Preparation method of high-concentration terbinafine hydrochloride aqueous solution

Abstract

The invention discloses a preparation method of a high-concentration terbinafine hydrochloride aqueous solution, and belongs to the technical field of pharmaceutical preparations. The preparation method comprises the following steps: (1) mixing a water-soluble molecule containing a benzene ring with terbinafine hydrochloride, adding water, uniformly stirring, and homogenizing to obtain a water-soluble molecule-terbinafine coupling body dispersion liquid containing the benzene ring; and (2) adding water-soluble nonionic amphiphilic molecules into the dispersion liquid, and continuing homogenizing treatment to obtain the terbinafine hydrochloride aqueous solution. The terbinafine preparation has the beneficial effects that through the p-p interaction between the benzene ring of the water-soluble molecule containing the benzene ring and the naphthalene ring in the terbinafine molecule and the synergistic effect of the water-soluble nonionic amphiphilic molecule, the complete dissolution of terbinafine in water is realized on the molecular level; the concentration of the prepared terbinafine hydrochloride aqueous solution is as high as 6wt%, and the problem that terbinafine is difficult to dissolve in water under the condition that a solubilizer is not added is solved.

Description

Technical Field

[0001] The present invention relates to a preparation method of terbinafine hydrochloride aqueous solution, and particularly relates to a preparation method of a high-concentration terbinafine hydrochloride aqueous solution, belonging to the technical field of pharmaceutical preparations. Background Art

[0002] Terbinafine is a highly effective anti-dermatophyte drug and is widely used in the treatment of fungal infections. The existing dosage forms of terbinafine include: tablets, capsules, creams, emulsions, gels, and solutions.

[0003] For terbinafine solution, due to the strong hydrophobicity of terbinafine, it is hardly soluble in water (the solubility in water at room temperature is less than 1 mg / mL) and is easily soluble in organic solvents. Therefore, the content of terbinafine in the terbinafine solution prepared with water as the solvent is very low. Currently, commercially available terbinafine liquid preparations are usually mainly prepared with ethanol (content 95%, ethanol is a good solvent for terbinafine), as well as a small amount of 1,2-propanediol and water as solvents, and the terbinafine content is about 1%. However, such products cannot be used by those allergic to ethanol, nor can they be used for the treatment of fungal infections in sensitive parts such as eyes and mucous membranes to ethanol. Moreover, they are flammable and pose a safety hazard. In addition, ethanol has a strong pungent smell and is not suitable as a pet anti-tinea spray.

[0004] Chinese Patent CN 1883475A discloses a veterinary compound terbinafine hydrochloride solution, which is composed of terbinafine hydrochloride, metronidazole, thiabendazole, cypermethrin, and an organic solvent. Among them, the organic solvent is any one or several of chloroform, benzene, xylene, acetone, propylene glycol, methyl ethyl ketone, ethanol, and dimethyl sulfoxide. Although the content of terbinafine in this solution is as high as 10 wt%, since most of the organic solvents therein are toxic or irritating to the skin, it is not suitable for animal use, let alone human use. And most of these organic solvents are flammable and pose a relatively large safety hazard.

[0005] In order to improve the solubility of terbinafine in water, the main current methods are as follows: 1. Prepare hydrochloride or malate (1) React terbinafine with hydrochloric acid to prepare the hydrochloric acid addition salt of terbinafine. The solubility of terbinafine hydrochloride in water at room temperature increases to 6.7 mg / mL.

[0006] (2) React terbinafine with malic acid to prepare the malic acid addition salt of terbinafine (CN 1491206A). The solubility of terbinafine malate in water at room temperature increases to 12 - 15 mg / mL. However, a large amount of organic solvent ethyl acetate is required when synthesizing terbinafine malate.

[0007] 2. Prepare cyclodextrin inclusion compound (1) Chinese Invention Patent CN 1843342A discloses an eye medicine for treating fungal keratitis. It uses terbinafine as the active ingredient, hydroxypropyl-β-cyclodextrin as the solubilizer, and water as the solvent to prepare terbinafine eye drops. The concentration of terbinafine is 0.25 wt% (2.5 mg / mL), and the concentration of hydroxypropyl-β-cyclodextrin is 3 - 3.5 wt% (30 - 35 mg / mL). The dosage of hydroxypropyl-β-cyclodextrin is 12 - 14 times that of terbinafine.

