Spray containing terbinafine hydrochloride and preparation method thereof

Abstract

The invention discloses a terbinafine hydrochloride spray and a preparation method thereof, and relates to the technical field of pharmaceutical preparations. The terbinafine hydrochloride spray comprises the following components in percentage by weight: 0.5%-2% of terbinafine hydrochloride, 30%-60% of ethanol, 10%-20% of a solubilizer, 1%-5% of an absorption enhancer, 0.05%-0.2% of a pH regulator, 0.01%-0.05% of a preservative and the balance of water. In-vitro transdermal experiments show that the steady-state transdermal rate and the skin drug retention volume of the composition are obviously superior to those of a single absorption enhancer group and an enhancer-free group. Animal pharmacodynamic experiments prove that the spray disclosed by the invention has a remarkable improvement effect on skin lesion symptoms caused by fungal infection. The preparation process is simple, the preparation stability is good, the antifungal curative effect is remarkable, and the preparation has a good application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparation technology, specifically relating to a spray containing terbinafine hydrochloride and its preparation method, and particularly to an antifungal spray with excellent transdermal absorption performance and synergistic effect and its preparation process. Background Technology

[0002] Terbinafine hydrochloride is an allylamine broad-spectrum antifungal drug that highly selectively inhibits fungal squalene epoxidase, blocking fungal cell membrane formation and thus effectively killing and inhibiting fungi. This drug has advantages such as short treatment course, significant efficacy, and good patient tolerance, and is widely recognized as a safe and effective treatment for superficial fungal infections (such as tinea corporis and tinea pedis). Currently, common topical formulations of terbinafine hydrochloride include creams, gels, and sprays. Among these, sprays are considered the ideal form of administration due to their ease of use, lack of mechanical friction, and uniform drug distribution.

[0003] However, existing topical formulations of terbinafine hydrochloride still have some unresolved issues. For example, Chinese patent application CN118121541A discloses a spray containing terbinafine hydrochloride and domperidone, which improves drug absorption by adding absorption enhancers such as propylene glycol. However, this formulation has a complex composition, and the addition of domperidone mainly targets the prevention of nausea caused by inhalation, failing to adequately address the fundamental issue of transdermal absorption efficiency. Furthermore, the choice of absorption enhancers is relatively conventional, resulting in limited effectiveness. In addition, Chinese patent application CN108210449A discloses a canine terbinafine hydrochloride cream, which enhances absorption through transdermal penetration agents such as propylene glycol and laurocapram, and adds humectants to maintain the cream's moisture. However, the cream formulation itself suffers from drawbacks such as a viscous texture, poor spreadability, and poor patient compliance. Moreover, its transdermal enhancement strategy also fails to break through conventional approaches.

[0004] More importantly, existing terbinafine hydrochloride sprays generally suffer from low transdermal absorption efficiency, resulting in insufficient drug concentration accumulation in the stratum corneum and deeper layers of the skin, affecting the full efficacy of the drug and often requiring more frequent applications or longer treatment courses. Furthermore, some formulations also exhibit poor stability and skin irritation. Therefore, developing a terbinafine hydrochloride spray with high transdermal absorption, large skin retention, good stability, and low irritation is of significant clinical importance. Summary of the Invention

[0005] (a) Technical problems to be solved The purpose of this invention is to overcome the shortcomings of the prior art and provide a terbinafine hydrochloride spray with excellent transdermal absorption performance, high skin drug retention, and good stability, as well as its preparation method.

[0006] (II) Technical Solution To achieve the above objectives, the present invention adopts the following technical solution: One objective of this invention is to provide a terbinafine hydrochloride spray, comprising the following components by weight percentage: terbinafine hydrochloride 0.5%-2%, ethanol 30%-60%, solubilizer 10%-20%, absorption promoter 1%-5%, pH adjuster 0.05%-0.2%, preservative 0.01%-0.05%, and water as the balance.

[0007] Furthermore, the solubilizer is selected from at least one of propylene glycol, polyethylene glycol, and polysorbate 80.

[0008] Furthermore, the absorption enhancer is selected from at least one of isopropyl myristate, L-menthol, and laurocapram.

[0009] Furthermore, the absorption promoter is isopropyl myristate and L-menthol, and the mass ratio of isopropyl myristate to L-menthol is (1-4):(1-4), preferably 1:1.

