Pharmaceutical composition and sterile powder for treatment of physiological disorders, conditions or diseases and their use

Abstract

FIELD: pharmaceutical compositions.SUBSTANCE: group of inventions relates to a pharmaceutical composition for treating physiological disorders, conditions or diseases in a patient, containing a compound of formula I or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the stabilizer is selected from one or more of arginine, glucose and sucrose, to a sterile powder for treating physiological disorders, conditions or diseases in a patient, containing a compound of formula I or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the stabilizer is selected from one or more of arginine, glucose and sucrose, wherein the sterile powder is obtained by freeze-drying or spray-drying the pharmaceutical composition, as well as to their use.EFFECT: production of a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, which is characterized by excellent stability.14 cl, 4 ex

Description

[0001] This application claims the right of priority under CN 202210032508.4, filed on January 12, 2022. TECHNICAL FIELD TO WHICH THE INVENTION RELATS

[0002] The present invention belongs to the field of pharmaceuticals and in particular relates to a pharmaceutical composition for the treatment of physiological disorders, conditions or diseases in a patient, comprising a prodrug compound that is a neurokinin-1 antagonist, to a sterile powder for the treatment of physiological disorders, conditions or diseases in a patient and to their use in the treatment of physiological disorders, conditions or diseases in a patient.BACKGROUND

[0003] Tachykinins are peptide ligands of neurokinin receptors. Neurokinin receptors such as NK1, NK2, and NK3 are involved in various biological processes. They can be found in the nervous and cardiovascular systems of mammals, as well as in surrounding tissues. Therefore, the regulation of these receptors has been studied for potential treatment or prevention of various physiological disorders, conditions, and diseases in mammals.

[0004] Meanwhile, drug-induced hemolysis is caused by the destruction of a large number of red blood cells due to immune factors after drugs enter the human body, and the clinical signs of hemolysis include anemia, jaundice, and soy sauce-colored urine. Drug-induced hemolytic anemia can be divided into the following three types: (1) drug-induced immune hemolytic anemia, which results in an antibody-mediated hemolytic reaction; (2) hemolytic anemia caused by drug exposure to red blood cells with congenital enzyme deficiency (such as G6PD deficiency); (3) hemolytic anemia caused by drug-induced hemolytic reaction to abnormal hemoglobin. The key factors in the treatment of this disease are to discontinue the use of specific drugs and control the occurrence of hemolysis to prevent complications.

[0005] WO2020259675 provides a novel prodrug compound which is an NK1 antagonist (formula I), which is effective in the treatment of various physiological disorders, conditions or diseases with minimal side effects and which is characterized by high pharmaceutical activity. ESSENCE OF THE PRESENT INVENTION

[0006] The object of the present invention is to provide a pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof, wherein the composition is characterized by excellent stability.

[0007] In a first aspect of the present invention, there is provided a pharmaceutical composition for the treatment of physiological disorders, conditions or diseases in a patient, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the stabilizer is selected from one or more of arginine, glucose and sucrose, .

[0008] In a preferred embodiment, the stabilizer is arginine and / or glucose.

[0009] In a preferred embodiment, the pharmaceutical composition further comprises a solvent, the solvent being selected from water, an organic solvent or a water / organic solvent co-solvent system.

[0010] In a preferred embodiment, the solvent is selected from water, ethanol, isopropanol, tert-butanol, a water / ethanol mixture, a water / isopropanol mixture, or a water / tert-butanol mixture.

[0011] In a preferred embodiment, the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof and the stabilizer is from 1:0.1 to 1:20; or wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a weight-volume percentage of 0.01-30%.

[0012] In a preferred embodiment, the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof and the stabilizer is from 1:1 to 1:7.5, or wherein the compound of formula I or a pharmaceutically acceptable salt thereof has a weight-volume percentage of 0.1-5%.

[0013] In a preferred embodiment, the stabilizer has a mass-volume percentage of 0.01-30%.

[0014] In a preferred embodiment, the stabilizer has a mass-volume percentage of 0.1-10%.