[0008] (2) Chinese Invention Patent CN 105687196A discloses an itraconazole-terbinafine compound injection for dogs and cats and its preparation method. First, terbinafine is completely dissolved in ethanol, and then it is dropped into an aqueous solution of hydroxypropyl-β-cyclodextrin to form a terbinafine / cyclodextrin inclusion complex. Among them, the concentration of terbinafine is 2 wt% (20 mg / mL), and the concentration of hydroxypropyl-β-cyclodextrin is 70 wt%. The dosage of hydroxypropyl-β-cyclodextrin is 35 times that of terbinafine.

[0009] 3. Prepare water-in-oil emulsions, micelles, etc. (1) Chinese Invention Patent CN 1927181A discloses a preparation method of a water-in-oil type terbinafine nanoemulsion. First, terbinafine is dissolved in ethanol, and then it is added to a mixed solution of oil (olive oil, isooctyl ester, castor oil, isopropyl myristate, liquid paraffin) and surfactant (polyoxyethylene ether (40) hydrogenated castor oil, castor oil polyoxyethylene ether, Tween80, Span80). After mixing evenly, water is added and stirred to emulsify to obtain the final product. However, in order to obtain an emulsion with an effective content of terbinafine reaching 2%, the amount of surfactant used is as high as 40% - 62.5%, and 4.4% - 15% of oil is also required.

[0010] (2) Chinese Invention Patent CN 102600192A discloses a compound terbinafine nano-drug for treating skin diseases and its preparation method. It requires the simultaneous use of oil (isopropyl myristate, liquid paraffin, vitamin E oil, jojoba oil, triacetin, ethyl acetate, almond oil, wheat germ oil, olive oil, castor oil), co-solvent (anhydrous ethanol, ethylene glycol, 1,2-propanediol, glycerol, PEG 200, PEG 400, PEG 600), and a large amount of surfactant (Tween-80, Tween-60, Tween-20, RH-40, EL-40, and Span-80) to solubilize terbinafine to prepare a nano-dispersion system.

[0011] (3) Chinese invention patent CN 105012235A discloses an ophthalmic antifungal nano-micelle solution containing terbinafine hydrochloride. It uses nano-micelles to solubilize terbinafine. Specifically, first dissolve terbinafine in glycerol, then add solubilizers (15-hydroxystearic acid polyethylene glycol ester, polyoxyethylene ether 40 hydrogenated castor oil), and after mixing evenly, add an aqueous phase containing a thickening agent, and stir and emulsify to obtain a nano-micelle solution. However, the content of terbinafine in the nano-micelle solution prepared by this method is only 1 wt%.

[0012] (4) Chinese invention patent CN 113440483A discloses a canine-use terbinafine hydrochloride spray and its preparation method. It uses up to 50% of ethylene glycol and 10% of non-ionic surfactants (polyoxyethylene stearate and polyoxyethylene alkyl ether) to solubilize terbinafine, and the maximum content of terbinafine can reach 3 wt%.

[0013] (5) Chinese invention patent CN 113786382A discloses a terbinafine hydrochloride gel and its preparation method. It uses 2 parts of terbinafine, 20 - 60 parts of Tween 20, and 5 - 15 parts of oil phase to prepare a terbinafine microemulsion, and the effective content of terbinafine in this microemulsion is 2 wt%.

[0014] (6) Chinese invention patent CN 115531312A discloses a preparation process of a terbinafine hydrochloride spray. It uses 10 times the mass of solubilizers polyethylene glycol 15-hydroxystearate (HS15) and laurocapram to prepare a terbinafine hydrochloride spray, and the effective content of terbinafine is about 0.88 wt%.

[0015] (7) Chinese invention patent CN 119564596A discloses a needle-free injection of terbinafine hydrochloride, a transdermal injection for treating superficial fungal infections, and its dosing device. It uses ethanol to solubilize terbinafine, and can make the concentration of terbinafine dissolved in water reach 0.1 - 0.5 wt%.

[0016] However, the above methods do not obtain an aqueous solution of terbinafine, but an oil-in-water emulsion containing terbinafine. Such technologies not only have complex preparation processes, but also the long-term stability of the emulsion needs to be tested over time. More importantly, after the water evaporates, terbinafine is mainly dissolved in the oil phase, and the skin permeability of this oil phase will determine the ease of terbinafine reaching the lesion site. These problems all need to be tested.

