WO2012039691A2

WO2012039691A2 - Synergic effect

Info

Publication number: WO2012039691A2
Application number: PCT/TR2011/000213
Authority: WO
Inventors: Mahmut Bilgic
Original assignee: Individual
Current assignee: Individual
Priority date: 2010-09-20
Filing date: 2011-09-20
Publication date: 2012-03-29
Anticipated expiration: 2013-03-20
Also published as: TR201007652A2; WO2012039691A3

Abstract

The present invention relates to use of N- Acetylcysteine which is a mucolytic agent and a non - sedating, third generation HI receptor antagonist such as levocetirizine and desloratadine in combination; and pharmaceutical compositions comprising said combination which can be used in respiratory tract diseases.

Description

SYNERGIC EFFECT

The present invention relates to use of N- Acetylcysteine which is a mucolytic agent and a non-sedating, third generation HI receptor antagonist in combination; and pharmaceutical compositions comprising said combination which can be used in respiratory tract diseases.

The present invention provides an effective combination that is indicated in acute and chronic bronchopulmonary diseases, bronchitis, rhinitis, allergic respiratory problems, expectoration and reduction of phlegm.

Desloratadine, which has the chemical name 8-chloro-6,l l-dihydro-l l-(4-piperidinyl)-5H- benzo[5,6]cyclohepta[l,2-b]pyridine(Formw/a I), is a long-acting, non-sedative antihistamine.

Desloratadine was first disclosed in the patent numbered US 4,659,716. This patent comprises processes for preparation of desloratadine; pharmaceutical compositions comprising desloratadine; and non-sedative antihistaminic activity of desloratadine.

Desloratadine is a non-sedative, third generation HI antagonist which does not cause sedation. It competes with histamine for HI receptors; and blocks binding of histamine to HI receptors. Desloratadine which is an active metabolite of loratadine is an oral HI antagonist. Levocetirizine, chemical name of which is 2-[2-[4-[(R)-(4-chlorophenyl)-phenyl-methyl] piperazine-l-yl]ethoxy] acetic acid {Formula II) is a non-sedative, long acting antihistamine.

(II)

Cetirizine was first disclosed in the patent numbered EP 0058146. Among the first patents relating to levocetirizine , an R-enantiomer of cetirizine, there exist the patent numbered GB 2225321 on the preparation process of levocetirizine and the patent numbered WO 9406429 on the use of levocetirizine in the treatment of allergic diseases. Levocetirizine, an R-enantiomer of cetirizine, is a strong, piperazine derivative, HI receptor antagonist. Levocetirizine is a new antihistaminic that binds to HI receptors with high affinity, even two times higher affinity than cetirizine. Levocetirizine inhibits the binding of histamine to HI receptors.

Both desloratadine and levocetirizine have antiallergic and anti-inflammatory activity. The studies have revealed that these two active ingredients inhibit the extensive series of events initiating and spreading the allergic inflammation.

As a result of allergic reactions; allergic respiratory tract problems such as allergic rhinitis, allergic sinusitis, allergic bronchitis, allergic bronchopulmonary diseases having symptoms of sneeze, nasal flow, itching, nasal obstruction, itching, lacrimation and redness on eyes, itchy palate and coughing have been observed. As a result of allergic bronchopulmonary diseases, expectoration and/or phlegm occurs irritating patients, preventing regular breathing and causing cough.

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

Due to sulphydryl 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.

When the prior art is taken into consideration, there is a need for novel pharmaceutical compositions which will be effective in the treatment of bronchopulmonary and all other allergic respiratory tract diseases; will prevent both recurrence of said diseases and relieve the symptoms thereof; do not present sedation effect resulting from use of histamine receptor antagonist; and will yield more effective and precise results in comparison with existing therapies.

The inventors have surprisingly found that a more effective composition than expected and a more significant therapeutic benefit are obtained due to the synergic effect between a third generation HI antagonist and N- Acetylcysteine as a mucolytic agent. The present invention is related to use of NAC in combination with a third generation HI antagonist.

