. A person of ordinary skill in the art, based upon the definitions herein, may utilize the present invention to its fullest extent. Unless otherwise as defined herein, all the technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the invention relates.

For the purpose of present invention, the term "respiratory diseases or respiratory disorders" collectively refers to, but not limited to, chronic and acute respiratory diseases and disorders like Obstructive Pulmonary Disorders (COPD), asthma, bronchitis, chronic bronchitis, pharyngitis, sinusitis, recurrence of chronic bronchitis, asthma like bronchitis allergic asthma, cough, airway blockage, obstructive bronchitis, symptomatic relief of bronchospasm, and related respiratory disorders.
For the purpose of present invention, the term 'therapeutically effective amount' refers to an amount of active pharmaceutical ingredient sufficient or composition to treat desired disease or disorder when administered alone or in combination at a reasonable effect to any medical treatment. Therefore, the term "therapeutically effective" as relates to a dose or an amount refers to that quantity of a compound or corresponding pharmaceutical composition that is sufficient to result in a desired activity upon administration to a mammal in need thereof. Thus, the term "therapeutically effective amount" refers to the quantity or dose of a compound or corresponding pharmaceutical composition that is sufficient to produce an effective response upon administration to a mammal.
For the purpose of present invention, the term "excipient(s)" or "'pharmaceutically acceptable excipients" collectively refers to inactive ingredient which is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the said active agent. The excipient(s) as used herein may include but not limited to, a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
For the purpose of present invention, the term "Bronchodilators" collectively refers to a class of agents, but not limited to, that acts on beta receptors like terbutaline and salbutamol; cholinergic receptors like ipratropium and tiotropium;

phosphodiesterases like theophylline, acebrophylline, aminophylline, Ambroxol, and deriphylline.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator.
In one aspect, the present invention relates to a pharmaceutical composition for the effective treatment, prevention and/or reduction of symptoms of respiratory disorders comprising therapeutically effective amount of Erdosteine and a Bronchodilator.
In an embodiment, the Bronchodilator used in the pharmaceutical combination of the present invention is selected from the group consisting of but not limited to Acebrophylline, Theophylline, Aminophylline, Ambroxol, Salbutamol and Deriphylline.
In an embodiment, the pharmaceutical composition of the present invention is useful for the effective treatment, prevention and/or reduction of symptoms of respiratory disorders, wherein respiratory disorders may include, but not limited to, chronic and acute respiratory diseases and disorders like Obstructive Pulmonary Disorders (COPD), asthma, bronchitis, chronic bronchitis, pharyngitis, sinusitis, recurrence of chronic bronchitis, asthma like bronchitis allergic asthma, cough, airway blockage, obstructive bronchitis, symptomatic relief of bronchospasm, and related respiratory disorders.
In another embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator; wherein Erdosteine and the Bronchodilator in the pharmaceutical composition are present in a weight ratio within the range of 1:9 to 9:1; for treatment, prevention and/or reduction of symptoms ofrespiratory disorders.

For the purpose of present invention, Erdosteine and Bronchodilator in the pharmaceutical composition are present in a weight ratio within the range of 1:9 to 9:1.
In the context of the present invention, the term "weight ratio" when used with respect to any element, for instance combination of Erdosteine-and Bronchodilator; it is intended to mean that the subject element consists of w/w (weight/weight) ratio ranging from 1:9 to 9:1 of the Erdosteine and Bronchodilator. All the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention.
In an embodiment, Erdosteine and Bronchodilator in the pharmaceutical composition are present in a weight ratio (w/w) within the range of 1:9 to 9:1
For the purpose of present invention, the pharmaceutical composition comprising a combination of Erdosteine and a Bronchodilator in a weight ratio within the range of 1:9 to 9:1 in a single dosage form, wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1,-2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 3:1, 4:1, 3:2, 4:2, 3:3,1:4, 6:2, 6:1, 5:1, 5:2 and the like.
In an embodiment, the pharmaceutical composition comprising a combination of Erdosteine and a Bronchodilator in a weight ratio within the range of 1:9 to 9:1 in a single dosage form, wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 2:1, 3:1, 4:1, 5:1, 2:1, 2:2", 2:3, 2:4, 2:5, 3:1, 3:2, 3:4, 3:4, 4:1, 4:2, 4:3, 4:5, 5:1, 5:2, 5:3, 5:4, 5:5, 6:2, 7:2, 8:3, 9:1 and the like; for treatment, prevention and/or reduction of symptoms of respiratory disorders.

In an embodiment, Erdosteine and Bronchodilator in the pharmaceutical composition are present in a weight ratio (w/w) within the range of 1:5 to-5:l; wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 1:2, 1:3, 1:4, 1:5, 2:1, 2:2, 2:3, 2:4, 2:5, 3:1, 3:2, 3:3, 3:4, 3:5, 4:1, 4:2, 4:3, 4:4, 4:5, 5:1, :2, 5:3, 5:3, 5:4 or 5:5
In an embodiment, Erdosteine and Bronchodilator in the pharmaceutical composition are present in a weight ratio (w/w) within the range of 1:3 to 3:l; wherein all the possible permutation and combination alternatives of weight ratio (w/w) are intended to be within the scope of the present invention, including but not limited to 1:1, 1:2, 1:3, 2:1,2:2, 2:3, 3:1, 3:2 or 3:3.
In yet another embodiment, Erdosteine and Bronchodilator in the pharmaceutical composition are present in a weight ratio (w/w) of 3:1.
According to a preferred embodiment of the present invention, the pharmaceutical composition comprising a combination of Erdosteine and a Bronchodilator in a weight ratio (w/w) within the range of, but not limited to 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.5, 1:2.75, 1:3.25, 1:3.5, 1:3.75, 1:4.25, 1:4.5, 1:4.75, 1:5.25, 1:5.5, 1:5.75, 1:6, 1:6.25,1:6.5, 1:6.75, 1:7,1:7.25, 1:7.5, 1:7.75, 1:8, 1: 8.25, 1:8.5, 1:8.75,1:9,1:9.25, 1:9.5, 1:9.75 2.75:1, 3.25:1, 3.5:1, 3.75:1, 4.25:1, 4.5:1 or 4.75:1.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients.
For the purpose of present invention, the Erdosteine and a Bronchodilator are present
as combination in a single dosage form.

