WO2020022975A2

WO2020022975A2 - New pharmaceutical compositions in the treatment of copd

Info

Publication number: WO2020022975A2
Application number: PCT/TR2018/000134
Authority: WO
Inventors: Mahmut Bi̇lgi̇ç
Original assignee: Neutec Ar Ge Sanayi Ve Ticaret AS
Current assignee: Neutec Ar Ge Sanayi Ve Ticaret AS
Priority date: 2017-12-29
Filing date: 2018-12-28
Publication date: 2020-01-30
Anticipated expiration: 2020-06-29
Also published as: WO2020022975A3; TR201722950A2

Abstract

The present invention relates to pharmaceutical compositions comprising N-Acetycysteine and mannitol for use in the treatment of COPD attacks.

Description

NEW PHARMACEUTICAL COMPOSITIONS ΪN THE TREATMENT OF COPD

The present invention relates to N-acetylcysteine and mannitol combinations, the use of these combinations in the treatment of respiratory diseases, and pharmaceutical compositions comprising them.

Acetylcysteine is a mucolytic drug. The sulfhydryl groups in the molecular structure react with disulfide bonds of the mucoproteins which present in the bronchial secretions. Thus, the density of mucus secretion in the lung decreases and removal of secretions is facilitated. Acetylcysteine can be administered try inhalation or taken by oral route. The chemical name of N-acetylcysteine is (2R>2- acetarmdo-3-sulfanyipropionic acid and it has been described for the first time with the patent application numbered US3184505.

N Acetylcysteine is present in the market in a variety of dosage forms such as capsules, tablets, powders, solutions, injectable.

The chemical name of mannhol is 1 ,2,3 ,4,5 ,6-Hexanehexol and it has been described for the first time with the application numbered US2516350.

The use of mannitol in the treatment of oliguria, cerebellar edema, urological irrigation and ischemia has been known. Surprisingly it has been found that a therapeutic benefit, in particular a synergistic therapeutic benefit, can be achieved by combination therapy using N-Acetylcysteine and mannitol in the treatment of respiratory diseases. This therapeutic benefit may be defined as; a reduction of dosages required for necessary therapeutic effect in the case of usage of N- Acetylcysteine and mannitol combinations when compared to the dosage of the treatment with N-Acetylcysteine alone or mannitol alone; and/or

a reduction in undesirable side effects and/or • observation of therapeutic effect in a shorter time period and/or

• observation of therapeutic effect for a longer time period and/or

• providing more effective treatment. In other words, the pharmaceutical composition m which N -acetylcysteine and mannitol are used together or simultaneously shows higher therapeutic benefit compared to the compositions using these two agents separately.

In another aspect, the combined usage of N- Acetylcysteine and mannitol provides that the therapeutic effect is seen in a shorter time and stronger effect than the usage of these two active ingredients separately . In this way, it is possible to provide a mote effective treatment for patients.

Surprisingly, all these positive effects are also demonstrated when administration of both active ingredients m a dosage form at the same time or administration in a dosage form simultaneously which in independent dosage forms of these active ingredients, as shown in the combination which both active ingredients administered sequentially. High therapeutic benefit can also be observed in the way of longer effect

Accordingly, the subject of the present invention is a pharmaceutical composition comprising the combination of N-Acetyicystefoe and mannitol as the active ingredient.

In other words, the present invention relates to pharmaceutical compositions comprising N- Acetylcystcine and mannitol together for sequential administration in separate dosage forms, for simultaneous administration in separate dosage forms, or for simultaneous administration in same dosage forms.

In another aspect, the present invention relates to the usage in the treatment ofCOPD attacks, bronchitis, cystic fibrosis and asthma with administration of effective amount of N*Acetykysteine and mannitol

In one aspect, (he present invention relates to pharmaceutical compositions comprising a pharmaceutically effective amount of N-Acetylcysteine and mannitol and at least one pharmaceutically acceptable excipient.

