Topiramate pharmaceutical composition and preparation method thereof

Abstract

The invention provides a preparation method of a topiramate pharmaceutical composition and the topiramate pharmaceutical composition. The preparation method comprises the following steps: dissolving a flavoring agent in an organic solvent which is heated to a certain temperature, and then adding topiramate, other organic solvents and other components. According to the preparation method disclosed by the invention, the dissolution rate of the flavoring agent is improved while the quality of the medicine is ensured, the process time is shortened, and the prepared pharmaceutical composition has remarkably improved quality stability.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical preparations, and particularly relates to a liquid pharmaceutical composition of topiramate and a preparation method thereof. Background Art

[0002] As a new type of anti-epileptic active ingredient, topiramate mainly works by blocking sodium channels in a state-dependent manner, increasing the frequency of γ-aminobutyric acid (GABA) activating GABAA receptors, and enhancing GABA-induced chloride ion influx into neurons. Topiramate can not only be used for monotherapy, but also has a high response rate in add-on therapy. Early add-on therapy is more likely to achieve seizure freedom. It can also be used for epileptic spasms, various types of epileptic seizures, difficult-to-type epileptic seizures, Lennox-Gastaut, etc. Topiramate tablets and capsules have been launched in China. However, during an epileptic seizure, the patient's body will experience brief involuntary convulsions in a certain part or the entire body (i.e., partial seizures or generalized seizures), sometimes accompanied by loss of consciousness or severe and persistent convulsions of muscle reflexes. The use of tablets and capsules is restricted. In order to facilitate oral administration by patients with dysphagia and children, Azurity Pharmaceuticals Inc. developed topiramate oral solution (Topiramate Oral Solution), which was approved by the FDA for the first time in the United States in November 2021. The trade name is EPRONTIA TM The specification is 25mg / ml. The original research has not been reported in China, so this oral liquid dosage form is not available for sale in China.

[0003] US2021169844A1 (original research patent) discloses a liquid preparation containing topiramate, including multiple components such as active ingredients, solvents, antibacterial agents, flavoring agents and aromatics, and realizes drug production through weighing, liquid preparation, filtration and filling processes. However, according to the original research patent embodiment 1, the liquid preparation process needs to be fed in five steps, in which the viscous material glycerol needs to be fed twice, and multiple feedings will increase material loss, which not only causes resource loss but also affects the accuracy of feeding. Secondly, the dissolution rate of the flavoring agent sucralose in polyethylene glycol 400 and glycerol is relatively small, which prolongs the liquid preparation time and increases the resource loss of manpower and material resources. Finally, the topiramate liquid preparation prepared according to the original research patent preparation process is unstable in active ingredients under high temperature conditions, and the content is significantly reduced after being placed under high temperature conditions for a period of time, or even unqualified, which is very unfavorable to its product quality. Therefore, there is still room for optimization of this process step to minimize resource waste while ensuring product quality. Summary of the invention

[0004] The main purpose of the present invention is to provide an improved preparation process of a topiramate liquid pharmaceutical composition, which can significantly improve the dissolution rate of the flavoring agent, shorten the total process time, reduce energy consumption, and reduce production costs while ensuring the quality of the drug. In addition, it is surprisingly found that the quality stability (especially high temperature stability) of the topiramate liquid pharmaceutical composition prepared by the present invention is significantly improved compared with the original preparation.

[0005] To achieve the above purpose, the technical solution adopted by the present invention is as follows:

[0006] The first aspect of the present invention provides a liquid pharmaceutical composition of topiramate, comprising: topiramate or a pharmaceutically acceptable salt thereof as an active ingredient, an organic solvent, and a flavoring agent (preferably a sweetener) and other components.

[0007] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight:

[0008] 0.1-18.0% topiramate or a pharmaceutically acceptable salt thereof;

[0009] 75.0-99.0%% organic solvent; and

[0010] 0.05%~4.0% flavor enhancer.

[0011] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight:

[0012] 0.1-18.0% topiramate or a pharmaceutically acceptable salt thereof;

[0013] 75.0~99.0%% organic solvent;

[0014] 0.05%~4.0% antibacterial agent;

[0015] 0.05% to 4.0% flavoring agent; and

[0016] 0.02~3.0% fragrance.