In one embodiment, the present invention relates to a pharmaceutical composition
comprising a combination of therapeutically effective amount of Erdosteine and a
Bronchodilator in a single dosage form, together with one or more pharmaceutically
acceptable excipients, wherein Erdosteine is present in an amount of 10 to 80 % w/w
oftotal weight of composition.
In one embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 30 to 60 % w/w of total weight of composition.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Bronchodilator is present in an amount of 5 to 50 % w/w of total weight of composition.
In dne embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Bronchodilator is present in an amount of 10 to 30 % w/w of total weight of composition.
For the purpose of present invention, the term 'pharmaceutically acceptable excipients' as used herein may include but not limited to, diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.

For the purpose of present invention, the term "diluent" refers to an agent used as filler in order to achieve the desired composition volume or weight. The diluent may be used in pharmaceutical composition as single compound or mixture of compounds. Examples of the diluents used in the present invention include are but not limited to, anhydrous or hydrated lactose, starch such as potato or corn or maize starch, and pre-gelatinized starch, sucrose, mannitol, sorbitol, lactitol, cellulose, powdered or microcrystalline cellulose, calcium phosphates, dibasic calcium phosphate and the like. The diluent may be used in an amount of 0.05 to 65% by weight.
For the purpose of present invention, the term "binder(s)" used herein include, but are not limited to, cellulose and its derivatives including, ethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose (hypromellose), hydroxyethyl cellulose, carboxymethyl cellulose, copovidone, gelatin, glucose, corn or maize starch, pre-gelatinized starch, hydrocolloids, sugars, -polyvinyl pyrrolidone, sodium alginate, acacia, alginic acid, tragacanth, xanthan and the like or mixture thereof. The binders may be used in an amount of 1 to 25% by weight.
For the purpose of present invention, the term "disintegrant" used herein may include, but are not limited to, povidone, crospovidone, sodium starch glycolate, hydroxypropyl starch, microcrystalline cellulose, carboxymethylcellulose sodium or calcium, croscarmellose sodium, pregelatinized starch, polacrilin potassium, low-subslituted hydroxypropylcellulose, sodium or calcium alginate, agar, guar gum, chitosan, alginic acid and the like or mixture thereof. The disintegrants may be used in an amount of 0.1 to 50% weight.
For the purpose of present invention, the term "glidant(s)" used herein may include, but are not limited to, fumed silica (colloidal silicon dioxide), colloidal silica, powdered cellulose, talc, tribasic calcium phosphate, magnesium stearate, magnesium carbonate, and the like or mixtures thereof. The glidants may be used in an amount of 0.1 to 15% weight.

For the purpose of present invention, the term "lubricant" used herein may include, but are not limited to sodium oleate, sodium stearate, sodium benzoate, sodium chloride, stearic acid, sodium stearyl fumarate, calcium stearate, magnesium stearate, stearic acid, glyceryl distearate, magnesium lauryl sulfate, sodium stearyl fumarate, sucrose esters or fatty acid, zinc, polyethylene glycol, talc, mixtures thereof and the like; or mixture thereof. The lubricants may be used in an amount of 0.1 to 15% weight.
For the purpose of present invention, the term "sweetener" used herein may include, but are not limited to any natural or artificial sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate, aspartame, acsulfame, fructose, glucose, maltitol, sorbitol, alitame, Neotame, sucralose or mixture thereof. The sweeteners may be used in an amount of 0.05 to 10% by weight.
For the purpose of present invention, the term "preservative" used herein may include, but are not limited to benzalkonium chloride, benzethonium chloride, benzoic acid, sodium benzoate, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorbutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, sodium propionate, thimerosal, methyl paraben, ethyl paraben, propyl paraben, butyl paraben, isobutyl paraben, benzyl paraben, sorbic acid and potassium sorbate and the like or mixture thereof. The preservative may be present in an amount of 0.05 to 10% by weight.
For the purpose of present invention, the term "solvent" and "co-solvent" used herein may include, but are not limited to, water, ketones, esters,"chlorinated solvents, alcohols, which are preferably aliphatic, alkanes or mixtures thereof and the like. Specific solvent examples, may include, but are not limited to C1 - C6 compound solvents, such as acetone, methyl ethyl ketone, methanol, ethanol, isopropanol, cyclohexane and methylene chloride and the like or mixture thereof.
For the purpose of present invention, the term "stabilizer and/or surface-active agent(s)" used herein may include, but are not limited to polysorbates, polyvinyl

