WO2011146031A1

WO2011146031A1 - Pharmaceutical composition comprising n- acetylcysteine and a xanthine

Info

Publication number: WO2011146031A1
Application number: PCT/TR2011/000110
Authority: WO
Inventors: Bilgic Mahmut
Original assignee: Bilgic Mahmut
Priority date: 2010-05-18
Filing date: 2011-05-16
Publication date: 2011-11-24
Also published as: EP2571499A1

Abstract

The present invention relates to pharmaceutical formulations prepared by combining N- Acetylcysteine which is a mucolytic agent and a xanthine derivative compound; the methods for preparation of said formulations and their use in the treatment of respiratory tract diseases.

Description

PHARMACEUTICAL COMPOSITION COMPRISING N-ACETYLCYSTEINE

Respiratory tract diseases are among the leading diseases threatening human health. Chronic obstructive pulmonary disease (COPD) is accepted as a serious health problem all over the world. COPD which is a chronic pulmonary disease narrowing respiratory tract and inhibiting smooth inhalation and exhalation of people ranks fourth in terms of mortality rates in the world. Allergic rhinitis, on the other hand, is allergy-induced inflammation of nasal mucosa. Allergic rhinitis is not a life-lxeatining disease but it substantially affects life quality of people. Therefore, it should be diagnosed easily and treated effectively.

The present invention relates to a pharmaceutical composition comprising N-Acetylcysteine (which will henceforward be called 'NAC') or a pharmaceutically acceptable salt thereof and a xanthine derivative compound or a pharmaceutically acceptable salt thereof. The invention also relates to use of said pharmaceutical composition in respiratory tract diseases, chronic obstructive pulmanory disease (COPD), allergic rhinitis, acute or chronic bronchitis, expectoration and reduction of phlegm caused by catarrh and cold, cases requiring to ease expectoration, pulmonary diseases, bronchopulmonary diseases, bronchial secretion disorders.

NAC (Formula I) is an N-acetylated derivative of L-cysteine and an agent used as mucolytic.

N-Acetylcysteine Due to sulfhydryl group in its structure, NAC breaks disulphide bonds in mucoproteins which are located in the bronchus secretory. Thus, volume of mucus secretion in the pulmonary is reduced.

N-Acetylcysteine, which has the chemical name N-acetyl-L-cysteine, is described in the patent numbered US 3 , 184,505 in detail.

Xanthine compounds are in the alkaloid group and they are also purine bases. Methyl xanthines are potent compounds used in the treatment of chronic obstructive pulmonary disesase (COPD) and other respiratory tract diseases.

The compounds of methylxanthine group are compounds such as theophylline and doxophylline, caffein, acepifylline, bamiphylline, bufylline, cafaminol, cafedrine, diprophylline, dihydroxypropyl theophylline, enprofylline, etamiphylline, etophyline, proxyphylline, suxamidofylline, theobromine, furafylline, 7-propyl-meophylline-doparnine, 3- isobutyl-1 -methylxanthine, torbaphylline, pentoxifylline, reproterol, denbufylline, arophylline and cymaphylline. Doxophylline {Formula II), which has the chemical name 7-(l,3-dioxolan-2-ylmethyl)-3,7- dmydro-l,3-dimethyl-lH-purine-2,6-dione is described in the patent numbered US 4,187,308.

doxophylline

Doxophylline is a methylxanthine compound which is known with its bronchial and antitussive activity. In addition, it is effective in indications of bronchospasm, obstructive chronic bronchitis and spasmodic cough.

Theophylline (Formula III) is a methylxanthine derivative. Theophylline, which has the chemical name 3,7-Dihydro-l,3-dimethyl-lH-purine-2,6-dione, is disclosed in Traube, Ber. 33,3035 in 1900.

theophylline

Theophylline is rather effective as a bronchodilator. In addition, it induces anti-imflammatory and immunomodulator effects. It causes loosening in bronchus smooth muscles and pulmonary blood vessels and relieves smooth muscle spasm.