[0015] In a preferred embodiment, the pharmaceutical composition satisfies one or more of the following conditions: (1) the pharmaceutical composition further comprises a buffer; (2) the pharmaceutical composition further comprises a pH adjuster; (3) the pharmaceutical composition further comprises a chelating agent; (4) the pharmaceutical composition is characterized by a pH of 3.0-8.0; (5) the pharmaceutical composition further comprises a 5-HT3 receptor antagonist; (6) the pharmaceutical composition comprises: a compound of Formula I or a pharmaceutically acceptable salt thereof; a stabilizer selected from one or more of arginine, glucose, and sucrose; or the pharmaceutical composition comprises: 0.01-10% of a compound of Formula I or a pharmaceutically acceptable salt thereof; 0.01-20% of a stabilizer selected from one or more of arginine, glucose, and sucrose;a solvent, wherein the solvent is selected from water and / or tert-butanol, wherein the solvent is characterized by a mass-volume percentage fraction of 70-99%; the percentage fractions are indicated in terms of mass-volume percentage fractions.

[0016] In a preferred embodiment, the pharmaceutical composition satisfies one or more of the following conditions: (1) the pharmaceutical composition further comprises a buffer, wherein the buffer is a phosphate buffer, a citrate buffer, an acetate buffer, a succinate buffer, a histidine salt buffer, or other organic acid salt buffers. (2) the pharmaceutical composition further comprises a buffer, wherein the buffer has a concentration of 5-40 mM; (3) the pharmaceutical composition further comprises a chelating agent, wherein the chelating agent is ethylenediaminetetraacetic acid or a salt thereof; (4) the pharmaceutical composition further comprises a chelating agent, wherein the chelating agent has a weight-volume percentage of 0.001-5%, or the weight ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof and the chelating agent is from 1000:1 to 1:1;(5) the pharmaceutical composition is characterized by a pH of 5.0-8.0;(6) the pharmaceutical composition further comprises a 5-HT3 receptor antagonist, wherein the 5-HT3 receptor antagonist is selected from granisetron, ondansetron, ramosetron, tropisetron, palonosetron, or dolasetron;(7) the pharmaceutical composition further comprises a 5-HT3 receptor antagonist, wherein the 5-HT3 receptor antagonist has a weight-volume percentage of 0.0001-1%, or the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the 5-HT3 receptor antagonist is from 2000:1 to 10:1;(8) the pharmaceutical composition comprises: a compound of formula I or a pharmaceutically acceptable salt thereof; a stabilizer selected from one or more of arginine, glucose, and sucrose; palonosetron, or its pharmaceutically acceptable salt; buffer; chelating agent;or the pharmaceutical composition comprises: 0.01-10% of a compound of formula I or a pharmaceutically acceptable salt thereof; 0.01-20% of a stabilizer selected from one or more of arginine, glucose, and sucrose; palonosetron or a pharmaceutically acceptable salt thereof with a weight-volume percentage of 0.0001-1%; a buffer with a concentration of 5-40 mM; a chelating agent with a weight-volume percentage of 0.01-2%; a solvent, where the solvent is selected from water and / or tert-butanol, wherein the solvent is characterized by a weight-volume percentage of 70-99%; the percentages are indicated in terms of weight-volume percentages.

[0017] In a second aspect of the present invention, there is further provided a sterile powder for the treatment of physiological disorders, conditions or diseases in a patient, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the stabilizer is selected from one or more of arginine, glucose and sucrose, wherein the sterile powder is obtained by freeze-drying or spray-drying the above pharmaceutical composition.

[0018] In a preferred embodiment, the sterile powder contains less than 5% impurities based on the original form of the drug.

[0019] In a preferred embodiment, the sterile powder contains less than 3% impurities based on the original form of the drug.

[0020] In a third aspect of the present invention, there is provided the use of the above pharmaceutical composition or the above sterile powder for the treatment of physiological disorders, conditions or diseases in a patient, wherein the physiological disorders, conditions or diseases are selected from the group consisting of respiratory diseases, cough, inflammatory diseases, skin disorders, ophthalmological disorders, depression, anxiety, phobia, bipolar disorder, alcohol dependence, substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDS-related dementia, Town's disease, stress-related disorders, obsessive-compulsive disorders, bulimia, anorexia nervosa, binge eating disorder, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disorder, obesity, type II diabetes, headache, neuropathic pain, pain after exercise,chronic pain syndrome, bladder disorders, genitourinary disorders, vomiting or nausea,

[0021] The “mass-volume percentage” (weight / volume) in the present invention refers to the mass (in g) of a component contained in 100 ml of a liquid system, i.e., g / 100 ml.