[0010] Furthermore, the pH adjuster is selected from sodium acetate or triethanolamine, and the preservative is selected from at least one of methylparaben, propylparaben, and sodium benzoate.

[0011] Furthermore, the terbinafine hydrochloride spray comprises the following components by weight percentage: 1% terbinafine hydrochloride, 40% ethanol, 15% solubilizer, 2% absorption promoter, 0.1% pH adjuster, 0.03% preservative, and the balance being water.

[0012] A second objective of this invention is to provide a method for preparing terbinafine hydrochloride spray, comprising the following steps: (1) Add terbinafine hydrochloride, solubilizer, absorption promoter, pH adjuster and preservative to a mixed solvent of ethanol and water according to the above weight percentages, and stir thoroughly until completely dissolved to form a clear solution; (2) Filter the solution through a microporous membrane to remove insoluble particles; (3) Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0013] A third objective of this invention is to provide a terbinafine hydrochloride spray, obtained by the above-described preparation method.

[0014] The fourth objective of this invention is to provide the application of the above-mentioned terbinafine hydrochloride spray in the preparation of antifungal drugs.

[0015] Furthermore, the fungi include Trichophyton.

[0016] (III) Beneficial Effects Compared with the prior art, the present invention has the following beneficial effects: Significant synergistic effect on transdermal absorption: Through extensive prescription screening and in vitro transdermal experiments, this invention has surprisingly discovered that when isopropyl myristate (IPM) and L-menthol are used together as absorption enhancers for terbinafine hydrochloride spray, a significant synergistic effect is produced, which can effectively promote the transdermal absorption of terbinafine hydrochloride and increase the accumulation of the drug in the skin.

[0017] Superior antifungal therapeutic effect: Due to the significant improvement in transdermal absorption and skin accumulation, the spray of this invention has shown excellent therapeutic effect in in vivo pharmacodynamic experiments, and can improve symptoms such as papules, scales and inflammation in tinea corporis models more quickly and effectively.

[0018] Good formulation stability: Under accelerated testing conditions, the active pharmaceutical ingredient content of the spray of this invention remained above 98% for 6 months, indicating good chemical stability. The addition of the absorption enhancer did not adversely affect the long-term stability of the formulation. Detailed Implementation

[0019] The embodiments of the present invention will be clearly and completely described below with reference to the examples. These embodiments are merely some, not all, of the embodiments of the present invention. The following description of at least one exemplary embodiment is merely illustrative and is in no way intended to limit the present invention or its application or use. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Those skilled in the art should understand that modifications or substitutions to the details and form of the technical solutions of this application can be made without departing from the spirit and scope of this application, but such modifications and substitutions all fall within the scope of protection of this application.

[0020] Furthermore, to better illustrate the present invention, numerous specific details are set forth in the following detailed embodiments. Those skilled in the art should understand that the present invention can be practiced without certain specific details. In some embodiments, materials, methods, and means well-known to those skilled in the art are not described in detail in order to highlight the spirit of the invention.

[0021] Unless otherwise specified, the instruments and materials used in the following embodiments are all commonly used laboratory equipment, and the technical solutions described are all conventional technologies in the field.