It has been disclosed in the patent numbered US 4,187,308 that doxophylline shows bronchial and anti-tussive activity. Methyl xanthines compounds which are xanthine derivatives are indicated in diseases such as bronchopulmonary diseases, bronchospasm, obstructive chronic bronchitis and spasmodic cough. However, it may not be enough to use a xanthine compound alone for removing the symptoms observed in respiratory tract diseases such as acute and chronic bronchopulmonary, COPD, allerginic rhinitis and bronchitis.

When the prior art is taken into consideration, there is need for novel pharmaceutical compounds which will be used in the treatment of respiratory tract diseases and yield more effective and precise results in comparison with existing therapies.

The inventors have surprisingly obtained a more advantageous mucolytic effect by combining NAC and xanthine derivative compounds and found that the treatment in which the combination of the present invention is administered induces greater therapeutic benefit in comparison with the treatment in which said active ingredients are administered separately. In another aspect, the inventors have found the use of xanthine derivative compounds in combination with N-Acetylcysteine that is a mucolytic agent both for the treatment of said diseases; expectoration and reduction of phlegm caused by these diseases and easing expectoration provides positive therapeutic effect.

In another aspect, use of NAC and xanthine derivative compounds in combination both constitutes an alternative and effective method in the treatment of bronchopulmanory diseases and provides reduction and expectoration of phlegm observed as a consequence of bronchopulmonary diseases and easing expectoration. Furthermore, it removes the difficulty of taking more than one drug for people who are diagnosed with said diseases.

The present invention is related to use of N-Acetylcysteine (NAC) in combination with xanthine derivative compounds.

The present invention also comprises use of NAC in combination with methylxanthine compounds.

In another aspect, the composition of the present invention can optionally comprise pharmaceutically acceptable excipients. According to the present invention, methylxanthine derivative compounds used in the pharmaceutical composition can be selected from the group comprising theophylline and doxophylline, caffein, acepifylline, bamiphylline, bufylline, cafaminol, cafedrine, diprophylline, dihydroxypropyl theophylline, enprofylline, etamiphylline, etophyline, proxyphylline, suxamidofylline, meobrornine, furafylline, 7-propyl-meophyllme-dopamine, 3- isobutyl-1 -methylxanthine, torbaphylline, pentoxifylline, reproterol, denbufylline, arophylline and cymaphylline.

In another aspect, the inventors have found that use of theophylline or doxopylline as a xanthine derivative compound in the pharmaceutical formulations of the present invention is more effective in the treatment of abovementioned diseases. In the present invention, the active agents of the said combination can be in free form or in the form of pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms and amorphous form thereof.

In another aspect, the composition of the present invention can be used simultaneously, sequentially or seperately for reducing the symptoms of respiratory tract diseases or slowing the progression of the disease.

According to the present invention; the combination of NAC and the xanthine derivative compounds can be used in the treatment of respiratory tract diseases, chronic obstructive pulmanory disease (COPD), allergic rhinitis, acute or chronic bronchitis, reduction and expectoration of phlegm caused by catarrh and cold, cases requiring to ease expectoration, pulmonary diseases, bronchopulmonary diseases, disorders of bronchial secretion. In another aspect, the compositions of the invention can be prepared as a drug composition for administration on mammals including humans in the treatment of respiratory tract diseases, chronic obstructive pulmanory disease(COPD), allergic rhinitis, acute or chronic bronchitis, reduction and expectoration of phlegm caused by catarrh and cold, cases requiring to ease expectoration, pulmonary diseases, bronchopulmonary diseases, disorders of bronchial secretion.

In another aspect, the present invention relates to a pharmaceutical composition which will be used for production of an effective medicament so as to be utilized in the treatment of respiratory tract diseases wherein said composition is characterized by comprising NAC and a xanthine derivative compound as active agents.