[0017] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight:

[0018] 0.5-14.0% topiramate or a pharmaceutically acceptable salt thereof;

[0019] 80.0-97.0% organic solvent;

[0020] 0.5% to 3.0% antibacterial agent;

[0021] 0.2% to 2.5% flavoring agent; and

[0022] 0.06~1.0% fragrance.

[0023] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight:

[0024] 1.0-5.5% topiramate or a pharmaceutically acceptable salt thereof;

[0025] 90.0-96.0% organic solvent;

[0026] 1.5% to 2.5% antibacterial agent;

[0027] 0.4% to 1.5% flavoring agent; and

[0028] 0.08~0.5% fragrance.

[0029] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight:

[0030] 2.08% topiramate or a pharmaceutically acceptable salt thereof;

[0031] 94.92% organic solvent;

[0032] 2.0% antibacterial agent;

[0033] 0.83% flavoring agents; and

[0034] 0.17% fragrance.

[0035] In some embodiments of the present invention, the organic solvent is selected from one or more of glycerol, ethanol, propylene glycol, polyether, polyethylene glycol and hydrogenated vegetable oil.

[0036] In some embodiments of the present invention, the organic solvent is a mixture of glycerol and polyethylene glycol with a molecular weight of 300-1000.

[0037] In some embodiments of the present invention, the organic solvent is a mixture of glycerol and polyethylene glycol with a molecular weight of 400.

[0038] In some embodiments of the present invention, the weight ratio of glycerol to polyethylene glycol in the mixture of glycerol and polyethylene glycol is 3:1 to 1:2, more preferably 2:1 to 1:1, and more preferably 53.25:41.67.

[0039] In some embodiments of the present invention, the antibacterial agent is selected from parabens, halogenated diphenyl ethers, plant extracts and quaternary ammonium salts.

[0040] In some embodiments of the present invention, the antibacterial agent is selected from one or more of methyl parahydroxybenzoate, ethyl parahydroxybenzoate, propyl parahydroxybenzoate and butyl parahydroxybenzoate.

[0041] In some embodiments of the present invention, the antibacterial agent is selected from a mixture of methylparaben and propylparaben.

[0042] In some embodiments of the present invention, the weight ratio of methylparaben to propylparaben is 15:1 to 1:15, more preferably 9:1.

[0043] In some embodiments of the present invention, the flavoring agent includes one or more of sucralose, sucrose, aspartame, mannitol, sorbitol, xylitol and high fructose corn syrup.

[0044] In some embodiments of the present invention, the flavoring agent is selected from sucralose.

[0045] In some embodiments of the present invention, the fragrance includes synthetic fragrances, natural oils, extracts from plants, leaves, flowers, fruits, etc., and combinations thereof.

[0046] In some embodiments of the present invention, the fragrance is selected from one or more of mixed berry essence, strawberry essence, orange essence, grape essence, cherry essence, vanilla essence, mint essence and citrus essence. Preferably, the fragrance is selected from mixed berry essence.

[0047] In some embodiments of the present invention, the pharmaceutical composition comprises, by weight:

[0048] 2.08% topiramate;

[0049] 53.25% glycerol;

[0050] 41.67% polyethylene glycol 400;

[0051] 1.80% methylparaben;

[0052] 0.20% propylparaben;

[0053] 0.83% sucralose;

[0054] 0.17% mixed berry flavor.

[0055] The second aspect of the present invention provides a method for preparing the pharmaceutical composition of the first aspect, the method comprising the following steps:

[0056] Solution 1

[0057] 1) heating an organic solvent 1 to 30-60° C., adding a flavoring agent (preferably a sweetener), and mixing and dissolving the organic solvent 1; the organic solvent 1 is selected from one or more of polyethylene glycol, polyether or hydrogenated vegetable oil;

[0058] 2) adding topiramate or a pharmaceutically acceptable salt thereof to the solution obtained in step 1);

[0059] 3) adding an organic solvent 2 to the solution obtained in step 2) to mix and dissolve; the organic solvent 2 is selected from one or more of glycerol, ethanol or propylene glycol;

[0060] Solution 2

[0061] 1) weighing an organic solvent 1, heating it to 30-60° C., adding a flavoring agent (preferably a sweetener), and mixing and dissolving; the organic solvent 1 is selected from one or more of polyethylene glycol, polyether or hydrogenated vegetable oil;

[0062] 2) adding an organic solvent 2 to the solution obtained in step 1) to mix and dissolve; the organic solvent 2 is selected from one or more of glycerol, ethanol or propylene glycol;

[0063] 3) Adding topiramate to the solution obtained in step 2) and mixing to dissolve.