[0022] Example 1 The formulation of terbinafine hydrochloride spray is as follows: ingredient percentage Terbinafine Hydrochloride 1% 40% ethanol 15% propylene glycol Isopropyl myristate 1% L-Menthol 1% Sodium acetate 0.1% Methylparaben 0.03% Water balance It is prepared using the following method: (1) Preparation of solution: The active pharmaceutical ingredient terbinafine hydrochloride and the excipients propylene glycol, isopropyl myristate, L-menthol, sodium acetate and methylparaben are added to a mixed solvent of ethanol and water in the above amounts, and stirred thoroughly until completely dissolved to form a clear solution. (2) Filtration and impurity removal: The solution is filtered through a microporous membrane to remove insoluble particles; (3) Filling and sealing: Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0023] Example 2 The formulation of terbinafine hydrochloride spray is as follows: ingredient percentage Terbinafine hydrochloride 0.5% 50% ethanol 10% propylene glycol Isopropyl myristate 2% L-Menthol 1.5% Sodium acetate 0.05% Methylparaben 0.01% Water balance It is prepared using the following method: (1) Preparation of solution: The active pharmaceutical ingredient terbinafine hydrochloride and the excipients propylene glycol, isopropyl myristate, L-menthol, sodium acetate and methylparaben are added to a mixed solvent of ethanol and water in the above amounts, and stirred thoroughly until completely dissolved to form a clear solution. (2) Filtration and impurity removal: The solution is filtered through a microporous membrane to remove insoluble particles; (3) Filling and sealing: Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0024] Example 3 The formulation of terbinafine hydrochloride spray is as follows: ingredient percentage Terbinafine Hydrochloride 2% 30% ethanol 20% propylene glycol Isopropyl myristate 1% L-Menthol 2% Sodium acetate 0.2% Methylparaben 0.05% Water balance It is prepared using the following method: (1) Preparation of solution: The active pharmaceutical ingredient terbinafine hydrochloride and the excipients propylene glycol, isopropyl myristate, L-menthol, sodium acetate and methylparaben are added to a mixed solvent of ethanol and water in the above amounts, and stirred thoroughly until completely dissolved to form a clear solution. (2) Filtration and impurity removal: The solution is filtered through a microporous membrane to remove insoluble particles; (3) Filling and sealing: Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0025] Example 4 The formulation of terbinafine hydrochloride spray is as follows: ingredient percentage Terbinafine Hydrochloride 1% 40% ethanol 15% propylene glycol Isopropyl myristate 2% Sodium acetate 0.1% Methylparaben 0.03% Water balance It is prepared using the following method: (1) Preparation of solution: The active pharmaceutical ingredient terbinafine hydrochloride and the excipients propylene glycol, isopropyl myristate, sodium acetate and methylparaben are added to a mixed solvent of ethanol and water in the above amounts, and stirred thoroughly until completely dissolved to form a clear solution; (2) Filtration and impurity removal: The solution is filtered through a microporous membrane to remove insoluble particles; (3) Filling and sealing: Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0026] Example 5 The formulation of terbinafine hydrochloride spray is as follows: ingredient percentage Terbinafine Hydrochloride 1% 40% ethanol 15% propylene glycol L-Menthol 2% Sodium acetate 0.1% Methylparaben 0.03% Water balance It is prepared using the following method: (1) Preparation of solution: The active pharmaceutical ingredient terbinafine hydrochloride and the excipients propylene glycol, L-menthol, sodium acetate and methylparaben are added to a mixed solvent of ethanol and water in the amounts mentioned above, and stirred thoroughly until completely dissolved to form a clear solution; (2) Filtration and impurity removal: The solution is filtered through a microporous membrane to remove insoluble particles; (3) Filling and sealing: Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0027] Comparative Example The formulation of terbinafine hydrochloride spray is as follows: ingredient percentage Terbinafine Hydrochloride 1% 40% ethanol 15% propylene glycol Sodium acetate 0.1% Methylparaben 0.03% Water balance It is prepared using the following method: (1) Preparation of solution: The active pharmaceutical ingredient terbinafine hydrochloride and the excipients propylene glycol, sodium acetate and methylparaben are added to a mixed solvent of ethanol and water in the above amounts, and stirred thoroughly until completely dissolved to form a clear solution; (2) Filtration and impurity removal: The solution is filtered through a microporous membrane to remove insoluble particles; (3) Filling and sealing: Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

[0028] Test Example 1: Stability Study of Terbinafine Hydrochloride Spray Accelerated tests were conducted on the terbinafine hydrochloride sprays prepared in Examples 1-5 and the comparative examples. The sprays were placed at a temperature of 40℃±2℃ and a relative humidity of 75%±5% for 6 months. Samples were taken at the 1st, 3rd and 6th months for testing, and the content of terbinafine hydrochloride in each drug was detected and calculated.

[0029] Table 1. Accelerated test results of terbinafine hydrochloride spray Accelerated testing over 6 months showed that the active pharmaceutical ingredient content in all examples and comparative samples was >98%, indicating good stability. The presence or absence of absorption enhancers (isopropyl myristate and L-menthol) and their varying dosages had no significant impact on the chemical stability of the formulations.