In another aspect, it is targeted to reduce symptoms of respiratory tract diseases, slow the progression of the disease and treat the disease by means of pharmaceutical compositions in which effective amounts of NAC and effective amounts of xanthine derivative compounds and sufficient amounts of excipient/excipients are combined. The phrase "reduction of the symptoms" refers to reducing the number of the symptoms observed in people who are diagnosed with said disease by means of administering the pharmaceutical composition comprising the combination of NAC and a xanthine derivative compound to diagnosed people. The phrase "slowing the progression of the disease" refers to administration of the pharmaceutical composition comprising the combination of NAC and a xanthine derivative compound to people who are diagnosed with said disease and/or in the first phase of said disease. The phrase "treatment of the disease" refers to removing present problems related to the disease by administering the pharmaceutical composition comprising the combination of NAC and a xanthine derivative compound to people who are diagnosed with said disease and in any phases of the disease. In another aspect, the composition of the present invention can be administered simultaneously, sequentially or seperately so as to be used in the treatment of respiratory tract diseases.

In another aspect, the active agents in the composition pertaining to the present invention can be formulated seperately in order to be used in a kit form where they are placed together. In the present invention, it has been observed that a more effective use is provided by formulating the combination comprising NAC and a xanthine derivative compound in the same dosage form.

In another aspect, the amount of the active agent in the composition of the present invention varies in the range of 0.5% to 95%, preferably in the range of 1% to 90% by weight with respect to total amount of the pharmaceutical composition. In addition, dosage of the active ingredient/ingredients in the pharmaceutical composition can vary according to the route of application, the patent's age and state of health.

In another aspect, the pharmaceutical composition of the present invention can comprise NAC in the range of 1% to 50%, preferably 1 % to 40 %, more preferably 1 % to 30% and a xanthine derivative compound in the range of 1 % to 40 %, preferably 1 % to 30 % and more preferably 1 % to 20 %.

In another aspect, the pharmaceutical composition of the present invention can comprise NAC in the range of 0.1 mg to 2000 mg and a xanthine derivative compound in the range of 0.1 mg to 800 mg .

According to the invention, the active agent NAC in the composition pertaining to the present invention is preferably in doses of 200, 600, 900, 1200 mg and xanthine derivative compounds are preferably in doses of 200, 400 mg.

In another aspect, the ratio of NAC to the xanthine derivative compounds in the composition pertaining to the present invention varies in the range of 8: 1 to 0.2:1, preferably 6:1 to 0.5:1 by weight.

In another aspect, the pharmaceutical composition pertaining to the present invention can be prepared as applicable by the oral or the inhalation route.

The pharmaceutical compositions of the present invention comprises oral dosage forms, inhalation dosage forms and pharmaceutical formulations comprising the active agents alone or together with pharmaceutically acceptable excipients.

According to the present invention, the oral dosage forms can be prepared in solid forms such as tablet; capsule; enteric coated or modified release tablet; prolonged release tablet; delayed release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; granule; pellet; minitablet; microtablet; granule capsule, pellet capsule, minitablet capsule, microtablet capsule; dry powder mixture for syrups; dragee; orally disintegrated tablets; water-soluble powder, tablet or granule; film tablet or solid forms comprising their combination, and in liquid forms such as suspensions. Inhalation dosage forms can be prepared as dry powder formulation, aerosol, suspension and/or solution. The pharmaceutically acceptable excipients can also be used in addition to the active agents used in the formulation of the present invention. These excipients are additives such as at least one pharmaceutically acceptable sweetener and/or flavoring agent and optionally stabilizing agent, diluent, binder, disintegrant, lubricant, an effervescent acid and an effervescent base, solvent or solvent mixtures, glidant and surfactant. Pharmaceutically acceptable sweeteners can be selected from a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythntol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulfame potassium, aspartam, D-tryptophane, monoammonium glycyrrhizinate, neohesperidine dihyrochalcon, thaumatin, neotam, alitam, stevioside and cyclamates. The amount of the sweetener used in the formulations is in the range of 0.1 % to 10, preferably 0.1% to 0.5 % by weight.