Within these pharmaceutical compositions, N-Acetylcysteine and mannitol can be in a single formulation together with at least one pharmaceutically acceptable excipient or N-Acetylcysteine and mannitol can be formulated separately with at least one pharmaceutically acceptable excipient. The obtained different formulations can be combined in a single dosage form or prepared in separate dosage forms. In the case of the formulations are present in separate dosage forms, the dosage forms may be the same or different from each other. The present invention also relates to the usage of N -Acetylcysteine and mannitol according to foe invention for the preparation of a medicament for use in combination therapy by means of simultaneous, sequential or separate administration in the treatment of COPD attacks, bronchitis, cystic fibrosis and asthma. According to the present invention, the N*Acetyicysteine in the pharmaceutical compositions can be in the form of pharmaceutically acceptable salts, hydrates, solvates, esters, enantiomers, diastereomcrs, racemates, and/or in any of the polymorphic forms such as amorphous, crystalline, or combinations thereof.

According to foe present invention the pharmaceutical compositions are preferably administered by inhalation.

Said forms suitable for inhalation may be dosage forms such as dry powder, nebu!e, aerosol, extended release aerosol, metered dose inhalation composition, extended release metered dose inhalation composition, capsule, and Mister, On the other hand, inhaler formulations used as nasal are also within the scope of the present invention. According to the present invention foe pharmaceutical compositions containing N-Acetylcysteine and mannitol preferably in dry powder or aerosol form suitable for inhalation.

According to foe present invention the pharmaceutical compositions specified as aerosol dosage forms Include all formulations in solution or suspension form, with or without propellant These dosage forms according to the invention would be referred to as aerosols. According to foe present invention the pharmaceutical compositions specified as dry powder dosage forms include all formulations such as capsule, blister or suitable for inhalation through reservoir. These dosage forms according to the invention would be referred to as dry powder.

In accordance with foe present invention, inhalation formulations comprising N Acetylcysteine and mannitol and/or pharmaceutically acceptable derivatives thereof can be administered to foe patient in an aerosol form. The pharmaceutical compositions containing N-acety!cysteme and mannitol according to the invention may contain various excipients in addition to foe active ingredients which arc N« Acetylcysteine and mannitol. These aerosol formulations according to the invention may optionally contain propellant, in addition to the active ingredients and excipients.

The propellants in aerosols provide the delivery of foe active ingredients) used in very small amounts to the patient's lung. These propellants ate preferably hydrocarbons and halo-hydrocarbons, as also known in the art Only one of these hydrocarbons or a mixture thereof can be used. Preferably used propellants are halogenated alkane derivatives selected from HFA134a, HFA227 or a mixture thereof and TGI 34a, TG227 or mixtures thereof. Aerosols according to the present invention with or without propellant; can comprise other excipients such as cosolvent, stabilizers, surfactants, antioxidants, lubricants and pH adjusters.

Preferred eosolvents are hydroxyl groups, alcohols, especially other polar groups containing isopropyl alcohol and glycols. The said other excipients are substances such as tocopherols, vitamins, provitamines, surfactants which do not have the active ingredient properties. Preservatives used to prevent contamination by pathogens are acetyl pyridinium chloride, benza!konium chloride, benzoic acid or benzoates, also known in the art.

Surfactant to be used in pharmaceutical compositions according to the present invention can be selected from vegetable oils and organic acids; in particular stearic acid, sorbic add, oleic acid, saccharin, ascorbic acid, cyclamic acid, aspartame.

The active ingredient(s) used in the aerosol formulations according to the present invention have a ratio of 0.001 to 8%; preferably from 0.001% to 5% by weight.

In these inhalation formulations, water, alcohol or a mixture of water-alcohol can be used as the solvent. In the case of water-alcohol mixtures are used, the ethanol content in the mixture is at most 80% and preferably 60%.

According to the present invention the pH value of the pharmaceutical aerosol formulations is from 2 to 7 and preferably from 2 to 5.