alcohol, hydroxypropyl methylcellulose, propylene glycol, sodium oleate and/or polyoxyethylenated sorbitan laurate, Tweens, poloxamers, blockcopolymers, SLS and the like or mixture thereof. The stabilizers may be present in an amount of 0.1 to 30% by weight.
For the purpose of present invention, the term "coating" used herein may include, but are not limited to sugar, ethyl cellulose, hydroxyl propyl methyl cellulose, acrylate polymers, polyamides (nylons), polymethacrylates, polyalkenes (polyethylene, polypropylene), bio-degradable polymers (including homo- or hetero-polymers of polyhydroxy butyric or valeric acids and homo or hetero-polymers of polylactic, polyglycolic, polybutyric, polyvaleric, and polycaprolactic acids), waxes, natural oils, other hydrophobic insoluble materials such as polydimethylsiloxane, hydrophilic materials such as cross-linked sodium carboxymethyl cellulose and cross-linked sodium or uncross-linked carboxymethyl starch and the like or mixture thereof.
For the purpose of present invention, the term "plasticizer" for use in the present invention may include, but are not limited to castor oil, and/or diethyl phthalate, and/or triethyl citrate and/or salicylic acid, glyceryl triacetate and the like or mixture thereof. The plasticizers may be present in an amount of 0.05 to 20% by weight.
Forihe purpose of present invention, the term "release modifying agent" refers to any agent which modifies the release of the active ingredient. It can be polymeric or non-polymeric. Polymeric release modifying agents may include, but are not limited to cellulose acetate phthalate, cellulose acetate trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate phthalate, polyvinyl alcohol phthalate, shellac; hydrogels and gel-forming materials, such as carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose, sodium carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl cellulose, ethyl cellulose, gelatin, starch, and cellulose based cross-linked polymers in which the degree of crosslinking is low so as to facilitate adsorption of water and expansion of the polymer matrix, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch, microcrystalline cellulose, chitin, pullulan, collagen, casein, agar,

gum arabic, sodium carboxymethyl cellulose, (swellable hydrophilic polymers) poly(hydroxyalkyl methacrylate) (molecular weight 5 k to 5000 k), polyvinylpyrrolidone (molecular weight 10 k to 360 k), anionia and cationic hydrogels, zein, polyamides, polyvinyl alcohol having a low acetate residual, a swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic anhydride and styrene, ethylene, propylene or isobutylene, pectin (molecular weight 30 k to 300 k), polysaccharides such as agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, POLYOX® polyethylene oxides (molecular weight 100 k to 5000 k), AQUAKEEP® acrylate polymers, diesters of polyglucan, crosslinked polyvinyl alcohol and poly N-vinyl-2-pyrrolidone, hydrophilic polymers such as polysaccharides, methyl cellulose, sodium or calcium carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers, methyl ethyl cellulose, ethylhydroxy ethylcellulose, cellulose acetate, cellulose butyrate, cellulose propionate, gelatin, starch, maltodextrin, pullulan, polyvinyl pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters, polyacrylamide, polyacrylic acid, natural gums, lecithins, pectin, alginates, ammonia alginate, sodium, calcium, potassium alginates, propylene glycol alginate, agar, and gums such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan, scleroglucan and mixtures and blends thereof. The polymers may be present in an amount of 0.1 to 50% by weight.
For the purpose of present invention, the term "flavouring agent" or "flavours used herein may include, natural or artificial flavours but are not limited to American Ice cream flavour, Vanillin, menthol, apple, fruity, mint, chocolate, anise oil, peppermint oil, lemongrass oil and the like or mixture thereof. The flavours may be present in an amount of 0.01 to 10% by weight.
For the purpose of present invention, the term "Suspending agents and/or thickeners" used herein may include but are not limited to microcrystalline cellulose, carboxymethyl cellulose sodium, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethyl cellulose, methylcellulose, carboxymethyl cellulose and its

salts/derivatives, and microcrystalline cellulose; carbomers; gums such as locust bean gum, xanthan gum, tragacanth gum, arabinogalactan gum, agar gum, gellan gum, guar gum, apricot gum, karaya gum, sterculia gum, acacia gum, gum arabic, and carrageenan; pectin; dextran; gelatin; polyethylene glycols; polyvinyl compounds such as polyvinyl acetate, polyvinyl alcohol, and polyvinyl pyrrolidone; sugar alcohols such as xylitol and mannitol; colloidal silica; and mixtures thereof. The suspending agent may be present in an amount of 0.1 to 20% by weight.
For the purpose of present invention, the term "buffering agent(s)" used herein may include but are not limited to citric acid, sodium citrate, sodium phosphate, potassium citrate, acetate buffer, and mixtures thereof. The buffering agents may be present in an amount of 0.001 to 5% by weight.
For the purpose of present invention, the term "Chelating agent(s)" used herein are selected from EDTA, dimercaprol. The chelating agents may be present in an amount of0.01 to 5%.
For the purpose of present invention, the term "pH adjusting agent(s)" used herein may include organic acid, inorganic acids, base but are not limited sodium hydroxide, hydrochloric acid, acetic acid, tartaric acid, sodium hhydrogen phosphate, sodium carbonate and mixtures thereof. The pH adjusting agents are added in the composition to maintain the required pH.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 10 to 80 % w/w of total weight of composition and the Bronchodilator is presen in an amount of 5 to 50 % of total weight of composition.
In an embodiment, the Erdosteine is present in an amount of 10 to 80 % w/w of total weight of composition, more preferably Erdosteine is present in an amount of 30 to 60 % w/w of total weight of composition.