[0022] The content (including percentage) of various substances and all ratios of various substances with each other in the present invention have an allowable error of ±5%. For example, the expression "the content of the compound of Formula I or a pharmaceutically acceptable salt thereof in the composition is from 5 to 20 mg / ml" means that the content of the compound of Formula I or a pharmaceutically acceptable salt thereof in the composition is from 4.75 to 21 mg / ml, which is within the scope of the present invention; the expression "the weight ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof and the stabilizer is selected from 1:1 to 1:100" means that the weight ratio of the compound of Formula I or a pharmaceutically acceptable salt thereof and the stabilizer is selected from 1:0.95 to 1:105, which is within the scope of the present invention.

[0023] The expressions "mixing...in..." and "mixing...with..." in the present invention mean that the sequence of adding the components is not limited. For example, "mixing in B" may mean adding to B and may also mean adding B to A, and "mixing with B" may mean adding A to B for mixing and may also mean adding B to A for mixing. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT

[0024] Example 1

[0025] According to the ratio (weight / volume) in the table below, 90% of the target volume of the solvent was taken, the prescribed amount of stabilizer was added to the solvent, the pH of the resulting solution was adjusted with hydrochloric acid to pH < 7, the starting material, which is a compound of Formula I, was added to the solution, and the resulting mixture was stirred to dissolve at room temperature. The pH was adjusted with dilute hydrochloric acid or sodium hydroxide, filtered with an organic filter membrane with a pore size of 45 μm to obtain a clear solution, and the volume of the clear solution was adjusted with solvent. The above solution was stored at 4 o C before packaging. After packaging according to the target volume, half of the stopper was compressed and freeze-dried. After the procedure was complete, nitrogen was flushed, the remaining stopper was compressed, and the freeze-dried compounds were removed from the container. № Content of compound of formula I Stabilizer Stabilizer content Solvent system pH of the system Other supporting materials 1 2% Sucrose 5% Water 8 2 2% Glucose 5% Water 8 3 2% Lactose 2% Water 8 4 2% Arginine 5% Water 8 5 2% Histidine 2% Water 8 6 2% Proline 5% Water 8 7 2% SBECD 5% Water 8 8 2% Hydroxyethyl starch 2% Water 8 9 2% PEG 4000 2% Water 8 10 2% PVP K12 2% Water 8 11 2% Dextran 40k 2% Water 8 12 4,36% Trehalose 5% 50% TBA 5 13 4,36% Mannitol 5% 50% TBA 5 14 4,35% NADA 8% 50% TBA 5 15 3,00% Maltose 5% 50% TBA 5 16 3,0% Arginine 5% 50% TBA 5 20 mM citrate buffer 17 2,1% Arginine 5% Water 8 0.05% EDTA-2NaCa 18 3,00% Arginine 5% 50% TBA 3 19 3,00% Arginine 5% 50% TBA 4 20 3,00% Arginine 5% 50% TBA 5 21 3,00% Arginine 5% 50% TBA 6 22 3,00% Arginine 5% 50% TBA 7 23 3,00% Arginine 5% 50% TBA 8 24 3,00% Sucrose 5% 50% TBA 5 25 3,00% Sucrose 5% 50% TBA 8 26 3,00% Glucose 3% 50% TBA 5 27 3,00% Glucose 3% 50% TBA 8

[0026] 50% TBA: 50% tert-butanol aqueous solution; SBECD: sulfobutyl ether β-cyclodextrin; PVP: polyvinylpyrrolidone; NADA: N-acetyl-D-alanine.

[0027] Example 2

[0028] Samples of the drug obtained in Example 1 were placed under accelerated research conditions (25 oC, 60% RH) and determined the content of the active substance and impurities. Detection method: detection was performed using a high-performance liquid chromatography system, where the chromatographic column was ACE Excel 3 SuperC18, 4.6 × 150 mm, 3 μm, the mobile phase was potassium dihydrogen phosphate solution with a concentration of 0.01 mol / L and pH 7.0, mobile phase B was acetonitrile, and the detection wavelength was 210 nm.