In order to ensure that the pH values in the aerosol formulations according to the invention are within these ranges, organic or inorganic acids, preferably hydrochloric acid, citric acid, nitric acid, phosphoric acid, ascorbic acid formic acid, fumaric acid, malic acid, tartaric acid malic acid, sulfuric acid, or a mixture of one or more of these can be used as the pH adj uster.

Moreover, pharmaceutical aerosol formulations according to the present invention may comprise in addition to the said agents, edetic acid (EDTA) or salts, excipients, sodium edeta!e, stabilizer or complexing agents. The sodium edetate contained in said aerosol formulations is from 0 mg/ 100 ml to 120 mg/100 ml, preferably from 0 mg/ 1 GO ml to 50 mg/100 mi, and most preferably from 0 mg/100 ml to 10 mg/100 ml.

Carrier excipient to be used in pharmaceutical compositions of the present invention may comprise is a fine-grained excipient, a coarse-grained excipient, or a combination thereof, preferably a combination of fine-grained and coarse-grained excipients. This excipient can be selected from monosaccharides (glucose, etc.), disaccharides (lactose, sucrose, maltose or pharmaceutically acceptable hydrates, anhydrides thereof or mixtures thereof, etc.), oligosaccharides and polysaccharides (dextran, etc.), polyalcohols (sorbitol, mannitol, xyirtol, etc.), salts (sodium chloride, calcium carbonate, etc.) or a mixture thereof. The same or different substances are preferably used as fine-grained excipients and coarse-grained excipients, although the same substances are preferably used, in the compositions according to the invention, the carrier is preferably lactose.

In the case of the pharmaceutical compositions according to the invention are formulated as inhalable dry powder, the preferred active ingredient particle size is from l pm to 10 pm in order to provide better flow properties

Disintegrant to be used in pharmaceutical compositions of the present invention can be selected from a group comprising carboxymethyl cellulose, carboxymcthyl cellulose calcium, carboxymethyi cellulose sodium, croscarmellose sodium, crospovidone, hydroxypropyl cellulose, microcrystalline cellulose, methyl cellulose, chitosan, starch, sodium starch glycoiate. The process for the preparation of pharmaceutical formulations in die form of dry powders comprising N-acetylcysteine and mannitol and/or pharmaceutically acceptable derivatives thereof according to the present invention consist of the following steps:

I. micronizing N -Acetylcysteine and mannitol to the desired particle size,

P. micronizing the excipient to the desired particle size,

III. muting in the mixer of the micronized active ingredients firstly with the fine-grained excipients and then with the coarse-grained excipient or mixing in the mixer of the micronized active ingredients firstly with the coarse-grained excipients and then with the fine-grained excipient.

IV, Finally, the mature obtained in dry powder form is transferred to suitable capsule, blister or reservoir and make ready for use.

In another aspect, the present invention relates to the inhalation of dry powder formulations comprising N -Acetylcysteine and mannitol and/or pharmaceutically acceptable derivatives thereof by inhalation devices comprising capsules, blisters or reservoirs. to die case of dry powder formulation according to the invention is inhaled from the capsule which is one of the inhalation methods, the inventors have found that inhalation occurs most efficiently if the capsule volume is from 0.1 to 0.5 ml, preferably from 0.15 to 0.45 ml, and most preferably form 0.2 to 0.4 ml.

Accordingly, the present invention is characterized by a capsule volume of 0.1 to 0.5 ml, preferably from 0.151» 0.45 ml and most preferably form 0.2 to 0.4 ml for the capsule used for storage and delivery' of drug in dry powder form which comprising N-Acetylcysteinc and mannitol and/or their pharmaceutically acceptable derivatives. In another aspect, in the case of the capsule in the form which hr high protection against moisture and other adverse external factors has the humidity rate of 5-20%, preferably of 7- 15%, the inventors have found that the active compound in fee capsule is protected from both external factors and feat fee possibility of getting humidity «fetch may result from tie structure of fee capsule is eliminated. Thus, agglomeration of the dry powder formulations of the present invention is prevented and effectively transmitted to fee patient's lungs.