[0064] In some embodiments of the present invention, the preparation method further comprises the following steps:

[0065] Antibacterial agents and aromatics are further added to Scheme 1 and Scheme 2.

[0066] In some embodiments of the present invention, the preparation method further comprises the following steps:

[0067] In step 2) of scheme 1 or step 3) of scheme 2, an antibacterial agent is added and mixed and dissolved. There is no requirement for the order of adding the topiramate or its pharmaceutically acceptable salt and the antibacterial agent.

[0068] In step 3) of scheme 1 or step 2) of scheme 2, a fragrance is added and mixed and dissolved. There is no requirement for the order of adding the organic solvent 2 and the fragrance.

[0069] In some embodiments of the present invention, the organic solvent 1 is polyethylene glycol, preferably polyethylene glycol with a molecular weight of 300 to 1000, and more preferably polyethylene glycol with a molecular weight of 400.

[0070] In some embodiments of the present invention, the organic solvent 2 is glycerol.

[0071] In some embodiments of the present invention, the particle size of the flavoring agent in step 1) is less than 300 μm, preferably 40 to 220 μm, more preferably 60 to 200 μm, and more preferably 80 to 180 μm.

[0072] In some embodiments of the present invention, in step 1), the organic solvent 1 is stirred and heated to 30-60°C, preferably 35-55°C, and more preferably 40°C.

[0073] In some embodiments of the present invention, in step 1), a flavoring agent is added under stirring and dissolved.

[0074] In some embodiments of the present invention, the dissolution time of the flavoring agent in step 1) is 0.5-4.5 h, preferably 1.0-3.5 h, more preferably 1.0-2.5 h, more preferably 1.5 h.

[0075] In some embodiments of the present invention, step 1) further comprises a step of cooling the temperature after the flavoring agent is dissolved, preferably to below 30°C, preferably 15-30°C, more preferably 20-30°C, more preferably room temperature.

[0076] In some embodiments of the present invention, in step 2) of scheme 1 or step 3) of scheme 2, topiramate or a pharmaceutically acceptable salt thereof is added under stirring, or topiramate or a pharmaceutically acceptable salt thereof and an antibacterial agent are added under stirring and stirred to dissolve.

[0077] In some embodiments of the present invention, the temperature of step 2) of scheme 1 or step 3) of scheme 2 is controlled below 30°C, for example, at 15-30°C, preferably 20-30°C, more preferably room temperature.

[0078] In some embodiments of the present invention, the dissolution time of topiramate or its pharmaceutically acceptable salt and the antibacterial agent in step 2) of scheme 1 or step 3) of scheme 2 is 0.2-2.5 h, preferably 0.5-1.5 h, and more preferably 0.75 h.

[0079] In some embodiments of the present invention, in step 3) of scheme 1 or step 2) of scheme 2, the organic solvent 2 is added under stirring, or the organic solvent 2 and the aromatic agent are added under stirring and stirred to dissolve.

[0080] In some embodiments of the present invention, the temperature of step 3) of scheme 1 or step 2) of scheme 2 is controlled below 30°C, preferably 15-30°C, preferably 20-30°C, and more preferably room temperature.

[0081] In some embodiments of the present invention, the mixing and dissolving time in step 3) of scheme 1 or step 2) of scheme 2 is 5-30 min, preferably 10-20 min, and more preferably 15 min.

[0082] In some embodiments of the present invention, the method further comprises passing the solution obtained in step 3) through a filtration system and then filling the product.

[0083] The third aspect of the present invention provides a topiramate liquid pharmaceutical composition prepared according to the second aspect of the present invention.

[0084] Compared with the prior art, the present invention has the following beneficial effects:

[0085] 1) The present invention optimizes the batching process of the prior art, selects a more reasonable feeding sequence, controls the temperature of each feeding step, and finally prepares the oral solution through a three-step feeding, temperature-control and liquid preparation process. While ensuring the quality of the drug, the dissolution rate of the flavoring agent is significantly improved, the process time is shortened, the energy consumption is reduced, the production cost is greatly reduced, and it is conducive to realizing industrial production.