[0029] The detection results are shown in the table below. The impurity, based on the original form of the drug, is rolapitant, formed by the degradation of the compound of formula I. № Stabilizer Stability condition Purity (%) Impurity based on the original form of the drug (%) 1 Sucrose 0 0 days 99,33 0,46` 25oC / 60% RH 14 days 98,82 0,94 30 days 98,54 1,24 60 days 98,19 1,63 2 Glucose 0 0 days 99,42 0,36 25oC / 60% RH 14 days 99,38 0,48 30 days 99,15 0,72 60 days 98,47 1,37 90 days 97,73 1,89 3 Lactose 0 0 days 98,4 1,04 25oC / 60% RH 14 days 95,38 3,16 4 Arginine 0 0 days 99,43 0,37 25oC / 60% RH 14 days 99,25 0,57 30 days 99,14 0,69 60 days 98,92 0,89 90 days 98,83 0,98 5 Histidine 0 0 days 98,37 1,12 25oC / 60% RH 14 days 94,58 3,89 90 days 88,43 9,01 6 Proline 0 0 days 99,39 0,43 25oC / 60% RH 14 days 96,53 2,79 90 days 50,71 40,80 7 SBECD 0 0 days 93,28 3,6 25oC / 60% RH 14 days 81,15 10,92 90 days 63,95 22,77 8 Hydroxyethyl starch 0 0 days 91,90 3,83 25oC / 60% RH 14 days 82,069 9,55 9 PEG 4000 0 0 days 90,44 4,74 25oC / 60% RH 14 days 78,772 10,881 10 PVP K12 0 0 days 88,20 5,81 25oC / 60% RH 14 days 86,121 / 11 Dextran 40k 0 0 days 92,79 3,59 25oC / 60% RH 14 days 82,914 9,168 12 Trehalose 0 0 days 99,087 0,504 25oC / 60% RH 7 days 98,36 1,06 14 days 97,63 1,58 13 Mannitol 0 0 days 98,949 0,494 25oC / 60% RH 7 days 98,09 1,03 14 days 97,19 1,56 14 NADA 0 0 days 98,87 0,39 25oC / 60% RH 7 days 97,85 1,01 14 days 97,15 1,45 30 days 95,65 2,36 15 Maltose 0 0 days 99,24 0,41 25oC / 60% RH 7 days 98,48 0,91 14 days 97,80 1,42 30 days 96,95 2,03 16 Arginine 0 0 days 99,19 0,43 25oC / 60% RH 7 days 99,13 0,51 14 days 98,91 0,63 30 days 98,72 0,74 60 days 98,34 0,97 90 days 98,12 1,21 17 Arginine 0 0 days 99,53 0,38 25oC / 60% RH 7 days 98,88 0,90 14 days 98,81 0,95 30 days 99,10 0,78 90 days 98,72 1,00 18 Arginine 0 0 days 99,21 0,40 25oC / 60% RH 07 days 98,86 0,64 14 days 98,49 0,76 30 days 97,95 1,24 60 days 97,33 1,82 90 days 96,51 2,74 19 Arginine 0 0 days 99,24 0,41 25oC / 60% RH 07 days 98,92 0,63 14 days 98,61 0,80 30 days 98,31 1,01 60 days 97,72 1,44 90 days 97,10 1,99 20 Arginine 0 0 days 99,24 0,40 25oC / 60% RH 07 days 98,94 0,60 14 days 98,71 0,75 30 days 98,36 0,96 60 days 97,75 1,37 90 days 97,25 1,88 21 Arginine 0 0 days 99,25 0,39 25oC / 60% RH 07 days 98,96 0,58 14 days 98,78 0,69 30 days 98,31 1,02 60 days 97,86 1,36 90 days 97,84 1,4 22 Arginine 0 0 days 99,27 0,37 25oC / 60% RH 07 days 98,92 0,61 14 days 98,75 0,88 30 days 98,34 1,06 60 days 97,88 1,40 90 days 97,56 1,76 23 Arginine 0 0 days 99,20 0,43 25oC / 60% RH 07 days 98,69 0,80 14 days 98,60 0,89 30 days 98,32 1,11 60 days 97,58 1,64 90 days 97,24 2,02 24 Sucrose 0 0 days 99,25 0,39 25oC / 60% RH 07 days 98,53 0,94 14 days 98,08 1,34 30 days 97,22 1,98 25 Sucrose 0 0 days 98,74 0,69 25oC / 60% RH 07 days 97,58 1,53 14 days 96,61 2,18 30 days 95,91 2,76 26 Glucose 0 0 days 99,24 0,41 25oC / 60% RH 07 days 98,97 0,62 14 days 98,63 0,90 30 days 98,03 1,23 60 days 97,34 1,85 90 days 95,82 3,37 27 Glucose 0 0 days 98,95 0,58 25oC / 60% RH 07 days 97,95 1,26 14 days 97,93 1,31 30 days 97,35 1,70 60 days 97,40 1,87 90 days 96,17 2,71