In an embodiment, the Bronchodilator is present in an amount of 5 to 50 % w/w of total weight of composition, more preferably Bronchodilator is present in an amount of 10 to 30 % w/w of total weight of composition.
For the purpose of present invention, the pharmaceutical composition comprising a combination of Erdosteine in an amount of 10 to 80 % w/w and a Bronchodilator in an amount of 5 to 50 % w/w of total weight of composition in a single dosage form, together with one or more pharmaceutically acceptable excipients.
For the purpose of present invention, the pharmaceutical composition comprising of active ingredients in an amount of % w/w of total weight of composition and one or more of the excipients in an amount of % w/w of total weight of composition as depicted in below Table-1:

Table-1
Ingredient amount % w/w of total weight of composition
Erdosteine 10 to 80% w/w
Bronchodilator 5 to 50 % w/w
Diluent 0.05 to 65% w/w
Binders 1 to 25% w/w
Disintegrants 0.1 to 50% w/w
Glidants 0.1 to 15% w/w
Lubricants 0.1 to 15% w/w
Sweeteners 0.05 to 10% w/w
Preservative 0.05 to 10% w/w
Stabilizers 0.1 to 30% w/w
Plasticizers 0.05 to 20% w/w
Polymers 0.1 to 50% w/w
Flavours 0.01 to 10% w/w

Suspending agent 0.1 to 20%w/w
Buffering agents 0.001 to 5% w/w
Chelating agents 0.01 to 5% w/w
For the purpose of present invention, the terms, "formulation" or "composition" or "pharmaceutical composition" or "dosage form" as used herein include the composition is suitable for oral administration in the form of Tablets, capsules, granules, powders, pellets, spheres, mini-tablets, layered tablets, beads and particles, multiunit particulate systems (MUPS), solution, colloids, suspension, powder for reconstitution, powder for suspension, emulsions, syrups, elixirs, kit, liquid-filled capsules and/or unit dose packets and the like.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator, wherein the present invention may be formulated into various dosage forms and may exhibit different drug release profile, including but not limited to immediate-release (IR) dosage form or Modified-release (MR)-dosage form including extended-release (ER) dosage, sustained-release (SR) dosage, Controlled-release (CR) dosage, Delayed Release (DR) dosage, Long-Acting Release (LAR) dosage, Prolonged Release (PR) dosage, Pulsatile release dosage and Timed Release (TR) dosage.
For the purpose of present invention, the terms, "formulation" or "composition" or "pharmaceutical composition" or "dosage form" as used herein include the composition is suitable for oral administration, wherein composition may be administered once-daily (QD), twice-daily (BID), thrice-daily (TID), or four-times daily.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a

Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and a Bronchodilator is present in an amount of 1 to 500 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 100 to 400 mg and the Bronchodilator is present in an amount of 10 to 200 mg..
In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 300 mg and the Bronchodilator is present in an amount of 100 mg.
In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the bronchodilator is particularly selected from phosphodiesterases inhibitor.
In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the bronchodilator is Acebrophylline.
In an embodiment, a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline;

wherein Erdosteine and Acebrophylline in the pharmaceutical composition are present in a weight ratio within the range of 1:9 to 9:1 in a single dosage form; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In one embodiment, the present invention relates to a pharmaceutical composition
comprising a combination of therapeutically effective amount of Erdosteine and
Acebrophylline in a single dosage form, together with one or more pharmaceutically
acceptable excipients, wherein Erdosteine is present in an amount of 10 to 80 % of
total weight of composition and Acebrophylline is present in an amount of 5 to 50 %
of total weight of composition. _
In an embodiment, Acebrophylline is present in an amount of 5 to 50 % of total weight of composition, more preferably Acebrophylline is present in an amount of 10 to 30 % of total weight of composition.
For the purpose of present invention, the pharmaceutical composition comprising a combination of Erdosteine in an amount of 10 to 80 % and Acebrophylline in an amount of 5 to 50 % w/w of total weight of composition in a single dosage form, together with one or more pharmaceutically acceptable excipients.
For the purpose of present invention, the pharmaceutical composition comprising a combination of Erdosteine in an amount of 10 to 80 % w/w and Acebrophylline in an amount of 5 to 50 % w/w of total weight of composition in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the one or more of the excipients in an amount of % w/w of total weight of composition are selected from, but not limited to, Diluent (0.05 to 65% w/w), Binders (1 to 25% w/w), Disintegrants (0.1 to 50% w/w), Glidants (0.1 to 15% w/w), Lubricants (0.1 to 15% w/w), Sweeteners (0.05 to 10% w/w), Preservative (0.05 to 10% w/w), Stabilizers (0.1 to 30% w/w), Plasticizers (0.05 to 20% w/w), Polymers (0.1 to 50% w/w), Flavours (0.01 to 10% w/w), Suspending agent (0.1 to 20% w/w), Buffering agents (0.001 to 5% w/w), Chelating agents (0.01 to 5% w/w).

In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the bronchodilator is Ambroxol.
In one aspect, the present invention relates to a pharmaceutical composition for treatment, prevention and/or reduction of symptoms of respiratory disorders comprising Erdosteine and Acebrophylline in a single dosage form; together with one or more pharmaceutically acceptable excipients.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and Acebrophylline is present in an amount of 1 to 500 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In one aspect, the present invention relates to a pharmaceutical composition for treatment, prevention and/or reduction of symptoms of respiratory disorders comprising Erdosteine in an amount of 1 to 700 mg and Acebrophylline in an amount of 1 to 500 mg; together with one or more pharmaceutically acceptable excipients.
In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein the Acebrophylline is present in an amount of 10 to 200 mg.
In an embodiment, the pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline in a single dosage

