A preparation method of terbinafine hydrochloride spray

Abstract

The present invention relates to the technical field of fungal treatment medicines, and specifically relates to a terbinafine hydrochloride spray. The terbinafine hydrochloride spray is prepared from the following raw materials, in parts by weight: 15 parts to 26 parts of a terbinafine hydrochloride and domperidone mixture solution, 2.3 parts to 3.5 parts of anhydrous sodium acetate, 2 parts to 5 parts of an absorption promoter, 6 parts to 8 parts of a moisturizer, 1.2 parts to 2.2 parts of a solubilizer, and 0.3 parts to 0.5 parts of a preservative. The absorption promoter added in the preparation method of the terbinafine hydrochloride spray provided by the present invention increases the absorption rate of the terbinafine hydrochloride spray after it is sprayed on an affected area, thereby preventing a large portion of the terbinafine hydrochloride spray from directly volatilizing during the absorption process, thereby preventing the terbinafine hydrochloride spray from fully exerting its effect.

Description

Technical Field

[0001] The present invention relates to the field of fungus treatment medicine, and in particular to a preparation method of terbinafine hydrochloride spray. Background Art

[0002] Terbinafine hydrochloride is an allylamine drug with broad-spectrum antifungal activity, effectively killing and inhibiting fungal growth. It was first developed by the Swiss company Sandoz in the 1990s and marketed under the trade name Lamisil. In 1997, my country approved the production and marketing of its raw materials, tablets, and ointment. This drug is widely used clinically to treat various fungal infections due to its multiple advantages. First, the course of treatment with terbinafine hydrochloride is typically short, allowing patients to recover more quickly. Second, it has significant efficacy, effectively treating fungal infections and preventing recurrences. Furthermore, it is generally well tolerated by patients and is less likely to experience adverse reactions, making it considered a safer treatment option. Years of clinical data have demonstrated that terbinafine hydrochloride is currently a safe and effective treatment for superficial fungal infections. It is widely recognized as a reliable antifungal agent for dermatophytes.

[0003] Terbinafine hydrochloride, after topical application, can penetrate the stratum corneum and closely combine with skin keratinocytes and be stored in the stratum corneum and dermal sebaceous glands, so it has a higher concentration in skin, hair and nail plate, and a long shelf life. Considering that small animal fungi often diffuse all over the body and hair, external dosage forms have a good therapeutic effect on local epidermis, and are characterized by being skin at the disease lesion site. Adopting external form administration, the liquid absorbs quickly and can rapidly bring into play drug effect, so the present invention decides to develop a dosage form suitable for topical application on skin, simultaneously because the terbinafine hydrochloride molecule contains a secondary amine group, it is made to present slightly alkaline property, so its solubility in water is lower, but it can be preferably dissolved in organic solvents such as isopropyl alcohol, methanol, ethanol, and is almost insoluble in ether. When preparing pharmaceutical dosage forms for topical application on skin, common selection includes emulsifiable paste, spray, gel etc. Compared with other dosage forms, spray form has some significant advantages. First, when using spray, there is no direct mechanical friction when the medicine contacts the skin, so the damage or stimulation to the skin can be reduced. Secondly, the spray is very convenient to use; it only requires a gentle spray, with no rubbing or massaging required. Furthermore, the uniform spray of medication helps ensure even distribution of the drug across the treatment area. Therefore, given these advantages, we decided to use the spray as our preferred delivery method.

[0004] Currently, the existing terbinafine hydrochloride spray has a slow absorption rate during use, resulting in a large portion of the terbinafine hydrochloride spray sprayed on the affected area being directly evaporated during the absorption process, and its effect cannot be fully exerted, requiring patients to use the drug multiple times and frequently. In addition, the terbinafine hydrochloride spray may be inhaled by the patient during use, causing nausea. Summary of the Invention

[0005] The object of the present invention is to provide a method for preparing a terbinafine hydrochloride spray, so as to solve the problem in the above-mentioned background art that the terbinafine hydrochloride spray has a slow absorption rate during use, thereby causing a large portion of the terbinafine hydrochloride spray sprayed on the affected area to directly evaporate during the absorption process, and thus failing to fully exert its effect.