[0017] 4. First dissolve terbinafine in a good solvent, and then add water to obtain a mixed solution Chinese Invention Patent CN 105395484A discloses a compound terbinafine spray and its preparation method. First, terbinafine and other antibiotics are dissolved in a mixed solution of ethylene glycol and dimethyl sulfoxide, and then water is added. This method can obtain a terbinafine solution with a maximum solid content of 2 wt%, however, the total amount of ethylene glycol and dimethyl sulfoxide used is as high as 50 - 90%.

[0018] 5. Loading terbinafine onto nanoparticles (1) Chinese Invention Patent CN 111629717A discloses nanoparticles formed by a polymer and terbinafine, which mixes terbinafine and polyhexamethylene guanidine to form nanoparticles in an alcohol - water mixed solution. The maximum content of terbinafine is 1 wt%. However, 30% ethanol is required.

[0019] (2) Chinese Invention Patent CN 119405676A discloses a co - loaded nanoparticle of baicalin self - assembled nanoparticles and terbinafine, its preparation method and application. First, terbinafine is loaded onto baicalin nanoparticles by ultrasonic method, and then a dispersion of baicalin nanoparticles containing terbinafine is obtained by membrane filtration. According to the given examples, the mass percentage concentration of terbinafine is approximately 0.063 wt%.

[0020] In the above patent applications, the maximum concentration of terbinafine is 3 wt% (CN 113440483A). However, to dissolve 3 wt% of terbinafine, 50 wt% of ethylene glycol and 10% of non - ionic surfactant are used in the mixed solution to solubilize terbinafine. Similarly, in Chinese Invention Patent CN 105395484A, the total amount of solubilizers ethylene glycol and dimethyl sulfoxide used is as high as 50 - 90% to achieve the dissolution of 2 wt% of terbinafine. In addition, ethanol, glycerol, oils, surfactants, cyclodextrins, etc. are also added in large amounts to solubilize terbinafine.

[0021] In summary, preparing a high - concentration aqueous dispersion system (aqueous solution, micelle, nanoparticle) of terbinafine remains a huge challenge. Summary of the Invention

[0022] To solve the deficiencies of the prior art, the purpose of the present invention is to provide a method for preparing a high - concentration (6 wt%) aqueous solution of terbinafine hydrochloride without using organic solvents and solubilizers, only using a small amount of surfactants (polysorbate - 80, PEG - 40 hydrogenated castor oil), through a simple process.

[0023] To achieve the above goal, the present invention adopts the following technical solutions: A method for preparing a high - concentration aqueous solution of terbinafine hydrochloride, comprising the following steps: (1) Mix a water-soluble molecule containing a benzene ring with terbinafine hydrochloride, add deionized water, stir evenly, and perform homogenization treatment to obtain a dispersion of a water-soluble molecule-terbinafine conjugate containing a benzene ring; (2) Add a water-soluble non-ionic amphiphilic molecule to the dispersion of the water-soluble molecule-terbinafine conjugate containing a benzene ring, and continue to perform homogenization treatment to obtain an aqueous solution of terbinafine hydrochloride.

[0024] Preferably, in step (1), the water-soluble molecule containing a benzene ring is selected from: phenylalanine, salicylic acid, sodium benzoate or hydroquinone; the mass ratio of the water-soluble molecule containing a benzene ring to terbinafine hydrochloride is 1:1, and the concentration of the water-soluble molecule containing a benzene ring is 6 wt%; the process parameters of the homogenization treatment are: homogenization treatment at a pressure of 500 - 1500 bar for 10 - 15 min.

[0025] Preferably, in step (2), the water-soluble non-ionic amphiphilic molecule is selected from: polysorbate-80 or PEG-40 hydrogenated castor oil; the concentration of the water-soluble non-ionic amphiphilic molecule is 1 wt%; the process parameters of the homogenization treatment are: homogenization treatment at a pressure of 500 - 1500 bar for 5 - 10 min.

[0026] The advantages of the present invention are as follows: (1) Through the p-p interaction between the benzene ring of the water-soluble molecule containing a benzene ring and the naphthalene ring in the terbinafine molecule, and the synergistic effect of the water-soluble non-ionic amphiphilic molecule, the complete dissolution of terbinafine in water is achieved at the molecular level. The concentration of the prepared aqueous solution of terbinafine hydrochloride is as high as 6 wt%, solving the problem that terbinafine is hardly soluble in water without adding a solubilizer; (2) Terbinafine hydrochloride exists in the aqueous solution in the form of small molecules, and the skin permeability and drug efficacy are significantly improved; (3) The high-pressure homogenization technology is adopted, with simple process, low cost, and easy industrial production; (4) The obtained aqueous solution of terbinafine hydrochloride has good stability, ensuring the stability of the drug efficacy during long-term storage and use. Description of the Drawings