Pharmaceutically acceptable flavoring agents can be selected from natural aroma oils (such as peppennint oil, oil of wintergreen, clove bud oil, parsley oil, eucalyptus oil, lemon oil, orange oil), menthol, menthane, anethole, methyl salicylate, eucalyptol, cinnamon, 1 -methyl acetate, sage, eugenol, oxanone, alpha-irison, marjoram, lemon, orange, propenyl guaetol acetyl, cinnamon, vanilla, thymol, linalol, cinnamaldehide glycerole acetal, N-substituted p- menthane-3-carboxamide, 3,1-methoxy propane 1,2-diol. The amount of the flavoring agents used in the formulations is in the range of 0.1 % to 10, preferably 0.1% to 0.5 % by weight.

Stabilizing agent/agents can be selected from chelating agents and alkalinizing agents. Chelating agents can be selected from the group comprising disodium EDTA, edetic acid, citric acid, sodium citrate, potassium citrate or combinations thereof.

Alkalinizing agents can be selected from alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen orthophosphate, sodium aluminate; alkaline earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines, Ν,Ν'- dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacryline sodium, sodium alginate. Pharmaceutically acceptable diluents can be selected from the group comprising lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactilol, powder cellulose, dextrose, dextrate, dextrine, sucrose, maltose, fructose, mannitol, sorbitol ve xylitol. The amount of diluents which can be used in the formulations is in the range of 0.1 % to % 80, preferably 0.1% to 70 % by weight.

Pharmaceutically acceptable binders can be selected from the group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums (such as acacia); gelatin; cellulose derivatives (such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose, ethyl cellulose); polyvinylpyrrolidone (PVP), polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols (such as sorbitol, xylitol, mannitol) and water. The amount of binders which can be used in the formulations is in the range of 0.1 % to % 30, preferably 0.1% to 20 % by weight. Pharmaceutically acceptable effervescent bases can be selected from the group comprising sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate or combinations thereof. In the case that the formulation of the present invention is in effervescent form, the amount of the effervescent base used in the formulations is in the range of 10 % to 80%, preferably 10 % to 60 %, more preferably 20 % to 60% by weight.

Pharmaceutically acceptable effervescent acids can be selected from the group comprising water soluble polybasic organic acids or their salts, hydrates or anhydrous forms such as sodium hydrogen sulphate, potassium hydrogen sulphate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, citric acid, citric acid anhydrous or combinations thereof. In the case that the formulation of the present invention is in effervescent form, the amount, the amount of the effervescent acid used in the formulations is in the range of 10 % to 80%, preferably 10 % to 60 %, more preferably 20 % to 50% by weight.

Pharmaceutically acceptable lubricants can be selected from the group comprising metallic stearates (e.g. magnesium stearate, calcium sterate, aluminium stearate), fatty acid esters (e.g. sodium stearil fumarate), fatty acids (e.g. stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (e.g. sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc. The amount of the lubricant used in the formulations is in the range of 0.1 % to 10%, preferably 0.1 % to 5 %. Pharmaceutically acceptable disintegrants can be selected from the group comprising starches such (corn starch, potato starch); sodium starch glicolate; pregelatinized starch; cellulose derivatives (e.g. croscarmellose sodium or microcyrstalline cellulose); polyvinylpyrrolidone (PVP); crospovidone; alginic acid; sodium aginate; clays (e.g. xanthangum or Veegum) or combinations thereof. Pharmaceutically acceptable glidants can be selected from the group comprising silicone dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates.

Pharmaceutically acceptable surfactants can be selected from the group comprising polyoxyethylene-sorbitan-fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearil fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, aminoacids such as L-leucine, sugar esters of fatty acids and glycerides of fatty acids.