[0006] To achieve the above objectives, the present invention provides the following technical solution: a terbinafine hydrochloride spray, which is prepared from the following raw materials, by weight: 15-26 parts of a terbinafine hydrochloride and domperidone mixture solution, 2.3-3.5 parts of anhydrous sodium acetate, 2-5 parts of an absorption enhancer, 6-8 parts of a moisturizer, 1.2-2.2 parts of a solubilizer, and 0.3-0.5 parts of a preservative.

[0007] Preferably, the absorption enhancer is one of propylene glycol, diglyceryl ether, and caprylic acid.

[0008] By using propylene glycol as an absorption enhancer for terbinafine hydrochloride spray, the drug can be evenly distributed in the treatment area, thereby improving the therapeutic effect. It can also improve the solubility of the drug in the skin or mucous membranes, helping the drug to be absorbed more quickly and effectively. At the same time, propylene glycol is generally considered to be a mild compound with low skin irritation, making it suitable for many skin treatment products.

[0009] Preferably, the moisturizing agent is one of glycerin, hyaluronic acid and mannitol.

[0010] By using glycerin as a moisturizer in terbinafine hydrochloride spray, it can absorb and lock in moisture, thereby helping to keep the affected area moisturized and reduce the evaporation rate. At the same time, glycerin is a relatively mild ingredient and is suitable for all skin types, including dry, sensitive and oily skin.

[0011] Preferably, the solubilizer is one of propylene glycol, PEG, and diglyceryl ether.

[0012] By using PEG as a solubilizer for terbinafine hydrochloride spray, PEG has a higher solubility and can dissolve water-insoluble or poorly soluble drugs in liquid, thereby improving the solubility of the drug.

[0013] Preferably, the preservative is one of p-hydroxybenzoic acid and its salts, and phenoxyethanol.

[0014] By using phenoxyethanol as a preservative for terbinafine hydrochloride spray, it can help prevent microbial contamination in the preparation, reduce the risk of deterioration of the preparation, and thus extend the shelf life of the product. Compared with some other preservatives, phenoxyethanol is generally less irritating to the skin and is therefore suitable for sensitive skin.

[0015] Preferably, the ratio of terbinafine hydrochloride, domperidone and water in the terbinafine hydrochloride and domperidone mixture solution is 5:1:9;

[0016] When preparing a terbinafine hydrochloride and domperidone mixture solution, first, terbinafine hydrochloride, domperidone and water need to be prepared in proportion, then the terbinafine hydrochloride and water are placed in a spiral stirrer and stirred at 800 rpm for 20 minutes to fully dissolve the terbinafine hydrochloride, then 0.5 parts of domperidone are added twice at 10 minutes, and a corresponding amount of sodium octane sulfonate is added as a dispersant at the same time, and the spiral stirrer is stirred at 1200 rpm. After the last addition of domperidone is completed, the spiral stirrer is adjusted to 2000 rpm and stirred for 30 minutes to obtain the terbinafine hydrochloride and domperidone mixture solution.

[0017] The preparation method of the terbinafine hydrochloride spray comprises:

[0018] (1) Ingredients: terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, absorption enhancer, humectant, solubilizer, and preservative are prepared in corresponding proportions;

[0019] (2) Mixing: mixing the terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, an absorption accelerator, a moisturizing agent, a solubilizing agent, and a preservative, and filtering to obtain a liquid terbinafine hydrochloride spray:

[0020] (3) finished product packaging, filling the liquid terbinafine hydrochloride spray through a filling machine, and then printing and packaging the outer side of the tank body after filling to obtain the finished product terbinafine hydrochloride spray;