[0086] 2) The present invention further improves the dissolution rate by controlling the particle size of the flavoring agent (such as sucralose), thereby further shortening the process time and reducing production costs while ensuring the quality of the drug.

[0087] 3) The topiramate liquid pharmaceutical composition prepared according to the preparation method of the present invention has significantly higher quality stability (especially high temperature stability) than the original preparation while achieving the same therapeutic effect as the original preparation, thereby ensuring the quality and safety of the pharmaceutical composition, and providing a better compliance option for pediatric patients. DETAILED DESCRIPTION

[0088] In order to make the purpose, technical solution and advantages of the present invention more clearly understood, the present invention is further described in detail below through examples. It should be understood that the specific embodiments described herein are only used to explain the present invention and are not used to limit the present invention.

[0089] If the specific conditions are not specified in the examples, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. If the manufacturers of the reagents or instruments are not specified, they are all conventional products that can be purchased commercially.

[0090] Example 1 Sucralose Particle Size Control

[0091] The preparation process of the original patent includes the step of dissolving the flavoring agent sucralose in polyethylene glycol 400. Since the dissolution rate of sucralose in polyethylene glycol 400 is low, if the particle size is not selected properly, it will extend the production time, increase resource costs, and affect the taste of the product. The present invention screens the particle size of sucralose and finds that controlling the particle size of sucralose within a suitable range can shorten the liquid preparation time. In order to prevent the masking effect of the temperature increase on the particle size, the particle size screening examples are all carried out at room temperature.

[0092] The ingredient prescription of the topiramate liquid pharmaceutical composition of this example is shown in Table 1.

[0093] Table 1 Ingredients prescription

[0094]

[0095]

[0096] The preparation process of the topiramate liquid pharmaceutical composition in this embodiment includes the following steps: methylparaben and propylparaben are added to polyethylene glycol 400 and stirred to dissolve, topiramate is added and stirred to dissolve, sucralose is added and stirred to dissolve, and finally glycerin and mixed berry flavor are added and stirred to dissolve. The obtained experimental data are shown in Table 2.

[0097] Table 2 Sucralose particle size screening

[0098]

[0099] According to Table 2, the particle size D of sucralose 90 When the particle size is 300 μm, the dissolution rate is low and it cannot be completely dissolved for a long time (> 24 hours). After testing, only 74.06% of sucralose is dissolved, which affects the production progress. 90 At 80-180 μm, the dispersion in polyethylene glycol 400 is good, and the time required for complete dissolution is shortened to 20-24 h.

[0100] Example 2 Rationalization of feeding steps and step-by-step temperature control

[0101] Since different materials have different solubilities in different solvents, different feeding sequences will affect the preparation time of the solution, thereby affecting production efficiency and cost. This embodiment studies the feeding sequence and the operating temperature of each liquid preparation process, screens out efficient feeding and liquid preparation processes, and maximizes resource utilization. The feeding percentages of each component in this embodiment and the comparative example are shown in Table 1, wherein the feeding amount of topiramate in Example 2-1 is 7.5 kg, the feeding amount of topiramate in Example 2-2 and Comparative Examples 1 and 2 is 2.5 g, and the particle size D of the sucralose used is 1.5 g. 90 The liquid preparation process, process temperature and dissolution time of each test are shown in Table 3-6.

[0102] Table 3 Example 2-1 Liquid Preparation Process

[0103]

[0104] Table 4 Example 2-2 Liquid preparation process

[0105]

[0106] Table 5 Comparative Example 1 Liquid Preparation Process

[0107]

[0108] Table 6 Comparative Example 2 Liquid Preparation Process

[0109]

[0110]

[0111] It can be seen from Table 3-6 that Examples 2-1 and 2-2 using the preparation process of the present invention have significantly shortened preparation time, requiring only 2.5 and 2.0 hours, respectively. This indicates that the optimization of the feeding sequence and step-by-step temperature control can both increase the dissolution rate of sucralose, significantly shorten the preparation time, and ensure product quality.