form, together with one or more pharmaceutically acceptable excipients, wherein the Acebrophylline is present in an amount of 100 mg.
In one embodiment, the present invention relates to a pharmaceutical composition
comprising a combination of therapeutically effective amount of Erdosteine and
Acebrophylline in a single dosage form, together with one or more pharmaceutically
acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and
Ambroxol is present in an amount of 1 to 500 mg; for treatment, prevention and/or
reduction of symptoms of respiratory disorders.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline, wherein the terms, "formulation" or "composition" or "pharmaceutical composition" or "dosage form" as used herein include the composition is suitable for oral administration in the form of Tablets, capsules, granules, powders, pellets, spheres, mini-tablets, layered tablets, beads and particles, multiunit particulate systems (MUPS), solution, colloids, suspension, powder for reconstitution, powder for suspension, emulsions, syrups, elixirs, kit, liquid-filled capsules and/or unit dose packets and the like.
In one embodiment, the present invention relates to a pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline, wherein the present invention may be formulated into various dosage forms and may exhibit different drug release profile, including but not limited to immediate-release (IR) dosage form or Modified-release (MR) dosage form including extended-release (ER) dosage, sustained-release (SR) dosage, Controlled-release (CR) dosage, Delayed Release (DR) dosage, Long-Acting Release (LAR) dosage, Prolonged Release (PR) dosage, Pulsatile release dosage and Timed Release (TR) dosage.

In an embodiment, the pharmaceutical composition is a Tablet dosage form comprising Erdosteine in an amount of 10 to 80% w/w, Acebrophylline in an amount of 5 to 50% w/w; and excipients selected from not limiting to a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
In one embodiment, the present invention relates to a Tablet dosage form comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 300 mg and Acebrophylline is present in an amount of 100 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
For the purpose of present invention, the suitable methods of manufacturing a Tablet include compression of the pharmaceutical composition in the form of a powder, that may include direct compression, or compression of the pharmaceutical composition in the form of granules, and if needed with additional excipients-. The granules of the pharmaceutical composition according to the invention may be prepared by methods well-known to the one skilled in the art. Preferred methods for the granulation of the active ingredients together with the excipients include wet granulation, dry granulation, also called roller compaction.
In one embodiment, the present invention relates to a Tablet dosage form comprising
a combination of therapeutically effective amount of Erdosteine and Acebrophylline
in a single dosage form, together with one or more pharmaceutically acceptable
excipients, wherein the composition is manufactured by a process comprising steps
of,
a) Co-sifting and mixing Erdosteine, Ammophylline (or other Bronchodilator) and
one or more pharmaceutical acceptable excipients,

b) Optionally granulate step a) using binder in a mixer granulator,
c) Co-sift glidant and lubricant, add to step-a or step-b materials in a blender and mix,
d) Compress the step c) blend using compression machine, and
e) Optionally, coat the compressed tablets using coating solution;
In an embodiment, the Bronchodilators is selected from Acebrophylline, Theophylline, Aminophylline, Ambroxol, Salbutamol and Deriphylline.
For the purpose of the present invention, the dry granulation process may be performed in machinery and apparatus known to a person skilled in the art. During the dry granulation process, substantially no water or liquid is-used. Similar to the direct compression process, in the dry granulation process, the components of each step may be sieved to obtain a desired particle size of each component. Optionally, the components may be grounded prior to the sieving. Different mesh sizes of sieves in one dry granulation process. Different types of punches can be employed to prepare compressed tablets of different sizes and shapes.
For the purpose of the present invention, the wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting. The procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation. The damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill. The overall process includes weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.
For the purpose of the present invention, the direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug. The active

ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended before being compressed into tablets.
For the purpose of the present invention, the Tablet coating is accomplished by adding selected constituents to the polymer and applying such dispersion having high solids loading to pharmaceutical dosages by conventional means in a coating pan.
For the purpose of present invention, the term "flavouring agent" or "flavours used herein may include, natural or artificial flavours, as defined herein.
It is evident from the Physicochemical evaluation of the Tablets prepared as per example 1 and example 2 of the present invention, that the use of flavouring agent, preferably American ice cream flavour helps to achieve significant reduction in unpleasant odour of the Tablet.
In one embodiment, the present invention relates to a Stable pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and a Bronchodilator in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and a Bronchodilator is present in an amount of 1 to 500 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In one embodiment, the present invention relates to a Stable pharmaceutical composition comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and Acebrophylline is present in an amount of 1 to 500 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
In one embodiment, the present invention relates to a Stable Tablet dosage form comprising a combination of therapeutically effective amount of Erdosteine and

Acebrophylline in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 300 mg and Acebrophylline is present in an amount of 100 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders; and wherein the Tablet composition shows following Physicochemical parameters :
(a) Disintegration time is less than 45 minutes,
(b) Friability is less than l%w/w,
(c) Hardness of 50-400 N,
(d) Theophylline impurity is less than 2.0 %w/w, and
(e) Not less than 75% (Q) of each labelled amount is released in 45 minutes using USP dissolution apparatus II.
For the purpose of present invention physicochemical evaluation of the Tablets prepared as per example 1 and example 2 is summarized in Table-2 and Table-3 respectively.
In still another embodiment, the present invention relates to a Stable Tablet dosage form comprising a combination of therapeutically effective amount of Erdosteine and Acebrophylline in a single dosage form, together with one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in an amount of 1 to 700 mg and Acebrophylline is present in an amount of 1 to 500 mg; for treatment, prevention and/or reduction of symptoms of respiratory disorders; and wherein the Tablet is stable at 40°C ±2°C /75%RH ±5% RH at accelerated storage condition (ACC).
It is evident from the stability data study of the Tablets prepared as per example 1 and example 2 of the present invention, that the product is stable for 6 month at 40°C±2°C/75%RH±5% RH. For the purpose of present invention, the coated tablets of finalized formulation were packed in blister pack respectively. The packed tablets were charged at accelerated storage condition (ACC) (40°C±2°C/75%RH±5% RH) to evaluate the stability of the drug product.