Accordingly, the present invention is characterized by humidity rate of 5-20%, preferably of 7-15% of a packaging in the form of capsule used for storage and delivery of drug in dry powder form which comprising N-Acetylcysteine and mannitol and/or their pharmaceutically acceptable derivatives.

In another aspect, in the case of dry powder formulation according to the invention is inhaled from the capsule, the preferred capsule for use in the present invention can be made of a substance selected from the group consisting of gelatin, chitosan, starch and/or starch derivatives, cellulose and/or cellulose derivatives or synthetic polymers and it consists of upper and lower sections which are interlocking each other.

Accordingly, in fee case of dry powder formulation according to the invention is inhaled from fee capsule, if the capsule to be used is cellulose and its derivatives, it can be selected from a group consisting of hydroxypropyt cellulose, hydroxyprorylmetbyl cellulose, methyl cellulose, hydroxymethyl cellulose, hydroxy ethyl cellulose, in case of dry powder formulation within fee scope of fee present invention is inhaled from fee capsule, if fee capsule to be used is a synthetic polymer, it can be selected from a group consisting of polyethylene, polyester, polyethylethcraphthalate, polycarbonate and polypropylene.

In case of dry powder formulation within die scope of the present invention is inhaled from the capsule, if tiie capsule to be used is gelatin, a variety of molecular weight polyethylene glycol, sorbitol, glycerol, propy lene glycol, polyethylene oxide-polypropylene oxide block copolymers and/or other polyalcohols and polyethers can be included as additives. In another aspect, in the case of said dry powder formulation is inhaled from the capsule, the inventors have found that the cavity of the capsule used should be 0.05 to 25%, preferably from 0.1 to 20%, most preferably from 0.5 to 15% to provide efficient inhalation.

Accordingly, in the case of said dry powder formulation is inhaled through capsule; the present invention is characterized by a fill rate of cavity of capsule used 0.05 to 25%, preferably 0.1 to 20% and most preferably 0.5 to 15%. In the case of said dry powder formulation according to the present invention is inhaled through blister, befog blister cavity volume uf 18 to 30 mm3, preferably 20 to 25 mm3 and most oreferablv 21 to 24 In the case of said dry powder formulation according to the present invention is inhaled through blister, befog blister cavity volume uf 18 to 30 mm3, preferably 20 to 25 mm3 and most preferably 21 to 24 mm3 provides an. effective inhalation.

Accordingly_» In the case of said dry powder fennuMon is inhaled through blisters the preseat invention is characterised by a cavity votenc of 18 to 30 nun³, preferably 20 to 25 mm³ and most preferably 21 to 24 mar' for the blister used for storage aad deliver)' of drug in dry powder form which comprising N- Acetylcysteine and mannitol and/etr their pharmaceutically acceptable derivatives.

The Inventors have found that the fill rate of cavity of blister used should be 15-95%, preferably 20-85% and most preferably 50-80% to provide an efficient and smooth inhalation from blister for formulation of the present invention. in the ease of said dry powder formulation is inhaled through blister, the present Invention is characterized by a till rate of 15 to 95%, preferably 20 to 85% and most preferably 59 to 80% of foe blister used for storage and delivery of drag in dry powder form which comprising N-Acetylcysteinc and mannitol and/or their pharmaceutically acceptable derivatives. In the ease of inhalation of the dry powder formulation according to the invention from the blister, the top and bottom layer forming the removable strip blister packaging in which the blisters containing the dry powder formulation of the invention are arranged side by side are tightly closed by any suitable method for sealing.

The top and bottom layers forming the removable strip blister packaging comprising the dry powder fonnulation of the present invention, consist of multiple layers. Polymeric layers, aluminum foil and preferably Actant* fluoropolymer Sim are the layers which forming the top and bottom layers.