[0112] Comparative Examples 1 and 2 prepare topiramate liquid pharmaceutical compositions according to the preparation process disclosed in the original patent US2021169844A1. Since the description of the preparation process of the topiramate liquid pharmaceutical composition in Example 1 of the original patent is inconsistent with the feeding amount and feeding number of glycerol stated in Table 1, Comparative Example 1 adds glycerol twice (process 2 and 5) according to Table 1 of the original patent, and Comparative Example 2 adds all glycerol in one process (process 5). It can be seen from Tables 4 and 5 that no matter which preparation process is adopted in the original patent, its liquid preparation time is much longer than the liquid preparation time of the present invention, and Comparative Example 2 still has undissolved material even after 28.3h.

[0113] Example 3 Product Stability

[0114] The stability of the topiramate liquid pharmaceutical composition prepared according to the preparation process of the present invention and the original preparation under different sample preparation conditions were investigated, and the stability data comparison is shown in Table 7.

[0115] Table 7 Comparison of stability data

[0116]

[0117] In the sampling conditions, "high temperature for 5 days" and "high temperature for 10 days" mean placing at a temperature of 60±2℃ for 5 days and 10 days respectively, "light for 10 days" means placing at room temperature for 10 days under a light ≥4500lx, and "high humidity for 10 days" means placing at room temperature for 10 days under a humidity of 92.5±5%RH.

[0118] It can be seen from Table 7 that the high temperature stability of the topiramate liquid pharmaceutical composition prepared according to the preparation process of the present invention is significantly better than that of the original preparation. The original preparation has a 14.8% decrease in topiramate content after being placed at high temperature for 5 days, and a 29.4% decrease in topiramate content after being placed at high temperature for 10 days, while the pharmaceutical composition prepared in Example 2-1 of the present invention has a 1.6% decrease in topiramate content after being placed at high temperature for 5 days, and a 3.4% decrease in topiramate content after being placed at high temperature for 10 days. This indicates that the optimized feeding sequence and step-by-step temperature control process of the present invention can further improve product stability, thereby improving product quality.

[0119] In the liquid preparation process of the present invention, sucralose is dissolved in polyethylene glycol 400 under the condition of controlling the temperature at 30-60° C., and a small amount of low-boiling organic matter such as ethylene oxide and formaldehyde remaining in the solvent is further volatilized, thereby avoiding the ring-opening reaction of ethylene oxide in a weak acid environment, maintaining a weak acid environment, and then inhibiting the hydrolysis of the alkaline ester of topiramate, thereby improving the stability of the product. In addition, step-by-step temperature control can prevent the influence of too low or too high temperature on product quality.

Claims

1. A method for preparing a topiramate liquid pharmaceutical composition, the method comprising the following steps: Solution 1 1) heating an organic solvent 1 to 30-60° C., adding a flavoring agent, and mixing and dissolving the organic solvent 1; the organic solvent 1 is selected from one or more of polyethylene glycol, polyether, or hydrogenated vegetable oil; 2) adding topiramate to the solution obtained in step 1); 3) adding an organic solvent 2 to the solution obtained in step 2) to mix and dissolve; the organic solvent 2 is selected from one or more of glycerol, ethanol or propylene glycol; Solution 2 1) weighing an organic solvent 1, heating it to 30-60° C., adding a flavoring agent, and mixing and dissolving; the organic solvent 1 is selected from one or more of polyethylene glycol, polyether or hydrogenated vegetable oil; 2) adding an organic solvent 2 to the solution obtained in step 1) to mix and dissolve; the organic solvent 2 is selected from one or more of glycerol, ethanol or propylene glycol; 3) Adding topiramate to the solution obtained in step 2) and mixing to dissolve.

2. The method for preparing a topiramate liquid pharmaceutical composition according to claim 1, further comprising the following steps: Further adding antibacterial agent and aromatic agent to scheme 1 and scheme 2; Preferably, an antibacterial agent is added in step 2) of scheme 1 or step 3) of scheme 2, mixed and dissolved, and there is no requirement for the order of adding the topiramate or its pharmaceutically acceptable salt and the antibacterial agent; an aromatic agent is added in step 3) of scheme 1 or step 2) of scheme 2, mixed and dissolved, and there is no requirement for the order of adding the organic solvent 2 and the aromatic agent.