It is evident from the stability data study of the Tablets prepared as per example 1 and example 2 of the present invention, that the product is stable for 6 month at 40°C±2°C/75%RH±5% RH, wherein the formation of Related Substances (%) impurity, precisely Theophylline impurity is less than 2.0 %w/w. For the purpose of present invention, the coated tablets of finalized formulation were packed in blister pack respectively. The packed tablets were charged at accelerated storage condition (ACC) (40°C±2°C/75%RH±5% RH) to evaluate the stability of the drug product, wherein the data shows that the Theophylline impurity is not detected (ND) even after 06 months stability.
For the purpose of present invention, there is provided dissolution profile of the formulation(s) obtained according to Example-1 and Example-2 in the instantly presented patent specification. Accordingly, Figure-1 and Figure-2 depicts graphic representation of dissolution profile of the formulation obtained according to Example-1 and Example-2, respectively. It is evident from the dissolution study of the formulation obtained from Examples 1 and Example 2, that the % drug release is more than 85% in 15 minutes. More precisely, the % drug release is more than 95% in 15 minutes.
For the purpose of present invention, two types of capsule are commonly used and are classified according to the nature and flexibility of the capsule shell: soft and hard capsules. The Soft capsules are single unit solid dosage forms comprising a liquid or semi-solid fill. It is formed, filled and sealed in one operation using a rotary die process. Similarly, the hard capsules have been conventionally used for delivery of solids in the form of powders, granulates and pellets. The Hard capsules are single unit dosage forms, consisting of a cap and a body, which are manufactured separately and which are supplied empty for filling.
The invention also provides a method of preparing an oral liquid pharmaceutical composition comprising: preparing suspending system, suspending at least one substantially insoluble pharmaceutical active in the suspending system and matching

the true density of the substantially insoluble pharmaceutical active with the specific gravity of the aqueous medium.
The Invention is further illustrated by the following examples which are provided to be exemplary of the invention, and do not limit the scope of the invention. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. These examples, which set forth the best mode presently contemplated for carrying out the invention, are intended to illustrate and not to limit the invention. Also, modifications that do not substantially affect the activity of the various embodiments of this invention are included within scope of the invention disclosed herein. Accordingly, the following examples are intended to illustrate but not to limit the scope of the present invention.
Examples:
Example 1: Tablet formulation of Erdosteine and Acebrophylline
According to the present invention there is provided a composition consisting of Erdosteine (300 mg) and Acebrophylline (100 mg), along with required ingredients.

Example 1: Tablet formulation
Ingredients Quantity in mg/Tab
Dry Mix
Erdosteine 300.00
Acebrophylline 100.00 -
Microcrystalline cellulose PH 101 78.00
Stearic acid 13.50
Povidone 35.50
Collidal silicon dioxide 22.50
Croscarmellose sodium 82.00
Solvent 869.49
Extragranular
Flavour 28.20

Glycceryl Distearate
9.00
Magnesium stearate 11.50
Coating
Hydroxypropyl methyl cellulose 13.52
Ethyl cellulose 7 cps 4.55
Triacetin BP 1.43
Hydroxypropyl methyl cellulose 7.83
Copovidone VA 64 2.83
Diethyl pthalate 2.00
Purified talc 1.76
Titanium dioxide 2.46
Weight of film coated 705.00
Manufacturing process for the formulation of example 1:

Process steps
sifting Erdosteine was sifted through # 20 sieves.
Acebrophylline was sifted through # 20 sieve
Co-sifting MCC PH 101, stearic acid, PVP k-30, colloidal silicon dioxide,
croscarmellose sodium through # 40 ASTM. Co sifting of above
through # 20 sieve.
binder solution Povidone k- 30 in suitable water to prepare the binder solution
Granulation materials were granulated
Milling material was milled through suitable screen using multimill and dried
in fluid bed drier till get desired LOD.
Dried granules of above sifted through suitable sieve and retained
granules milled through suitable screen using multimill.
Blending and For Prelubrication I , sift valina deluxe DM 11046 and Flavour
Prelubrication peppermint DM 9140 and added into blender and blended it for 5
minutes
For Prelubrication II, Sifting of CCS and Aerosil through # 40 and
added into blender and blended it for 5 minutes.

Sifting of Glyceryl distearate and magnesium stearate through # 60
and added into blender and blended it for 3 minutes.
Compression Pack the lubricated blend in triple laminated pack-and compression
and packing done .
Seal coating- Seal coating solution prepared and coat the tablets
Check the parameters for seal coated tablets .and then film coating
performed and check the film coated tablets parameters.
Table-2 ; Physicochemical evaluation of the Tablets prepared as per example 1:

Table-2
Parameters Observation
Core Tablets
Average Weight (mg) 663.00
Weight variation (mg) 662.7-664.5
Hardness (N) 115-142
Friability (%) 0.09
Disintegration time 5 to 6 min
Weight of seal coated tablets 678.00
Disintegration time 7 to 8 min
Weight of coated tablets 705.00
Dissolution
Medium: 0.1 N HC1,900 ml, Apparatus: USP II (Paddle), 75 rpm, 45 minutes.
Time Points (minutes) % drug dissolved
Erdosteine Acebrophylline
0 0 0
10 95.8 98.9
15 97.5 101.0

30
94.6 100.4
45 95.6 100.0
Assay 98.8 98.0
Observation Flow of granules improved, sticking for tablets was not observed, sticking resolved.
Conclusion By using American ice cream flavour, the tablets' unpleasant odor was reduced.
Example 2: Tablet formulation of Erdosteine and Acebrophylline
According to the present invention there is provided a composition consisting of Erdosteine (300 mg) and Acebrophylline (100 mg), along with required ingredients.