The inventors have found that foe addition of desiccant to the polymeric layers in order to reduce the humidity sad gas permeability of foe top and bottom layes forming foe blister packaging in case of inhalation of the formulation according to the invention from the blister is effecti ve Is maintaining the stability of foe dry powder formulation. The desiccant agents added to the layers forming the strip blister packaging comprising the fey powder fonnulation of the present invention are .selected from silica gel, zeolite, alumina, bauxite, anhydrous calcium sulfate, activated carbon, water-absorbing days. in the case of Inhalation of the dry powder formulation according to foe invention from foe blister, the polymeric layers in the lower and upper layers of the removable strip blister packaging containing the said dry powder formulation, composed of identical or different polymers, The thickness of these polymeric layers varies based on the type and properties of the polymeric material used. Therefore, the thickness of the polymeric layer varies between 15-55 pm, preferably 20*30 pm based on the type of polymeric material used.

The aluminum foil in contact with the dry powder formulation in the blister cavity causes the inhalation of the uncontrolled dose by the porous structure of the aluminum foil and the adhesion of a portion of the dry powder formulation on the inner surface of die blister cavity due to electrostatic forces and therefore the inner surface of the cavity is a polymeric layer. Polymers composing the polymeric layer may be preferably selected from thermoplastic polymers such as polyethylene, polypropylene, polystyrene, polyolephine, polyamide, polyvinylchloride, polyurethane or from the synthetic polymers. The pharmaceutical compositions according to the invention may contain N-Acetylcysteine in the range of 0.1 to 99% by weight, preferably from 1 to 98%, and most preferably from 5 to 95% by weight.

The pharmaceutical compositions according to the invention may contain mannitol in the range of 0.1 to 99%, preferably 1 to 98%, and most preferably 5 to 95% by weight.

N -acetylcysteine contained in the pharmaceutical compositions according to tire invention can be in the range of i meg to 1500 mg, preferably 1 meg to 1400 mg, and most preferably I meg to 1300 mg.

In the pharmaceutical compositions according to the invention, mannitol can be in the range of 1 meg to 100 mg, preferably 1 meg to 90 mg and most preferably 1 meg to 80 mg.

According to the invention the pharmaceutical compositions containing N-acetylcysteine and mannitol may optionally comprise a third active ingredient in addition to N-Acetylcysteine and mannitol. The third active ingredient may be selected from antacids, anticholinergics, antispasmodics, antiemetics, antibiotics, antipropulsives, antiallergics, antidiarrhcals, antiobesity agents, antithrombotics, antiftbrinolytics, antianemics, antihypertensives, antifungals, antipruritics, antipsoriatscs, antiseptics, antiacne-bacterials, antimycotics, antivirals, antineoplastics, antiarrhythnucs, antiadrenergics, antiepileptics, anti-parkinson agents, antiprotozoal*, anthelmintics, anti-inflammatories, diuretics, laxatives, sulfonamide, imtdazol, corticosteroids, thiazolidinediones, biguanides, immunostimulants, immunosuppressants, muscle relaxants, analgesics, psycholeptics, psychoanaleptic peripheral vasodilators, beta blockers, calcium channel blockers and lipid modifying agents; alpha-glucosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin Bl, vitamin C, vitamin B, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.

The pharmaceutical composition according to the invention can be used to prevent and treat COPD attacks, bronchitis, cystic fibrosis and asthma. The following «(ample is given to illustrate the combinations of the present invention and the present invention cannot be limited to this example.

EXAMPLE 1:

The composition comprising mannitol or a pharmaceutically acceptable derivative thereof and N- acetylcysteine or a pharmaceutically acceptable derivative thereof is brought to the average particle size which is suitable for inhalation by micronization.

Active ingredients which has suitable particle size are mixed with a sufficient amount of earner to give a homogeneous mixture. The homogeneous powder mixture obtained is optionally supplied to the patient with a capsule or blister device.

Claims

1. A pharmaceutical composition comprising the combination of N-Acctylcysteine and mannitol as the active ingredient.

2. A pharmaceutical composition comprising N-acetylcysteine and matmitol according to Claim 1, wherein said composition contains N-Acety {cysteine between 1 meg and 1500 mg per unit dosage form.