[0030] Experimental Example 2: Evaluation of the in vitro transdermal absorption effect of terbinafine hydrochloride spray Experimental Methods: SPF-grade Kunming mice were acclimatized for 7 days, then fasted and deprived of water for 12 hours prior to the experiment. After hair removal, the mice were euthanized, and the skin was immediately cut off. The fat was carefully removed, and intact skin was selected. The skin was rinsed thoroughly with physiological saline. The treated mouse skin was then fixed onto a Franz diffusion cell, with the keratin layer facing the diffusion cell side. PBS solution at pH 6.8 was used as the receiving medium, and the rotation speed was 600 rpm. The interface area was 1.77 cm². 2 The temperature was 32℃. After the temperature stabilized, terbinafine hydrochloride spray solutions prepared in Examples 1, 4, 5, and the comparative example were applied to the stratum corneum of the skin in the diffusion pool. 2 ml of the receiving solution was collected at 0.5h, 1h, 2h, 4h, 8h, 12h, and 24h (with the same volume of fresh blank receiving solution added simultaneously). The content of terbinafine hydrochloride in the receiving solution was determined by HPLC, and the steady-state transdermal rate (J) was calculated. Based on the drug concentration measured at each time point, the cumulative permeation per unit area (Q, μg / cm²) was calculated according to the formula. A graph of cumulative permeation (Q) against time (t, h) was plotted, and linear regression was performed on the linear portion of the curve. The slope of the resulting line is the steady-state transdermal rate (J, μg·cm⁻²·h⁻¹), which reflects the speed at which the drug permeates the skin.

[0031] After the transdermal test, carefully remove the skin and thoroughly clean the skin surface of any residual medication with physiological saline and cotton swabs. Blot dry with filter paper, cut a piece of skin from the effective penetration area, and weigh it. Mince the skin, place it in a homogenizer, add an appropriate amount of methanol, homogenize thoroughly, and sonicate for a certain time. After centrifugation, collect the supernatant and determine the drug concentration using HPLC to calculate the amount of drug retained per unit mass of skin (μg / g).

[0032] The experimental results are shown in Table 2 below: Table 2. In vitro transdermal efficacy of terbinafine hydrochloride spray ( x̄±s ) Note: Compare with the comparative example. a P <0.05; compared with Example 4, b P <0.05, c P <0.01; compared with Example 5, d P <0.05,e P <0.01 Based on the results of in vitro transdermal experiments (Table 2), Example 1, which simultaneously added isopropyl myristate (IPM) and L-menthol, exhibited significantly higher steady-state transdermal absorption rate (20.71 μg·cm⁻²·h⁻¹) and skin drug retention (241.04 μg / g) than Examples 4 (IPM) and 5 (L-menthol), which contained only a single absorption enhancer, as well as the comparative example (without an absorption enhancer). Compared to the comparative example, Example 1 showed nearly double the transdermal absorption rate and approximately 1.5 times the retention. Furthermore, both indicators of Example 1 were significantly superior to either single absorption enhancer group (P<0.05). These results indicate that the combined use of IPM and L-menthol has a significant synergistic effect, effectively promoting the transdermal absorption of terbinafine hydrochloride and increasing drug accumulation in the skin, providing a basis for optimizing spray formulations.

[0033] Experimental Example 3: Evaluation of the therapeutic effect of terbinafine hydrochloride spray on fungal infections in rats. Experimental Methods: SPF-grade Wistar rats, half male and half female, were used. Hair was removed from the backs of the rats (4 cm × 4 cm). The skin at the hair removal site was scraped with a scalpel until bleeding occurred. The wound was inoculated with *Trichophyton mentagrophytes*, containing 1 × 10⁻⁶ spores. 7 Apply a bacterial suspension of 1 mL / cm² to the wound surface using a blade, with an inoculation volume of 1 mL / cm². 2 The inoculation site was covered with vitreous humor, bandaged with gauze, and secured with adhesive tape. On the 4th day, clinical symptoms similar to human tinea corporis appeared at the inoculation site. Fungal culture and microscopic examination showed a positive result, indicating that the tinea corporis model was successfully established.

[0034] Fifty successfully modeled rats were randomly divided into 5 groups (n=10 per group, half male and half female): model group; treatment group 1 (administered with terbinafine hydrochloride spray prepared in Example 1); treatment group 2 (administered with terbinafine hydrochloride spray prepared in Example 4); treatment group 3 (administered with terbinafine hydrochloride spray prepared in Example 5); and treatment group 4 (administered with terbinafine hydrochloride spray prepared in the comparative example). Except for the model group which was treated with physiological saline, each treatment group was treated with 1 mL of the corresponding terbinafine hydrochloride spray twice daily for 12 consecutive days.