3. The method for preparing a topiramate liquid pharmaceutical composition according to claim 1 or 2, characterized in that: In step 1), the particle size of the flavoring agent is less than 300 μm, preferably 40 to 220 μm, more preferably 60 to 200 μm, more preferably 80 to 180 μm; and / or In step 1), the organic solvent 1 is heated to 30-60° C. with stirring, and a flavoring agent is added under stirring, and stirring is continued until dissolved; and / or The dissolution time of the flavoring agent in step 1) is 0.5-4.5h; and / or Step 1) also includes a step of cooling the temperature after the flavoring agent is dissolved, preferably cooling the temperature to below 30°C.

4. The method for preparing a topiramate liquid pharmaceutical composition according to any one of claims 1 to 3, characterized in that: In step 2) of scheme 1 or step 3) of scheme 2, topiramate or a pharmaceutically acceptable salt thereof is added under stirring, or topiramate or a pharmaceutically acceptable salt thereof and an antibacterial agent are added under stirring, and stirring is continued until dissolved; and / or The temperature of step 2) of scheme 1 or step 3) of scheme 2 is controlled below 30°C; and / or The dissolution time of topiramate or its pharmaceutically acceptable salt and the antibacterial agent in step 2) of scheme 1 or step 3) of scheme 2 is 0.2-2.5h.

5. The method for preparing a topiramate liquid pharmaceutical composition according to any one of claims 1 to 4, characterized in that: Scheme 1 step 3) or scheme 2 step 2) adding organic solvent 2 under stirring, or adding organic solvent 2 and aromatic agent under stirring, and continuing stirring until dissolved; and / or The temperature of step 3) of scheme 1 or step 2) of scheme 2 is controlled below 30°C; and / or The mixing and dissolving time in step 3) of scheme 1 or step 2) of scheme 2 is 5-30 minutes.

6. The method for preparing a topiramate liquid pharmaceutical composition according to any one of claims 1 to 5, characterized in that: Further including: After the solution obtained in step 3) passes through the filtration system, the product is filled.

7. A topiramate liquid pharmaceutical composition prepared according to the preparation method according to any one of claims 1 to 6.

8. The topiramate liquid pharmaceutical composition according to claim 7, characterized in that: include: Topiramate or a pharmaceutically acceptable salt thereof, an organic solvent and a flavoring agent.

9. The topiramate liquid pharmaceutical composition according to claim 7 or 8, characterized in that: By weight, including: 0.1-18.0% topiramate or a pharmaceutically acceptable salt thereof; 75.0-99.0%% organic solvent; and 0.05%~4.0% flavoring agent; Preferably, the pharmaceutical composition comprises, by weight: 0.1-18.0% topiramate or a pharmaceutically acceptable salt thereof; 75.0~99.0%% organic solvent; 0.05%~4.0% antibacterial agent; 0.05% to 4.0% flavoring agent; and 0.02~3.0% fragrance.

10. The topiramate liquid pharmaceutical composition according to any one of claims 7 to 9, characterized in that: The organic solvent includes one or more of glycerol, ethanol, propylene glycol, polyether, polyethylene glycol and hydrogenated vegetable oil; Preferably, the organic solvent is a mixture of glycerol and polyethylene glycol with a molecular weight of 300 to 1000; Preferably, the organic solvent is a mixture of glycerol and polyethylene glycol with a molecular weight of 400; Preferably, the weight ratio of glycerol to polyethylene glycol in the mixture of glycerol and polyethylene glycol is 3:1 to 1:

2.

11. The topiramate liquid pharmaceutical composition according to any one of claims 7 to 10, characterized in that: The antibacterial agent is selected from p-hydroxybenzoic acid esters, halogenated diphenyl ethers, plant extracts and quaternary ammonium salts.

12. The topiramate liquid pharmaceutical composition according to any one of claims 7 to 11, characterized in that: The flavoring agent is a sweetener, and the sweetener includes one or more of sucralose, sucrose, aspartame, mannitol, sorbitol, xylitol and high fructose corn syrup.

13. The topiramate liquid pharmaceutical composition according to any one of claims 7 to 12, characterized in that: The fragrance includes synthetic fragrance, natural oil, extract from plants, leaves, flowers, fruits, etc. and combinations thereof.

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