In an aspect, the invention provides a treatment method comprising use of the synergistically effective combination of NAC and a third generation HI antagonist in respiratory tract diseases. The pharmaceutical combination of the present invention comprises;

- N- Acetylcysteine

- A third generation HI receptor antagonist

- At least one pharmaceutically acceptable excipient. According to the invention; the third generation receptor antagonist is selected from a group comprising levocetirizine, desloratidine or their combination.

The combination of the present invention comprises use of NAC as a mucolytic agent in combination with levocetirizine, desloratidine or a combination thereof. Treatments in which the combination of the present invention is used comprises administration of a third generation HI receptor antagonist and N- Acetylcystein in therapeutically effective amounts and activity of said combination is synergistic against the bronchopulmonary diseases and allergic respiratory tract 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 separately for reducing the symptoms of respiratory tract diseases or slowing the progression of the diseases. According to the present invention, the pharmaceutical composition of the present invention is indicated particularly in acute and chronic bronchopulmonary diseases; seasonal and/or perennial rhinitis, sinusitis, bronchitis, allergic and/or inflammatory diseases of upper and lower respiratory tracts and allergic respiratory problems.

In another aspect, combinations of the present invention can be prepared as medicament compositions so as to be administered to mammals including human particularly for the treatment of acute and chronic bronchopulmonary diseases; seasonal and/or perennial rhinitis, sinusitis, bronchitis, allergic and/or inflammatory diseases of upper and lower respiratory tracts and allergic respiratory problems.

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 third generation HI receptor antagonist as active agents.

In another aspect, it is targeted to reduce symptoms of respiratory tract diseases, slow the progression of the diseases and treat the diseases by means of pharmaceutical compositions in which effective amounts of NAC and effective amounts of a third generation HI receptor antagonist 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 third generation HI receptor antagonist 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 third generation HI receptor antagonist 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 third generation HI receptor antagonist 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 separately so as to be used in the treatment of respiratory tract diseases.

In another aspect, the active agents in the composition of the present invention can be formulated separately in order to be used in a kit form where they are placed together.

In another aspect, it has been observed that a more effective use is ensured by formulating the combination of the present invention in the same dosage form.

In another aspect, the amount of 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 in proportion to total amount of the pharmaceutical composition. In addition, dosage of the active agents in the pharmaceutical composition can vary according to the route of administration, the patent's age and state of health.

According to the invention, in the treatment of respiratory tract diseases, the ratio of NAC and a third generation HI receptor antagonist by weight in the oral composition varies in range of 1 :0,05 to 1:5.

According to the invention, the ratio of the third generation HI receptor antagonist to the total amount of substances in the composition varies in the range of 1-50% by weight and the ratio of N- Acetylcysteine to the total amount of substances in the composition varies in the range of 1-90% by weight.

According to the invention, the pharmaceutical composition of the present invention can comprise a third generation HI receptor antagonist in the range of 0,1 mg to 50 mg and NAC in the range of 10 mg to 2000 mg in one dose.

In another aspect, the pharmaceutical composition of the present invention can be prepared as applicable by the oral route.

The pharmaceutical compositions of the present invention comprise oral 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 in which said composition will be formulated can be solid forms such as tablet; capsule; enterically coated or modified release tablet; prolonged release tablet; delayed release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; water soluble powder, tablet, or granule; granule; pellet; minitablet; microtablet; granule capsule, pellet capsule, minitablet capsule, microtablet capsule; or dry powder mixture for syrup preparation; dragee; orally disintegrated tablets; film tablet or solid forms comprising their combination, or in liquid forms such as suspensions.

According to the present invention, the pharmaceutical composition of the present invention can be formulated preferably in the form of water-soluble powder, tablet or granule. The absorption of the pharmaceutical formulation from the gastrointestinal tract increases when it is formulated this way.

Effervescent formulations according to the present invention dissolve completely in water at the room temperature in less than 5 minutes. In another aspect, degradation is observed in the combination of the present invention due to the fact that third generation HI receptor antagonist agents are unstable; thus it is hard to formulate them. Therefore, ratio of the third generation HI receptor antagonist to binder in the composition of the present invention is in the range of 1 :20 to 1 :45 and the amount of NAC is in the range of 1-50% by weight of the total weight. In another aspect, using polyvinylpyrrolidone as binder in the pharmaceutical composition of the present invention provides a more stable pharmaceutical composition.