3. A pharmaceutical composition comprising N-acety!cystcine and mannitol according to Claim 1-2, wherein said composition contains N-Acety kysteine between 1 meg and 1400 mg per unit dosage form.

4. A pharmaceutical composition comprising N-acctylcysteine and mannitol according to any of Claim 1-3, wherein said composition contains N-Acetylcysteine between 1 meg and 1300 mg per unit dosage fbtm.

5. A pharmaceutical composition comprising N-acctylcysteine and mannitol according to any of Claim 1-4. wherein said composition contains mannitol between 1 meg and 1000 mg per «mil dosage form.

6. A pharmaceutical composition comprising N-acctylcysteine and mannitol according to any of Claim 1-5, wherein said composition contains mannitol between 1 meg and 90 mg per unit dosage form.

7. A pharmaceutical composition comprising N-acctylcysteine and mannitol according to any of Claim 1-6, wherein said composition contains mannitol between 1 meg and 80 mg per unit dosage form.

8. A pharmaceutical composition comprising N-acetylcysteine and mannitol according to any of Claim 1*7, wherein the pharmaceutically acceptable salts of N-acctylcysteine may be in the forms of hydrates, solvates, esters, enantiomers, diastcrcomers and/or any of the polymorphic forms such as amorphous or crystalline forms or in the form of combination of these.

9. A pharmaceutical composition comprising N-acetylcysteine and mannitol according to any of Claim 1-8. wherein N-Acety kysteine and mannitol are present in the same pharmaceutical formulation.

10. A pharmaceutical composition comprising N-acetylcysteine and mannitol according to any of Claim 1-8, wherein N-Acety Icy steine and mannitol are present In the different pharmaceutical formulation.

11. A pharmaceutical composition comprising N-acetylcysteine and mannitol according to Claim 10, wherein different pharmaceutical formulations containing N-acetylcysteine and mannitol are incorporated m the same dosage form.

12. A pharmaceutical composition comprising N acetylcystemc and mannitol according to any of the preceding claims, wherein said composition contains at least one pharmaceutically acceptable excipient in addition to N-acetylcystemc and mannitol.

13. A pharmaceutical composition comprising N-ecetylcysteine and mannitol according to Claim ! , wherein the composition is a dosage form suitable for inhalation.

14. A pharmaceutical composition comprising N -acetylcysteine and mannitol according to Claim 13, wherein the said suitable inhalation dosage forms can be selected from dry powder, nebulc, aerosol, extended release aerosol, metered dose inhalation composition, extended release metered dose inhalation composition, capsule, and blister.

15. A pharmaceutical composition comprising N-acetyicysteme and mannitol according to any of the preceding claims, wherein said composition contains, in addition to N -acetylcysteine and mannitol, at least one third active ingredient selected from antacids, anticholinergics, antispasmodics, antiemetics, antibiotics, antipropulsives, antiailergics, antidiarrheals, antiobesity agents, antithrombotics, antifihrinoiyties, antianemics, antihypertensives, antiftmgais, antipruritics, antipsoriatics, antiseptics, antiacne-bactcriais, antimycotics, antivirals, antineoplastics, antiarrhythmics, antiadrenergics, antiepUeptics, anti-parfcinson agents, antiprotozoals, anthelmintics, anti-inflammatories, diuretics, laxatives, sulfonamide, imidazol, corticosteroids, Ihiazolidinedioncs, biguanides, immunostimulants, immunosuppressants, muscle relaxants, analgesics, psychoieptics, psychoanaleptic peripheral vasodilators, beta blockers, calcium channel blockers and lipid modifying agents; alpha- glocosidase inhibitors, aldose reductase inhibitors, ACE inhibitors; multivitamin and minerals, vitamin A, vitamin D and analogs, vitamin B1 , vitamin C, vitamin E, vitamin B6, vitamin B2, vitamin K, calcium, potassium, sodium, zinc, magnesium, fluoride, selenium.

16. A pharmaceutical composition comprising combination of 1 meg to 1500 mg of N- Acefylcysteine and 1 mg to 80 mg mannitol as active ingredient.