[0027] Figure 1 It is a state diagram of dispersion liquid 6, dispersion liquid 1 and aqueous solution 1, from left to right are dispersion liquid 6, dispersion liquid 1, aqueous solution 1; Figure 2 It is a state diagram of dispersion liquid 2, dispersion liquid 3, dispersion liquid 4 and dispersion liquid 5, from left to right are dispersion liquid 2, dispersion liquid 3, dispersion liquid 4, dispersion liquid 5; Figure 3It is the state diagram of aqueous solution 2, aqueous solution 3, aqueous solution 4 and aqueous solution 5. From left to right, they are aqueous solution 2, aqueous solution 3, aqueous solution 4, and aqueous solution 5 respectively; Figure 4 It is the infrared spectrogram of terbinafine hydrochloride, phenylalanine, phenylalanine-terbinafine conjugate, and phenylalanine-terbinafine mixed powder in the range of 1250 - 1850 cm -1 ; Figure 5 It is the infrared spectrogram of terbinafine hydrochloride, phenylalanine, phenylalanine-terbinafine conjugate, and phenylalanine-terbinafine mixed powder in the range of 725 - 1050 cm -1 ; Figure 6 It is the particle size distribution detection result diagram of dispersion liquid 1, measured in parallel 3 times; Figure 7 It is the particle size distribution detection result diagram of aqueous solution 1, measured in parallel 3 times; Figure 8 It is the particle size distribution detection result diagram of aqueous solution 1 after being stored at room temperature for 3 months, measured in parallel 3 times. Specific Embodiments

[0028] The present invention will be specifically introduced below in conjunction with the accompanying drawings and specific embodiments.

[0029] I. Preparation of a water-soluble molecule-terbinafine conjugate containing a benzene ring Utilize the p-p interaction between the benzene ring of the water-soluble molecule containing a benzene ring and the naphthalene ring in the terbinafine molecule, and with the strong shearing action of high-pressure homogenization, intercalate the water-soluble molecule containing a benzene ring into the terbinafine crystal, thereby causing the terbinafine crystal to disintegrate and form a water-soluble molecule-terbinafine conjugate containing a benzene ring.

[0030] In this specific embodiment, the water-soluble molecule containing a benzene ring selected is: phenylalanine, salicylic acid, sodium benzoate, gallic acid, hydroquinone.

[0031] Example 1

[0032] Mix 3.0 g of phenylalanine with 3.0 g of terbinafine hydrochloride, add 50 mL of deionized water, and stir evenly to obtain a mixture. Place the mixture in a high-pressure homogenizer and homogenize it at a pressure of 500 bar (which can be increased to 1500 bar) for 10 min (which can be extended to 15 min) to obtain a phenylalanine-terbinafine conjugate dispersion liquid, denoted as dispersion liquid 1.

[0033] The state of dispersion liquid 1 is shown in Figure 1 . From Figure 1It can be seen that: Most of the terbinafine hydrochloride is dissolved in water, and the solution is clear and transparent. Only a very small amount of particles adhere to the bottle wall.

[0034] Example 2

[0035] Mix 3.0 g of salicylic acid with 3.0 g of terbinafine hydrochloride, add 50 mL of deionized water, and stir evenly to obtain a mixture. Place the mixture in a high-pressure homogenizer and homogenize it at a pressure of 1000 bar for 10 min to obtain a salicylic acid-terbinafine conjugate dispersion, denoted as Dispersion 2.

[0036] The state of Dispersion 2 is shown in Figure 2 . It can be seen from Figure 2 that: Most of the terbinafine hydrochloride is dissolved in water, the solution is slightly turbid, and a small amount of particles (slightly more than those in System 1) adhere to the bottle wall.

[0037] Example 3

[0038] Mix 3.0 g of sodium benzoate with 3.0 g of terbinafine hydrochloride, add 50 mL of deionized water, and stir evenly to obtain a mixture. Place the mixture in a high-pressure homogenizer and homogenize it at a pressure of 1000 bar for 10 min to obtain a sodium benzoate-terbinafine conjugate dispersion, denoted as Dispersion 3.

[0039] The state of Dispersion 3 is shown in Figure 2 . It can be known from Figure 2 that: Most of the terbinafine hydrochloride is dissolved in water, the solution is clear and transparent, and a small amount of particles (slightly more than those in System 1) adhere to the bottle wall.