In another aspect, the combination of the present invention is produced from NAC, a third generation HI receptor antagonist, and preferably a pharmaceutically acceptable excipient by conventional techniques.

Pharmaceutically acceptable excipients can also be used in addition to the active agents used in the formulation of the present invention. These excipients can be selected from additives such as pharmaceutically acceptable binder, sweetener, lubricant, flavoring agent, diluent, disintegrant, surfactant and glidant. Pharmaceutically acceptable binders can be selected from, but not limited to, a 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.

Pharmaceutically acceptable sweeteners can be selected from, but not limited to, a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulfame potassium, aspartam, D-tryptophane, monoammonium glycyrrhizinate, neohesperidine dihyrochalcon, thaumatin, neotam, alitam, stevioside, cyclamates and sodium chloride.

Pharmaceutically acceptable lubricants can be selected from, but not limited to, a group comprising metallic stearates (such as magnesium stearate, calcium stearate, aluminium stearate), fatty acid esters (such as sodium stearyl fumarate), fatty acids (such as. stearic acid), fatty alcohols, glyceryl behenate, mineral oil, paraffins, hydrogenated vegetable oil, leucine, polyethylene glycols (PEG), metallic lauryl sulphates (such as sodium lauryl sulphate, magnesium lauryl sulphate), sodium chloride, sodium benzoate, sodium acetate and talc. Pharmaceutically acceptable diluents can be selected from, but not limited to, a 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, cellulose powder, dextrose, dextrates, dextrine, sucrose, maltose, fructose, mannitol, sorbitol and xylitol.

Pharmaceutically acceptable disintegrants can be selected from, but not limited to, a group comprising starches (corn starch, potato starch); sodium starch glycolate; pregelatinized starch; cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose); polyvinylpyrrolidone (PVP); crospovidone; alginic acid; sodium alginate; clays (such as xanthan gum or Veegum); ion exchange resins and effervescent systems (alkaline 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 such as sodium hydrogen sulphate, potassium hydrogen sulphate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, citric acid, etc).

Pharmaceutically acceptable glidants can be selected from, but not limited to, a 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, but not limited to, a group comprising polyoxyethylene-sorbitan-fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearyl 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. In addition to these, other pharmaceutically acceptable excipients such as solubility modulators, effervescent couple, coloring agents and coating agents can be used in the formulation.

The combination of the present invention and the pharmaceutical compositions comprising said combination and their preparation methods can be explained with the help of the following examples, yet the invention should not be limited to these examples. EXAMPLES EXAMPLE 1:

The active agents N-Acetylcysteine and desloratadine are prepared as a pharmaceutical composition by the conventional techniques in the prior art. The homogenous mixture obtained thereafter is dried and shaped as required.

EXAMPLE 2:

The active agents N-Acetylcysteine and levocetirizine are prepared as a pharmaceutical composition by the conventional techniques in the prior art. The homogenous mixture obtained thereafter is dried and shaped as required.

Claims

1. A pharmaceutical composition characterized in that said composition comprises N- Acetylcysteine and a third generation HI receptor antagonist in combination.

2. The pharmaceutical composition according to claim 1 characterized in that said composition comprises a pharmaceutically acceptable excipient in addition to the combination of N- Acetylcysteine and a third generation HI receptor antagonist.

3. The pharmaceutical composition according to claim 1 characterized in that the third generation HI receptor antagonist is selected from levocetirizine, desloratadine or a combination thereof.

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

5. The composition according to claim 1, wherein said composition is used for the treatment of acute and chronic bronchopulmonary diseases, seasonal and/or perennial rhinitis, sinusitis, bronchitis, allergic and/or inflammatory diseases related to upper and lower respiratory tracts and allergic respiratory problems.

6. The pharmaceutical composition according to claim 1 characterized in that the active agents constituting the composition are formulated simultaneously, sequentially or separately.

7. The pharmaceutical composition according to claim 1 characterized in that the active agents constituting the composition are formulated in a kit form where they are placed together.

8. The pharmaceutical composition according to claim 1 characterized in that the pharmaceutical composition is formulated in the same dosage form.