[0021] Wherein, in step (2), first, the terbinafine hydrochloride and domperidone mixture solution, the anhydrous sodium acetate, the absorption enhancer and moisturizer are mixed, and after mixing, the mixture is allowed to stand for 10 minutes to 30 minutes, and the mixing state between the components is observed. The mixture should be free of flocs and particulate matter and remain clear;

[0022] Then, an aqueous solution containing the solubilizer and the preservative is added to the obtained mixture and mixed again. After mixing, the mixture is allowed to stand for 30-40 minutes and the state of the mixture is observed. The mixture should be clear without flocs and particles.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] The absorption promoter added in the preparation method of the terbinafine hydrochloride spray provided by the present invention increases the absorption speed of the terbinafine hydrochloride spray after it is sprayed on the affected area, thereby preventing a large portion of the terbinafine hydrochloride spray from directly volatilizing during the absorption process and failing to fully exert its effect.

[0025] The moisturizer added to the terbinafine hydrochloride spray can facilitate moisturizing after the terbinafine hydrochloride spray is sprayed onto the affected area, reduce the volatilization rate, and the addition of anhydrous sodium acetate can disinfect the affected area.

[0026] By changing the internal raw materials of terbinafine hydrochloride spray to a terbinafine hydrochloride and domperidone mixture solution, the nausea caused by the human body inhaling terbinafine hydrochloride spray can be reduced through domperidone. DETAILED DESCRIPTION

[0027] Below, the scheme of the present invention will be explained in conjunction with embodiment.It will be understood by those skilled in the art that the following examples are only used to illustrate the present invention and should not be regarded as limiting the scope of the present invention.In the embodiment, if specific technology or conditions are not indicated, the technology or conditions described in the literature in this area or the product instructions are used.The reagents or instruments used are not indicated by the manufacturer, and are all conventional products that can be obtained by commercial purchase.

[0028] In the following examples, absorption enhancers, humectants, solubilizers, and preservatives are used as follows:

[0029] Wherein, the absorption enhancer is at least one of propylene glycol, diglyceryl ether, and caprylic acid;

[0030] Wherein, the moisturizing agent is at least one of glycerin, hyaluronic acid, and mannitol;

[0031] Wherein, the solubilizer is at least one of propylene glycol, PEG, and diglyceryl ether.

[0032] Among them, the preservatives are p-hydroxybenzoic acid and its salts, and phenoxyethanol.

[0033] Example 1

[0034] Preparation of terbinafine hydrochloride and domperidone mixture solution:

[0035] The ratio of terbinafine hydrochloride, domperidone and water in the terbinafine hydrochloride-domperidone mixture solution is 5:1:9;

[0036] When preparing a terbinafine hydrochloride and domperidone mixture solution, first, terbinafine hydrochloride, domperidone and water need to be prepared in proportion, then the terbinafine hydrochloride and water are placed in a spiral stirrer and stirred at 800 rpm for 20 minutes to fully dissolve the terbinafine hydrochloride, then 0.5 parts of domperidone are added twice at 10 minutes, and a corresponding amount of sodium octane sulfonate is added as a dispersant at the same time, and the spiral stirrer is stirred at 1200 rpm. After the last addition of domperidone is completed, the spiral stirrer is adjusted to 2000 rpm and stirred for 30 minutes to obtain the terbinafine hydrochloride and domperidone mixture solution.

[0037] A terbinafine hydrochloride spray - prescription:

[0038]

[0039] The preparation method of the above prescription is as follows:

[0040] (1) Ingredients: terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, absorption enhancer, humectant, solubilizer, and preservative are prepared in corresponding proportions;

[0041] (2) Mixing: mixing the terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, an absorption accelerator, a moisturizing agent, a solubilizing agent, and a preservative, and filtering to obtain a liquid terbinafine hydrochloride spray:

[0042] (3) finished product packaging, filling the liquid terbinafine hydrochloride spray through a filling machine, and then printing and packaging the outer side of the tank body after filling to obtain the finished product terbinafine hydrochloride spray;