[0040] Example 4

[0041] Mix 3.0 g of gallic acid with 3.0 g of terbinafine hydrochloride, add 50 mL of deionized water, and stir evenly to obtain a mixture. Place the mixture in a high-pressure homogenizer and homogenize it at a pressure of 1000 bar for 10 min to obtain a gallic acid-terbinafine conjugate dispersion, denoted as Dispersion 4.

[0042] The state of Dispersion 4 is shown in Figure 2 . It can be known from Figure 2 that: The terbinafine hydrochloride is not dissolved in water. Part of the particles agglomerate and deposit at the bottom of the bottle, and part of the particles adhere to the bottle wall.

[0043] Example 5

[0044] Mix 3.0 g of hydroquinone with 3.0 g of terbinafine hydrochloride, add 50 mL of deionized water, and stir evenly to obtain a mixture. Place the mixture in a high-pressure homogenizer and homogenize it at a pressure of 1000 bar for 10 min to obtain a hydroquinone-terbinafine conjugate dispersion, denoted as Dispersion 5.

[0045] The state of Dispersion 5 is shown in Figure 2 . It can be seen from Figure 2 that most of the terbinafine hydrochloride is dissolved in water, the solution is turbid, and there are a small number of particles (slightly more than those in System 1) adhering to the bottle wall.

[0046] Comparative Example 1 Add 3.0 g of terbinafine hydrochloride to 50 mL of deionized water, stir evenly, then place it in a high-pressure homogenizer and homogenize it at a pressure of 1000 bar for 10 min to obtain a terbinafine hydrochloride aqueous dispersion, denoted as Dispersion 6.

[0047] The state of Dispersion 6 is shown in Figure 1 . It can be seen from Figure 1 that the terbinafine hydrochloride is not dissolved in water, part of the particles agglomerate and deposit at the bottom of the bottle, and part of the particles adhere to the bottle wall.

[0048] Comparative Example 2 Dissolve 3.0 g of phenylalanine in 50 mL of deionized water, then add 3.0 g of terbinafine hydrochloride, and stir vigorously at 80 °C for 10 min. No dissolution of terbinafine hydrochloride is observed, and a suspension containing phenylalanine and terbinafine hydrochloride is obtained. Then place the container containing the suspension in a 200 W ultrasonic cleaner and ultrasonically treat it at room temperature for 10 min. The state of the suspension does not change significantly, and this suspension is denoted as Dispersion 7.

[0049] The state of Dispersion 7: The terbinafine hydrochloride is not dissolved in water and still exists in the form of a suspension. Part of the particles agglomerate and deposit at the bottom of the bottle, and part of the particles adhere to the bottle wall.

[0050] Comparative Example 3 Mix 3.0 g of phenylalanine with 3.0 g of terbinafine hydrochloride, add them to a mixed solvent of 50 mL of deionized water and ethanol (30 mL of deionized water and 20 mL of ethanol), heat and stir in a water bath at 75 °C for 10 min. The phenylalanine and terbinafine hydrochloride are completely dissolved to obtain a clear and transparent mixed solution. Let this mixed solution stand at room temperature. After the temperature of the mixed solution drops to room temperature, white particles precipitate again. The white particles mainly adhere to the bottom and the wall of the bottle. Then, place the container containing this mixed solution in a water bath at 90 °C again, heat and stir it open to the air. The white particles redissolve, and continue to heat and stir it open to the air until the solvent completely evaporates to obtain white particulate matter. Re-mix the white particulate matter with 50 mL of deionized water and ultrasonicate it for 10 min at room temperature to obtain a suspension, denoted as dispersion 8.

[0051] State of dispersion 8: A white particle suspension system. After standing, some particles deposit at the bottom of the bottle and some particles adhere to the wall of the bottle.

[0052] By comparing the states of dispersions 1 to 8, it can be seen that: (1) Without adding water-soluble molecules containing benzene rings, simple high-pressure homogenization has no obvious promoting effect on the dissolution of terbinafine hydrochloride in water; (2) When adding water-soluble molecules containing benzene rings (phenylalanine), in addition to high-pressure homogenization, ultrasonic treatment and heating and stirring have no obvious promoting effect on the dissolution of terbinafine hydrochloride in water; even by preparing an alcohol-water mixed solution of the two to make terbinafine hydrochloride and phenylalanine first mix uniformly at the molecular level and then evaporate the solvent to precipitate, it cannot promote the dissolution of terbinafine hydrochloride in water; (3) When adding water-soluble molecules containing benzene rings, under the shearing action of high-pressure homogenization, except for gallic acid, phenylalanine, salicylic acid, sodium benzoate, and hydroquinone all have a solubilizing effect on terbinafine hydrochloride. Among them, phenylalanine has the best solubilizing effect. This is mainly because the benzene rings of molecules such as gallic acid, salicylic acid, sodium benzoate, and hydroquinone are directly connected to relatively large-volume groups such as hydroxyl groups and carboxyl groups. The relatively large steric hindrance effect results in a weak p-p interaction between the benzene ring of these molecules and the naphthalene ring of the terbinafine molecule. Moreover, the phenylalanine molecule is more soluble in water than the above several molecules, thus endowing the phenylalanine-terbinafine conjugate with better water solubility.