Example 2: Tablet formulation
Ingredients Quantity in mg/Tab
Dry Mix
Erdosteine 300.00
Acebrophylline 100.00
Microcrystalline cellulose PH 101 78.00
Stearic acid 13.50
Povidone 35:50
Collidal silicon dioxide 22.50
Croscarmellose sodium 82.00
Water 869.49
Extragranular
Flavour 28.20
Glycceryl Distearate 9.00
Magnesium stearate 11.50
Coating —
Hydroxypropyl methyl cellulose 13.52
Ethyl cellulose 7 cps 4.55
Triacetin BP 1.43
Hydroxypropyl methyl cellulose 7.83
Copovidone VA 64 2.86
Diethyl pthalate 2.00

Purified talc
1.76
Titanium dioxide 2.46-
Weight of film coated 705.00
Manufacturing process for the formulation of example 2:

Process steps
sifting Erdosteine was sifted through # 20 sieves.
Acebrophylline was sifted through # 20 sieve
Co-sifting MCC PH 101, stearic acid, PVP k-30, colloidal silicon dioxide,
croscarmellose sodium through # 40 ASTM. Co sifting of above
through # 20 sieve.
binder solution Povidone k- 30 in suitable water to prepare the binder solution
Granulation materials were granulated
Milling material was milled through suitable screen using multimill and dried
in fluid bed drier till get desired LOD.
Dried granules of above sifted through suitable sieve and retained
granules milled through suitable screen using multimill.
Blending and For Prelubrication I , sift valina deluxe DM 11046 and Flavour
Prelubi ication peppermint DM 9140 and added into blender and blended it for 5
minutes
For Prelubrication II, Sifting of CCS and Aerosil "through # 40 and
added into blender and blended it for 5 minutes.
Sifting of Glyceryl distearate and magnesium stearate through # 60
and added into blender and blended it for 3 minutes.
Compression Pack the lubricated blend in triple laminated pack and compression
and packing done.
Seal coating- Seal coating solution prepared^and coat the tablets
Check the parameters for seal coated tablets .and then film coating
performed and check the film coated tablets parameters.

Table-3 : Phvsicochemical evaluation of the Tablets prepared as per example 2:

TabIe-3
Parameters Observation
Core Tablets
Average Weight (mg) 663.00
Weight variation (mg) 661.3-663.4
Hardness (N) 111-138
Friability (%) 0.09
Disintegration time 5 to 6 min
Weight of seal coated tablets 678.00
Disintegration time 7 to 8 min
Weight of coated tablets 705.00
Disintegration time 8 to 9 min
Dissolution -
Medium: 0.1 N HC1, 900 ml,A pparatus: USP II (Paddle), 75 rpm i, 45 minutes.
Time Points (minutes) % drug dissolved
Erdosteine Acebrophylline
0 0 0
10 96.4 _ 99.2
15 97.8 100.2
30 96.7 100.7
45 96.8 100.3
Assay 100.0 98.2

Observation Granule flow increased, tablet-sticking was not seen, and sticking was removed.
Conclusion By using American ice cream flavour, the tablets' unpleasant odor was reduced.
Example 3 : Stability data of the Tablets formulation prepared as per example 1 and example 2:
The coated tablets of finalized formulation were packed in blister pack respectively. The packed tablets were charged at accelerated storage condition (ACC) (40°C±2°C/75%RH±5% RH) to evaluate the stability of the drug product.
The obtained stability results are summarized as follows:
Pack: Alu-Alu Blister
Storage Condition: 40°C±2°C/75%RH±5% RH (ACC)

Sr.
No.
Parameters Specification Example 1 Example 2

Initial 3 Months 6 Months Initial 3 Months 6 Months
i. Description # Complies Complies Complies Complies Complies Complies
2. Assay (%) Erdosteine
- % label claim NLT 90.0%
and NMT
110.0% 99.7 100.2 99.5 100.0 99.1 98.5

Acebrophylline
- % label claim
98.1 99.2 99.7 98.2 99.1 99.4

Dissolution (%)
0.1N HC1, volume-
900ml,paddle- II, Not less than 95.6 96.8 97.5 96.8 97.3 98.1
3. speed 75 ,time 45 70%(Q)of -

minutes labeled
Erdosteine
- % label claim amount

- Acebrophyllin e
100.0 100.2 99.4 100.3 98.4 97.3
- % label claim •
Related Substances (%)

Theophylline NMT 0.2 ND ND ND - ND ND ND

Any individual
4. Unknwon impurity NMT 0.2 0.07 0.09 0.11 0.08 0.09 0.08

Total Unknown impurities NMT 2.0 0.27 0.35 0.32 0.29 0.31 0.32
# White to off white colored, capsule shaped, biconvex film coated tablets having plain surface on both sides.
NMT: Not more than, ND- Not detected. (ACC) - 40°C±2°C/75%RH±5% RH
f
Conclusion : The above data indicates that the product is stable for 6 month at 40°C±2°C/75%RH±5% RH