[0043] Wherein, in step (2), first, the terbinafine hydrochloride and domperidone mixture solution, the anhydrous sodium acetate, the absorption enhancer and moisturizer are mixed, and after mixing, the mixture is allowed to stand for 10 minutes to 30 minutes, and the mixing state between the components is observed. The mixture should be free of flocs and particulate matter and remain clear;

[0044] Then, an aqueous solution containing the solubilizer and the preservative is added to the obtained mixture and mixed again. After mixing, the mixture is allowed to stand for 30-40 minutes and the state of the mixture is observed. The mixture should be clear without flocs and particles.

[0045] Example 2

[0046] Preparation of terbinafine hydrochloride and domperidone mixture solution:

[0047] The ratio of terbinafine hydrochloride, domperidone and water in the terbinafine hydrochloride-domperidone mixture solution is 5:1:9;

[0048] When preparing a terbinafine hydrochloride and domperidone mixture solution, first, terbinafine hydrochloride, domperidone and water need to be prepared in proportion, then the terbinafine hydrochloride and water are placed in a spiral stirrer and stirred at 800 rpm for 20 minutes to fully dissolve the terbinafine hydrochloride, then 0.5 parts of domperidone are added twice at 10 minutes, and a corresponding amount of sodium octane sulfonate is added as a dispersant at the same time, and the spiral stirrer is stirred at 1200 rpm. After the last addition of domperidone is completed, the spiral stirrer is adjusted to 2000 rpm and stirred for 30 minutes to obtain the terbinafine hydrochloride and domperidone mixture solution.

[0049] A terbinafine hydrochloride spray - prescription:

[0050]

[0051] The preparation method of the above prescription is as follows:

[0052] (1) Ingredients: terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, absorption enhancer, humectant, solubilizer, and preservative are prepared in corresponding proportions;

[0053] (2) Mixing: mixing the terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, an absorption accelerator, a moisturizing agent, a solubilizing agent, and a preservative, and filtering to obtain a liquid terbinafine hydrochloride spray:

[0054] (3) finished product packaging, filling the liquid terbinafine hydrochloride spray through a filling machine, and then printing and packaging the outer side of the tank body after filling to obtain the finished product terbinafine hydrochloride spray;

[0055] Wherein, in step (2), first, the terbinafine hydrochloride and domperidone mixture solution, the anhydrous sodium acetate, the absorption enhancer and moisturizer are mixed, and after mixing, the mixture is allowed to stand for 10 minutes to 30 minutes, and the mixing state between the components is observed. The mixture should be free of flocs and particulate matter and remain clear;

[0056] Then, an aqueous solution containing the solubilizer and the preservative is added to the obtained mixture and mixed again. After mixing, the mixture is allowed to stand for 30-40 minutes and the state of the mixture is observed. The mixture should be clear without flocs and particles.

[0057] Example 3

[0058] Preparation of terbinafine hydrochloride and domperidone mixture solution:

[0059] The ratio of terbinafine hydrochloride, domperidone and water in the terbinafine hydrochloride-domperidone mixture solution is 5:1:9;

[0060] When preparing a terbinafine hydrochloride and domperidone mixture solution, first, terbinafine hydrochloride, domperidone and water need to be prepared in proportion, then the terbinafine hydrochloride and water are placed in a spiral stirrer and stirred at 800 rpm for 20 minutes to fully dissolve the terbinafine hydrochloride, then 0.5 parts of domperidone are added twice at 10 minutes, and a corresponding amount of sodium octane sulfonate is added as a dispersant at the same time, and the spiral stirrer is stirred at 1200 rpm. After the last addition of domperidone is completed, the spiral stirrer is adjusted to 2000 rpm and stirred for 30 minutes to obtain the terbinafine hydrochloride and domperidone mixture solution.