Pharmaceutically acceptable solvents can be selected from the group comprising toluene, benzene, acetone, methyl acetate, tetrahydrofurane, heptanes, hexane, acetonitrile, alcohol and/or alcohol mixtures or combinations thereof.

In addition to these, other pharmaceutically acceptable excipients such as solubility modulators, coloring agents, coating agents can be used in the formulation. According to the present invention, pharmaceutical compositions can be formulated preferably in the form of water-soluble powder, tablet or granule. More preferred form is effervescent form.

The absorption ant thus the bioavailability of the pharmaceutical formulation from the gastrointestinal tract increases when it is formulated in an effervescent dosage form.

In addition, effervescent dosage forms are also advantageous in respect to easy use and addressing the wide range patient profile.

However, the inventors have found as a result of the studies within the scope of the invention that xanthine derivative compound does not dissolve in water sufficiently and thus there are some difficuties in the manufacture of effervescent formulations. This solubility problem is solved with a new manufacturing method which has been developed according to the present invention.

The characteristic feature of said method is that it is carried out as wet granulating the xanthine derivative compound after optionally mixing it with another excipient. Xanthine derivative compound is mixed with at least one effervescent acid and at least one effervescent base. According to the invention, preffered effervescent acid is citric acid or derivative thereof and preffered effervescent base is sodium hydrogen carbonate.

Another characteristic feature of said method is that this is carried out as wet granulating the xanthine derivative compound after mixing it with at least one pharmaceutically acceptable effervescent acid and at least one effervescent base. The ratio of effervescent acid and effervescent base herein is 0.1 to 5, preferably 0.1 to 4, more preferably 0.1 to 3.

Another characteristic feature of said method is that this is carried out as wet granulating the xanthine derivative compound after mixing it with at least one pharmaceutically acceptable effervescent acid and at least one effervescent base and adding pharmaceutically acceptable amount of NAC and optionally at least one sweetener, glidant and flavoring agent to the obtained granules so as to manufacture the final granules.

Another characteristic feature of said method is that the granulation solution comprises at least one pharmaceutically acceptable binder, at least one solvent or solvent mixture and deionized water. The pharmaceutically acceptable solvent in the granulation solution is preferably alcohol derivative and it composes at least 50 % by weight of the granulation preferably alcohol derivative and it composes at least 50 % by weight of the granulation solution. The amount of pharmaceutically acceptable binder in the granulation solution is 1 %-30% by weight.

The solubility of the xanthine derivative compound in the effervescent product manufactured by this method has been succesfully provided.

The combination of the present invention and the pharmaceutical compositions comprising said combination and their preparation methods can be explained with the help of following examples, but the invention should not be limited to these examples.

EXAMPLES

Example 1:

The active agents N-Acetylcysteine and theophylline can be formulated as a pharmaceutical composition by the conventional techniques in the prior art. Thereafter the homogenous mixture obtained is dried and shaped as required.

EXAMPLE II:

The active agents N-Acetylcysteine and doxophylline can be formulated as a pharmaceutical composition by the conventional techniques in the prior art. Thereafter the homogenous mixture obtained is dried and shaped as required.

EXAMPLE III.

*s.a: sufficient amount

The method for manufacturing the effervescent doxofylline and NAC formulation given above is as follows:

1. The granulation solution is prepared by mixing sufficient amount of deionized water, ethyl alcohol and binder,

2. Doxofylline, the effervescent acid and the effervescent base are sieved and mixed,

3. The mixture obtained from the second step is wet granulated with the granulation solution obtained by the first step,

4. The granules are dried and sieved,

5. NAC, sweetener, flavoring agent and lubricant are added to the sieved granules and mixed again,

6. The mixture is optionally tablet pressed.

Claims

1. A pharmaceutical composition charactarized in that N- Acetylcysteine and a xanthine derivative compound are used in combination.

2. The composition according to claim 1 characterized in that the xanthine derivative compound is a methylxanthine compound.