[0030] After being placed under accelerated conditions, the freeze-dried preparations in which the stabilizers are sucrose, glucose and arginine have a slight change in purity and contain a small amount of impurity based on the original form of the drug formed as a result of destruction, indicating good stability.

[0031] Example 3

[0032] A freeze-dried compound preparation containing a compound of the formula I and palonosetron hydrochloride was prepared using the method of Example 1 according to the ratio (weight / volume) in the table below. № Content of compound of formula I Palonosetron hydrochloride content Stabilizer Solvent system pH of the system Buffer Chelating agent 1 3,11% 0,004011% 5% Arginine Water 6,5 20 mM Citrate 0.5% EDTA-2NaCa

[0033] Example 4

[0034] The drug sample obtained in Example 3 was placed under accelerated research conditions (25 o C, 60% RH) and determined the active substance content and impurities. The results are shown in the table below. № Stability condition Total impurity content (%) Impurity based on the original form of the drug (%) 1 0 0 days 1,18 0,37 25oC / 60% RH 7 days 1,32 0,53 1 M 1,42 0,82 2 M 1,48 1,07

Claims

1. A pharmaceutical composition for the treatment of physiological disorders, conditions or diseases in a patient, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the stabilizer is selected from one or more of arginine, glucose and sucrose .

2. The composition according to claim 1, wherein the stabilizer is arginine and / or glucose.

3. The composition according to claim 1 or 2, wherein the pharmaceutical composition additionally contains a solvent, the solvent being selected from water, an organic solvent or a water / organic solvent co-solvent system.

4. The composition according to claim 3, wherein the solvent is selected from water, ethanol, isopropanol, tert-butanol, a water / ethanol mixture, a water / isopropanol mixture, or a water / tert-butanol mixture.

5. A composition according to any one of claims 1 to 4, wherein the weight ratio of the compound of formula I or its pharmaceutically acceptable salt to the stabilizer is from 1:0.1 to 1:20, or wherein the compound of formula I or its pharmaceutically acceptable salt has a mass-volume percentage of 0.01-30%.

6. The composition according to claim 5, wherein the weight ratio of the compound of formula I or its pharmaceutically acceptable salt and the stabilizer is from 1:1 to 1:7.5 or wherein the compound of formula I or its pharmaceutically acceptable salt is characterized by a mass-volume percentage of 0.1-5%.

7. The composition according to any one of paragraphs 1-6, wherein the stabilizer is characterized by a mass-volume percentage of 0.01-30%.

8. The composition according to claim 7, wherein the stabilizer is characterized by a mass-volume percentage of 0.1-10%.

9. The composition according to any one of claims 1-8, wherein the pharmaceutical composition satisfies one or more of the following conditions: (1) the pharmaceutical composition further comprises a buffer; (2) the pharmaceutical composition additionally contains a pH regulator; (3) the pharmaceutical composition further comprises a chelating agent; (4) the pharmaceutical composition is characterized by a pH value of 3.0-8.0; (5) the pharmaceutical composition further comprises a 5-HT3 receptor antagonist; (6) the pharmaceutical composition contains: a compound of formula I or a pharmaceutically acceptable salt thereof; a stabilizer selected from one or more of arginine, glucose and sucrose; or the pharmaceutical composition contains: 0.01-10% of a compound of formula I or a pharmaceutically acceptable salt thereof; 0.01-20% of a stabilizer selected from one or more of arginine, glucose and sucrose; a solvent, wherein the solvent is selected from water and / or tert-butanol, wherein the solvent is characterized by a mass-volume percentage of 70-99%; The percentages are given in terms of mass-volume percentages.