[0061] A terbinafine hydrochloride spray - prescription:

[0062]

[0063]

[0064] The preparation method of the above prescription is as follows:

[0065] (1) Ingredients: terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, absorption enhancer, humectant, solubilizer, and preservative are prepared in corresponding proportions;

[0066] (2) Mixing: mixing the terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, an absorption accelerator, a moisturizing agent, a solubilizing agent, and a preservative, and filtering to obtain a liquid terbinafine hydrochloride spray:

[0067] (3) finished product packaging, filling the liquid terbinafine hydrochloride spray through a filling machine, and then printing and packaging the outer side of the tank body after filling to obtain the finished product terbinafine hydrochloride spray;

[0068] Wherein, in step (2), first, the terbinafine hydrochloride and domperidone mixture solution, the anhydrous sodium acetate, the absorption enhancer and moisturizer are mixed, and after mixing, the mixture is allowed to stand for 10 minutes to 30 minutes, and the mixing state between the components is observed. The mixture should be free of flocs and particulate matter and remain clear;

[0069] Then, an aqueous solution containing the solubilizer and preservative is added to the resulting mixture and mixed again. After mixing, the mixture is allowed to stand for 30-40 minutes and the state of the mixture is observed. The mixture should be clear and free of flocculent matter and particulate matter.

[0070] Drug screening experimental research:

[0071] (1) First, the terbinafine hydrochloride spray obtained in Examples 1 to 3 is prepared and packaged.

[0072] (2) Experimental methods: To study the anti-inflammatory effect of terbinafine hydrochloride spray prepared with different dosages of absorption enhancers and moisturizers on epidermal fungal infection in rats: SD male rats were randomly divided into 8 groups; each group of rats was sprayed with terbinafine hydrochloride spray prepared with different absorption enhancers on the epidermis, 3 sprays each time; 4 times a day, for 3 consecutive days; the control group was given the corresponding volume of normal saline; 180 minutes after the last administration, the size and area of ​​epidermal fungi were evaluated.

[0073] At the same time, after each epidermal administration, the size of the administration area of ​​the affected area was measured every 5 minutes, and observation was conducted for 6 consecutive times, for a total of 30 minutes. Based on the changes in the size of the administration area, the effect of reducing the volatilization of the terbinafine hydrochloride spray made with different amounts of moisturizers was obtained.

[0074] The following is the experimental data of Example 1:

[0075] <![CDATA[Group A / Infection area (cm 2 )]]> 1day 2day 3day Rat 1 1.2 0.8 0.5 Rat 2 1.5 1.1 0.7 Rat 3 1.3 0.9 0.4 Rat 4 1.2 0.7 0.3 Rat 5 1.5 0.9 0.5 Rat 6 1.4 0.6 0.2 Rat 7 1.5 0.9 0.4 Rat 8 1.1 0.5 0.2

[0076] The following is the experimental data of Example 2:

[0077] <![CDATA[Group B / Infected area (cm 2 )]]> 1day 2day 3day Rat 1 1.5 1.2 0.8 Rat 2 1.6 1.1 0.7 Rat 3 1.7 1.3 0.8 Rat 4 1.5 1.2 0.9 Rat 5 1.8 1.5 1.2 Rat 6 1.4 1.0 0.6 Rat 7 1.6 1.1 0.7 Rat 8 1.9 1.5 1.2

[0078] The following is the experimental data of Example 3:

[0079]

[0080]

[0081] From the above three sets of tables, it can be seen that in Example 1, in which the absorption enhancer was added up to 5 parts and the moisturizer was added up to 8 parts, the overall 3-day fungal infection area of ​​the rats was the smallest, and in Example 3, in which the absorption enhancer was added up to 3 parts and the moisturizer was added up to 7 parts, the overall 3-day fungal infection area of ​​the rats was the largest. Therefore, it can be concluded that the maximum addition of the absorption enhancer can improve the overall efficacy.