3. The composition according to claim 2 characterized in that the methylxanthine compounds can be selected from the group comprising theophylline and doxophylline, caffein, acepifylline, bamiphylline, bufylline, cafaminol, cafedrine, diprophylline, dihydroxypropyl theophylline, enprofylline, etamiphylline, etophyline, proxyphylline, suxamidofylline, theobromine, furafylline, 7-propyl-theophylline-dopamine, 3- isobutyl-1 -methylxanthine, torbaphylline, pentoxifylline, reproterol, denbufylline, arophylline and cymaphylline.

4. The composition according to claim 3 characterized in that the memylxanthine compound is theophylline or doxophylline.

5. The composition according to claim 1, wherein the active agents composing the composition can be in free form or in the form of pharmaceutically acceptable salts, enantiomers, racemates, solvates, hydrates, different polymorphic forms and amorphous forms thereof.

6. The composition according to claim 1 characterized in that said composition comprises pharmaceutically acceptable excipients in addition to the combination of N- Acetylcysteine and a xanthine derivative compound.

7. The pharmaceutical composition according to claim 1 characterized in that said composition is used for the treatment of respiratory tract diseases.

8. The pharmaceutical composition according to claim 1, wherein said composition is used in the treatment of respiratory tract diseases; chronic obstructive pulmanory disease (COPD), allergic rhinitis, acute and chronic bronchitis, reduction and expectoration of phlegm caused by catarrh and cold, cases requiring to ease expectoration, pulmonary diseases, bronchopulmonary diseases, disorders of bronchial secretion.

9. The pharmaceutical composition according to claim 1 characterized in that the components composing the composition can be used simultaneously, sequentially or seperately.

10. The pharmaceutical composition according to claim 1, wherein the components composing to the composition can be formulated seperately to be used in a kit form where they are placed together.

11. The pharmaceutical composition according to claim 1 characterized in that the components composing the pharmaceutical composition are formulated to be in the same dosage form.

12. The pharmaceutical composition according to claim 1 characterized in that said composition can be administered by the oral route or the inhalation route.

13. The pharmaceutical composition according to claim 1 characterized in that the composition can be prepared as tablet; capsule; enteric coated or modified release tablet; prolonged release tablet; delayed release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; granule; pellet; minitablet; microtablet; granule capsule, pellet capsule, minitablet capsule, microtablet capsule; dry powder mixture for syrups; dragee; orally disintegrated tablets; water-soluble powder, tablet or granule; film tablet or the solid forms comprising their combination; liquid forms such as suspensions or dry powder formulation, aerosol, suspension and/or solution.

14. The pharmaceutical composition according to claim 13 characterized in that the composition can be formulated as water-soluble powder, tablet or granule.

15. The pharmaceutical composition according to claim 6 characterized in that the composition comprises at least a pharmaceutically acceptable sweetener and/or flavoring agent and optionally a stabilizing agent, diluent, binder, disintegrant, lubricant, glidant and surfactant as excipients.

16. The pharmaceutical composition according to claim 15 characterized in that the stabilizing agent used in said composition is selected from chelating agents and alkalinizing agents.

17. The pharmaceutical composition according to claim 16 characterized in that the chelating agent is selected from a group comprising disodium EDTA, edetic acid, citric asid, sodium citrate, potassium citrate or combinations thereof.

18. The pharmaceutical composition according to claim 16 characterized in that the alkalinizing agent is selected from a group comprising alkali metal salts such as sodium carbonate, sodium hydrogen carbonate, sodium hydroxide, sodium silicate, disodium hydrogen ortophosphate, sodium aluminate; alkaline-earth metal salts such as calcium carbonate, calcium hydroxide, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium acetate, calcium gluconate, calcium glycerophosphate, magnesium carbonate, magnesium hydroxide, magnesium sulphate, magnesium acetate, magnesium silicate, magnesium aluminate; and organic compounds such as primary, secondary and tertiary amines, cyclic amines, Ν,Ν'- dibenzylethylenediamine, diethanolamine, ethylenediamine, meglumine, monosodium glutamate, polacryline sodium, sodium alginate.