9. The pharmaceutical composition according to claim 1 characterized in that the ratio of the third generation HI receptor antagonist to total amount of substances in said pharmaceutical composition varies in range of 1 to 50% by weight and the ratio of N-Acetylcysteine to total amount of substances in said pharmaceutical composition varies in the range of 1 to 90% by weight.

10. The pharmaceutical composition according to claim 1 characterized in that the ratio of NAC and the third generation receptor antagonist in the composition varies in the range of 1 :0,05 to 1 :5 by weight.

11. The pharmaceutical composition according to claim 1 characterized in that the amount of the third generation HI receptor antagonist in one dose is in the range of 0,1 to 50 mg by weight and the amount of N- Acetylcysteine is in the range of 10 to 2000 mg by weight.

12. The pharmaceutical composition according to claim 1 characterized in that said composition is formulated to be administered by the oral route.

13. The pharmaceutical composition according to claim 1 characterized in that the composition is formulated in solid forms such as tablet; capsule; enterically coated or modified release tablet; prolonged release tablet; delayed release tablet; fast soluble tablet; effervescent tablet; effervescent granule; fast soluble powder mixture; water soluble powder, tablet or granule; granule; pellet; minitablet; microtablet; granule capsule, pellet capsule, minitablet capsule, microtablet capsule; or dry powder mixture for syrup preparation; dragee; orally disintegrated tablets; film tablet or a combination thereof; or in liquid forms such as suspension.

14. The pharmaceutical composition according to claim 13 characterized in that the combination of N- Acetylcysteine and a third generation HI receptor antagonist is formulated in water-soluble powder, tablet or granule form.

15. The pharmaceutical composition according to claim 14 characterized in that said composition dissolves completely in water at room temperature in less than 5 minutes.

16. The pharmaceutical composition according to claim 1 characterized in that the ratio of the third generation HI receptor antagonist to binder is in the range of 1:20 to 1:45 and the ratio of NAC to total substance amount in the pharmaceutical formulation is in the range of 1-50% by weight.

17. The pharmaceutical composition according to claim 2 characterized in that the pharmaceutically acceptable excipients such as binder, sweetener, lubricant, flavoring agent, diluent, disintegrant, surfactant, glidant, solubility modulators, effervescent couple, coloring agent andcoating agents are also used in the active agent combination.

18. The pharmaceutical composition according to claim 17 characterized in that the binder used in said composition is selected from a 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.

19. The pharmaceutical composition according to claim 18 characterized in that and polyvinylpyrrolidone is used as binder in said pharmaceutical composition.

20. The pharmaceutical composition according to claim 17 characterized in that the sweetener used in said composition is selected from a group comprising sucralose, sucrose, fructose, glucose, galactose, xylose, dextrose, levulose, lactose, maltose, maltodextrin, mannitol, maltitol, maltol, sorbitol, xylitol, erythritol, lactitol, isomalt, corn syrup, saccharine, saccharine salts, acesulfam potassium, aspartam, D- tryptophane, monoammonium glycyrrhizinate, neospherydine dihydrochalcone, thaumatine, neotame, alitame, stevioside, cyclamates and sodium chloride.

21. The pharmaceutical composition according to claim 17 characterized in that the lubricant used in said composition is selected from metallic stearates (such as magnesium stearate, calcium stearate, aluminum stearate), fatty acid esters (such as sodium stearyl 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.

22. The pharmaceutical composition according to claim 17 characterized in that the diluent used in said composition is selected from a 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.

23. The pharmaceutical composition according to claim 17 characterized in that the disintegrant used in said composition is selected from starches (corn starch, potato starch); sodium starch gyicolate, pregelatinized starch, cellulose derivatives (such as croscarmellose sodium or microcrystalline cellulose), polyvinylpyrrolidone (PVP), crospovidone, alginic acid, sodium alginate, clays (such as xanthan gum 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 such as sodium hydrogen sulphate, potassium hydrogen sulphate, sodium dihydrogen phosphate, succinic acid, tartaric acid, adipic acid, citric acid).

24. The pharmaceutical composition according to claim 17 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.

25. The pharmaceutical composition according to claim 17 characterized in that the surfactant used is selected from a group comprising polyoxyethylene-sorbitan-fatty acid esters (polysorbates), sodium lauryl sulphate, sodium stearyl 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.