10. The composition according to any one of claims 1-8, wherein the pharmaceutical composition satisfies one or more of the following conditions: (1) the pharmaceutical composition further comprises a buffer, wherein the buffer is a phosphate buffer, a citrate buffer, an acetate buffer, a succinate buffer, a histidine salt buffer, or buffers based on salts of other organic acids; (2) the pharmaceutical composition additionally contains a buffer, wherein the buffer has a concentration of 5-40 mM; (3) the pharmaceutical composition further comprises a chelating agent, wherein the chelating agent is ethylenediaminetetraacetic acid or a salt thereof; (4) the pharmaceutical composition further comprises a chelating agent, wherein the chelating agent is characterized by a mass-volume percentage of 0.001-5%, or the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the chelating agent is from 1000:1 to 1:1; (5) the pharmaceutical composition is characterized by a pH value of 5.0-8.0; (6) the pharmaceutical composition further comprises a 5-HT3 receptor antagonist, wherein the 5-HT3 receptor antagonist is selected from granisetron, ondansetron, ramosetron, tropisetron, palonosetron or dolasetron; (7) the pharmaceutical composition further comprises a 5-HT3 receptor antagonist, wherein the 5-HT3 receptor antagonist is characterized by a mass-volume percentage of 0.0001-1%, or the weight ratio of the compound of formula I or a pharmaceutically acceptable salt thereof to the 5-HT3 receptor antagonist is from 2000:1 to 10:1; (8) the pharmaceutical composition contains: a compound of formula I or a pharmaceutically acceptable salt thereof; a stabilizer selected from one or more of arginine, glucose and sucrose; palonosetron or its pharmaceutically acceptable salt; buffer; chelating agent; or the pharmaceutical composition contains: 0.01-10% of a compound of formula I or a pharmaceutically acceptable salt thereof; 0.01-20% of a stabilizer selected from one or more of arginine, glucose and sucrose; palonosetron or its pharmaceutically acceptable salt with a mass-volume percentage of 0.0001-1%; buffer with a concentration of 5-40 mM; chelating agent with a mass-volume percentage of 0.01-2%; a solvent, wherein the solvent is selected from water and / or tert-butanol, wherein the solvent is characterized by a mass-volume percentage of 70-99%; The percentages are given in terms of mass-volume percentages.

11. A sterile powder for treating physiological disorders, conditions or diseases in a patient, comprising a compound of formula I or a pharmaceutically acceptable salt thereof and a stabilizer, wherein the stabilizer is selected from one or more of arginine, glucose and sucrose, wherein the sterile powder is obtained by freeze-drying or spray-drying the pharmaceutical composition according to any one of claims 1-10.

12. The powder of claim 11, wherein the sterile powder contains less than 5% impurities based on the original form of the drug.

13. The powder of claim 12, wherein the sterile powder contains less than 3% impurities based on the original form of the drug.

14. Use of a pharmaceutical composition according to any of claims 1-10 or a sterile powder according to any of claims.11-13 for the treatment of physiological disorders, conditions or diseases in a patient, wherein the physiological disorders, conditions or diseases are selected from the group consisting of respiratory diseases, cough, inflammatory diseases, skin disorders, ophthalmological disorders, depression, anxiety, phobia, bipolar disorder, alcohol dependence, substance abuse, epilepsy, nociception, psychosis, schizophrenia, Alzheimer's disease, AIDS-related dementia, Town's disease, stress-related disorders, obsessive-compulsive disorders, bulimia, anorexia nervosa, binge eating disorder, mania, premenstrual syndrome, gastrointestinal dysfunction, atherosclerosis, fibrotic disorder, obesity, type II diabetes, headache, neuropathic pain, pain after exercise, chronic pain syndrome, bladder disorders, genitourinary disorders system, vomiting or nausea.

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