19. The pharmaceutical composition according to claim 15 characterized in that the diluent used in said composition is selected from the group comprising lactose, microcrystalline cellulose, starch, pregelatinized starch, modified starch, calcium phosphate (dibasic and/or tribasic), calcium sulphate trihydrate, calcium sulphate dihydrate, calcium carbonate, kaolin, lactitol, cellulose powder, dextrose, dextrates, dextrine, sucrose, maltose, fructose, mannitol, sorbitol ve xylitol.

20. The pharmaceutical composition according to claim 15 characterized in that the binder used in said composition is selected from the group comprising starches (potato starch, corn starch, wheat starch); sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums (such as acacia); gelatin; cellulose derivatives (such as microcrystalline cellulose, HPC, HEC, HPMC, carboxymethyl cellulose, methyl cellulose, ethyl cellulose); polyvinylpyrrolidone (PVP), polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols (such as sorbitol, xylitol, mannitol) and water.

21. The pharmaceutical composition according to claim 15 characterized in that the disintegrant used in said composition is selected from starches (corn starch, potato starch); sodium starch glicolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcyrstalline cellulose), polyvinylpyrrolidone (PVP), crospovidone, alginic acid, sodium aginate, clays (such as xanthangum or Veegum), ion exchange resins and effervescent systems (alkali or alkaline-earth metal carbonates[sodium carbonate, sodium hydrogen carbonate, potassium carbonate, potassium hydrogen carbonate, calcium carbonate]; water soluble polybasic organic acids or their salts, hydrates or anhydrous forms such as sodium hydrogen sulphate, potassium hydrogen sulphate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, citric acid, citric acid anhydrous or combinations thereof.

22. The pharmaceutical composition according to claim 15 characterized in that the lubricant used in said composition is selected from metallic stearates (such as magnesium stearate, calcium sterate, aluminium stearate), fatty acid esters (such as sodium stearil fumarate), fatty acids (such as stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oils, leucine, polyoxyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc.

23. The pharmaceutical composition according to claim 15 characterized in that the glidant used in said composition is selected from a group comprising silicone dioxide, magnesium trisilicate, cellulose powder, starch, talc, tribasic calcium phosphate, metallic stearates, calcium silicate and metallic lauryl sulphates.

24. The pharmaceutical composition according to claim 15 characterized in that the surfactant used is selected from a group comprising polyoxyethylene-sorbitan-fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearil fumarate, polyoxyethylene alkyl ethers, sorbitan fatty acid esters, polyethylene glycols (PEG), polyoxyethylene castor oil derivatives, docusate sodium, quaternary ammonium compounds, aminoacids such as L-leucine, sugar esters of fatty acids and glycerides of fatty acids.

25. The pharmaceutical composition according to claim 1 characterized in that N- Acetylcysteine is in doses of 200, 600, 900 and 1200 mg and xanthine derivative compound is in doses of 200, 400 mg in said pharmaceutical composition.

26. The method for manufacturing the pharmaceutical composition according to claim 1 characterized in that it is carried out as wet granulating the xanthine derivative compound after mixing it with another excipient.

27. The method for manufacturing the pharmaceutical composition according to claim 26 characterized in that at least one excipient which is mixed with xanthine derivative compound is at least one effervescent acid and at least one effervescent base.

28. The method for manufacturing the pharmaceutical composition according to claim 27 characterized in that this is carried out as wet granulating the xanthine derivative compound after mixing it with at least one pharmaceutically acceptable effervescent acid and at least one effervescent base and adding pharmaceutically acceptable amount of NAC and optionally at least one sweetener, glidant and flavoring agent to the obtained granules so as to manufacture the final granules.