[0035] After drug administration, the skin lesions of the rats were observed. Skin lesion symptom scoring: Skin lesions manifested as papules, scales, and inflammation, with the severity of the lesions graded on a scale of 1, 2, and 3 points, respectively. No skin lesions were recorded as "0 points"; scores between these scales were used. The skin lesion symptom score was the sum of the scores for papules, scales, and inflammation. Specific scoring criteria are shown in Table 3 below. Table 3 Skin Lesion Scoring Criteria The experimental results are shown in Table 4 below: Table 4. Effects of terbinafine hydrochloride spray on skin lesion symptom scores in a rat tinea corporis model ( x̄±s ) Note: Comparison with model group. a P <0.05, b P <0.01; compared with group 2, c P <0.05; compared with treatment group 3, d P <0.05 According to the results in Table 4, the skin lesion score of group 1 (terbinafine hydrochloride spray, Example 1) (2.24±0.31) was significantly lower than that of group 2 (3.28±0.65), group 3 (3.51±0.52), and group 4 (4.62±0.79), and was also better than that of the model group (8.46±1.37). This indicates that the combination of IPM and L-menthol can synergistically enhance the antifungal efficacy of terbinafine hydrochloride spray and significantly improve the symptoms of tinea corporis.

[0036] Unless otherwise defined, all technical and scientific terms used in this invention have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used in this specification is for the purpose of describing particular embodiments only and is not intended to be limiting of the invention.

[0037] As used in this invention, the terms "comprising" and "including" are open-ended expressions, meaning they include the contents specified in this invention but do not exclude other aspects.

[0038] As used in this invention, the term "and / or" includes any one or more of the related listed items and all combinations thereof.

[0039] The scope of protection of this invention is not limited to the above embodiments. Any variations and advantages that can be conceived by those skilled in the art without departing from the spirit and scope of this invention are included in this invention and are protected by the appended claims.

Claims

1. A terbinafine hydrochloride spray, characterized in that, It comprises the following components by weight percentage: terbinafine hydrochloride 0.5%-2%, ethanol 30%-60%, solubilizer 10%-20%, absorption promoter 1%-5%, pH adjuster 0.05%-0.2%, preservative 0.01%-0.05%, and water as the balance.

2. The terbinafine hydrochloride spray according to claim 1, characterized in that, The solubilizer is selected from at least one of propylene glycol, polyethylene glycol, and polysorbate 80.

3. The terbinafine hydrochloride spray according to claim 1, characterized in that, The absorption enhancer is selected from at least one of isopropyl myristate, L-menthol, and laurocapram.

4. The terbinafine hydrochloride spray according to claim 3, characterized in that, The absorption enhancer is isopropyl myristate and L-menthol, and the mass ratio of isopropyl myristate to L-menthol is (1-4):(1-4), preferably 1:

1.

5. The terbinafine hydrochloride spray according to claim 1, characterized in that, The pH adjuster is selected from sodium acetate or triethanolamine, and the preservative is selected from at least one of methylparaben, propylparaben, and sodium benzoate.

6. The terbinafine hydrochloride spray according to any one of claims 1-5, characterized in that, It comprises the following components by weight percentage: terbinafine hydrochloride 1%, ethanol 40%, solubilizer 15%, absorption promoter 2%, pH adjuster 0.1%, preservative 0.03%, and water balance.

7. The method for preparing terbinafine hydrochloride spray according to any one of claims 1-6, characterized in that, Includes the following steps: (1) Add terbinafine hydrochloride, solubilizer, absorption promoter, pH adjuster and preservative to a mixed solvent of ethanol and water according to the above weight percentages, and stir thoroughly until completely dissolved to form a clear solution; (2) Filter the solution through a microporous membrane to remove insoluble particles; (3) Under aseptic conditions, the filtrate is filled into a pre-cleaned and sterilized spray bottle and sealed immediately to obtain terbinafine hydrochloride spray.

8. A terbinafine hydrochloride spray, characterized in that, It is obtained by the preparation method described in claim 7.

9. The use of the terbinafine hydrochloride spray according to any one of claims 1-6 or claim 8 in the preparation of antifungal drugs.

10. The application according to claim 9, characterized in that, The fungi include Trichophyton.

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