We claim
1. A pharmaceutical composition comprising a combination of therapeutically
effective amount of Erdosteine and a Bronchodilator;
wherein Erdosteine and the Bronchodilator in the pharmaceutical composition are present in a weight ratio within the range of 1:9 to 9:1; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
2. The pharmaceutical composition of claim 1, wherein the Bronchodilator is selected from Acebrophylline, Theophylline, Aminophylline, Ambroxol, Salbutamol and Deriphylline.
3. The pharmaceutical composition of claim 1, wherein Erdosteine is present in an amount of 10 to 80 % w/w of total weight of composition.
4. The pharmaceutical composition of claim 1, wherein Bronchodilator is present in an amount of 5 to 50 % w/w of total weight of composition.
5. The pharmaceutical composition of claim 1, wherein Erdosteine is present in an amount of 1 to 700 mg in the composition.
6. The pharmaceutical composition of claim 1, wherein Bronchodilator is present in an amount of 1 to 500 mg in the composition.
7. The pharmaceutical composition of claim 1, wherein respiratory disorders are selected from chronic and acute respiratory disorders as Obstructive Pulmonary Disorders (COPD), asthma, bronchitis, chronic bronchitis, pharyngitis, sinusitis, recurrence of chronic bronchitis, asthma, bronchitis allergic asthma, cough, airway blockage, obstructive bronchitis, symptomatic relief of bronchospasm, and related respiratory disorders.

8. The pharmaceutical composition of claim 1, wherein Erdosteine and the
Bronchodilator or pharmaceutically acceptable salt thereof are present in a single
dosage form, together with one or more pharmaceutically acceptable excipients.
9. The pharmaceutical composition of claim 1 or claim 8, wherein the composition is
suitable for oral administration in the form of Tablets, capsules, granules, powders,
pellets, spheres, mini-tablets, layered tablets, beads and particles, multiunit
particulate systems (MUPS), solution, colloids, suspension, powder for
reconstitution, powder for suspension, emulsions, syrups, elixirs, kit, liquid-filled
capsules and/or unit dose packets.
10. The pharmaceutical composition of claim 1 or claim 8, wherein composition may be in the form of immediate-release (IR) dosage form or Modified-release (MR) dosage form including extended-release (ER) dosage, sustained-release (SR) dosage, Controlled-release (CR) dosage, Delayed Release (DR) dosage, Long-Acting Release (LAR) dosage, Prolonged Release (PR) dosage, Pulsatile release dosage and Timed Release (TR) dosage.
11. The pharmaceutical composition of claim 1 or claim 8, wherein composition may be administered once-daily (QD), twice-daily (BID), thrice-daily (TID), or four-times daily.
12. The pharmaceutical composition of claim 1 or claim 8, wherein the
pharmaceutical composition comprising a combination of therapeutically effective
amount of Erdosteine and a Bronchodilator in a single dosage form, together with
one or more pharmaceutically acceptable excipients, wherein Erdosteine is present in
an amount of 1 to 700 mg and a Bronchodilator is present in an amount of 1 to 500
mg.
13. A pharmaceutical composition comprising Erdosteine in an. amount of 1 to 700
mg and Acebrophylline in an amount of 1 to 500 mg in a single dosage form;

together with one or more pharmaceutically acceptable excipients; for treatment, prevention and/or reduction of symptoms of respiratory disorders.
14. The pharmaceutical composition of claim 13, wherein the composition is suitable for oral administration in the form of Tablets, capsules, granules, powders, pellets, spheres, mini-tablets, layered tablets, beads and particles, multiunit particulate systems (MUPS), solution, colloids, suspension, powder for reconstitution, powder for suspension, emulsions, syrups, elixirs, kit, liquid-filled capsules and/or unit dose packets.
15. The pharmaceutical composition of claim 13, wherein the composition is a Tablet dosage form comprising Erdosteine in an amount of 10 to 80% w/w, Acebrophylline in an amount of 5 to 50% w/w in a single dosage form; along with one or more excipients selected from a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents, suspending agents, filers or their combination.
16. The pharmaceutical composition of claim 13, wherein the composition is a Tablet dosage form comprising Erdosteine in an amount of 300 mg, Acebrophylline in an amount of 100 mg in a single dosage form; along with one or more excipients selected from a diluent, binder, disintegrant, glidant, lubricant, diluent, flavouring agent, coating material, release modifying agents, sweetener, preservative, solvent, co-solvant, stabilizer, colourant, film forming polymer, plasticizer, anti-caking agent, vehicle, surfactants, stabilizers, antioxidants, tonicity agents^ suspending agents, filers or their combination.
17. The pharmaceutical composition of claim 16, wherein the tablet composition has

(a) Disintegration time is less than 45 minutes,
(b) Friability is less than l%w/w,

(c) Hardness of 50-400 N,
(d) Theophylline impurity is less than 2.0 %w/w, and
(e) Not less than 75% (Q) of each labelled amount is released in 45 minutes using USP dissolution apparatus II.
18. The pharmaceutical composition of claim 12 or claim 16 wherein the composition is manufactured by a process comprising steps of,
(a) Co-sifting and mixing Erdosteine, Bronchodilator and one or more
pharmaceutical acceptable excipients,
(b) Optionally granulate step a) using binder in a mixer granulator,
(c) Co-sift glidant and lubricant, add to step-a or step-b materials in a blender and mix,
(d) Compress the step c) blend using compression machine, and
(e) Optionally, coat the compressed tablets using coating solution;
wherein Bronchodilators is selected from Acebrophylline, Theophylline, Ammophylline, Ambroxol, Salbutamol and Deriphylline.