[0082] The following is the experimental data of the change in the drug administration area every 5 minutes after the rats were administered the drug in Example 1:

[0083]

[0084] The following is the experimental data of the change in the drug administration area every 5 minutes after the rats were administered the drug in Example 2:

[0085]

[0086]

[0087] The following is the experimental data of the change in the drug administration area every 5 minutes after the rats were administered the drug in Example 3:

[0088]

[0089] From the above three sets of tables, it can be seen that the 30-minute fungal infection area of ​​the rats in Example 1 with 8 parts of moisturizer added was the smallest, while the 3-day fungal infection area of ​​the rats in Example 1 with 6 parts of moisturizer added was the largest. Therefore, it can be concluded that the maximum amount of moisturizer added can improve the overall moisturizing effect and reduce the volatility of terbinafine hydrochloride spray.

[0090] Those skilled in the art should understand that the discussion of any of the above embodiments is merely illustrative and is not intended to imply that the scope of the present invention (including the claims) is limited to these examples. Within the scope of the present invention, the technical features in the above embodiments or different embodiments may be combined, the steps may be implemented in any order, and there are many other variations of the different aspects of the present invention as described above, which are not provided in detail for the sake of simplicity.

[0091] The present invention is intended to cover all such substitutions, modifications and variations that fall within the broad scope of the appended claims. Therefore, any omissions, modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A terbinafine hydrochloride spray, characterized in that, The invention is prepared from the following raw materials in parts by weight: 15-26 parts of terbinafine hydrochloride and domperidone mixture solution, 2.3-3.5 parts of anhydrous sodium acetate, 2-5 parts of absorption promoter, 6-8 parts of moisturizing agent, 1.2-2.2 parts of solubilizing agent, and 0.3-0.5 parts of preservative. The absorption enhancer is propylene glycol; The moisturizing agent is glycerin; The solubilizing agent is PEG; The preservative is phenoxyethanol; The weight ratio of terbinafine hydrochloride, domperidone and water in the terbinafine hydrochloride and domperidone mixture solution is 5:1:9; When preparing a terbinafine hydrochloride and domperidone mixture solution, first, terbinafine hydrochloride, domperidone and water need to be prepared in proportion, then the terbinafine hydrochloride and water are placed in a spiral stirrer and stirred at 800 rpm for 20 minutes to fully dissolve the terbinafine hydrochloride, then 0.5 parts of domperidone are added twice at 10 minutes, and a corresponding amount of sodium octane sulfonate is added as a dispersant at the same time, and the spiral stirrer is stirred at 1200 rpm. After the last addition of domperidone is completed, the spiral stirrer is adjusted to 2000 rpm and stirred for 30 minutes to obtain the terbinafine hydrochloride and domperidone mixture solution.

2. A method for preparing terbinafine hydrochloride spray according to claim 1, comprising: (1) Ingredients: prepare the terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, absorption enhancer, moisturizer, solubilizer, and preservative according to corresponding proportions; (2) Mixing: Mix the terbinafine hydrochloride and domperidone mixture solution, anhydrous sodium acetate, absorption enhancer, moisturizer, solubilizer, and preservative, and filter to obtain a liquid terbinafine hydrochloride spray: (3) Finished product packaging: filling the liquid terbinafine hydrochloride spray through a filling machine, and then printing and packaging the outer side of the can body after filling to obtain the finished product terbinafine hydrochloride spray; Wherein, in step (2), first, the terbinafine hydrochloride and domperidone mixture solution, the anhydrous sodium acetate, the absorption enhancer and moisturizer are mixed, and after mixing, the mixture is allowed to stand for 10 minutes to 30 minutes, and the mixing state between the components is observed. The mixture should be free of flocs and particulate matter and remain clear; Then, an aqueous solution containing the solubilizer and the preservative is added to the obtained mixture and mixed again. After mixing, the mixture is allowed to stand for 30-40 minutes and the state of the mixture is observed. The mixture should be clear without flocs and particles.

Images