[0053] Perform infrared detection on the raw material terbinafine hydrochloride, the raw material phenylalanine, the phenylalanine-terbinafine conjugate obtained in Example 1, and the phenylalanine-terbinafine mixed powder obtained in Comparative Example 3 in the range of 1250 - 1850 cm -1 The detection results are shown in Figure 4 .

[0054] Aromatic compounds containing benzene rings can stack through p-p interactions, which will cause broadening or displacement of the C=C skeleton and C-H vibration absorption peaks related to the benzene ring in the infrared spectrum. From Figure 4 it can be seen that: (1)Phenylalanine shows two strong absorption peaks in the range of 1460 - 1610 cm -1 , at 1494 cm -1 and 1563 cm -1 respectively, which are typical characteristic absorption peaks of the benzene ring, corresponding to symmetric and asymmetric C=C stretching vibrations respectively. After high-pressure homogenization shearing treatment, the absorption peak of phenylalanine originally at 1563 cm -1 shows obvious broadening, and a shoulder peak appears near 1580 cm -1 . Although the change of the absorption peak at 1494 cm -1 is not as obvious as the former, the shoulder peak appearing near 1514 cm -1 is still clearly visible. After heat stirring treatment, the obtained infrared spectrum is only a simple superposition of the infrared spectra of phenylalanine and terbinafine hydrochloride, and the absorption peaks at 1563 cm -1 and 1494 cm -1 do not show broadening. This indicates that the high shear energy provided by high-pressure homogenization is a necessary condition for promoting the formation of a conjugate of phenylalanine and terbinafine through p-p interaction.

[0055] (2)The absorption peaks at 1307 cm -1 and 1409 cm -1 correspond to the C-O stretching vibration in the carboxylate group (COO - ) and the symmetric stretching vibration of the carboxylate group. Before and after high-pressure homogenization shearing treatment, there is no change in the vibration absorption of the carboxylate group, indicating that there is no bonding through the carboxylate group between terbinafine and phenylalanine, and possible esterification reaction and hydrogen bonding between the phenolic hydroxyl group in terbinafine and the carboxyl group in phenylalanine can be excluded.

[0056] Infrared detection was carried out on the raw material terbinafine hydrochloride, the raw material phenylalanine, the phenylalanine-terbinafine conjugate obtained in Example 1, and the phenylalanine-terbinafine mixed powder obtained in Comparative Example 3 in the range of 725 - 1050 cm -1 , and the detection results are shown in Figure 5 .

[0057] From Figure 5 it can be seen that: Terbinafine hydrochloride shows four relatively strong absorption peaks in the range of 725 - 1050 cm -1 , at 777.3 cm -1 , 792.7 cm -1, 808.6 cm -1 and 959.2 cm -1 , these four absorption peaks can be attributed to the C-H bending vibration on the naphthalene ring. After high-pressure homogenization shearing treatment, these four peaks broaden significantly. In particular, the two absorption peaks located at 792.7 cm -1 and 808.6 cm -1 are the most illustrative because there is no absorption peak of phenylalanine in this wavenumber range, so the superposition interference of the vibration absorption peak of phenylalanine can be excluded.

[0058] The above infrared spectroscopy analysis shows that after high-pressure homogenization shearing treatment, a p-p interaction occurs between phenylalanine and terbinafine molecules. Through this p-p interaction, phenylalanine molecules are intercalated into the terbinafine molecular crystal. Under the strong shearing force provided by high-pressure homogenization, the originally strongly hydrophobic terbinafine crystal disintegrates and is dispersed in water in the form of a phenylalanine-terbinafine conjugate (the strong polar functional groups amino and carboxyl in the phenylalanine molecule endow the conjugate with good water solubility).

[0059] Among phenylalanine, salicylic acid, sodium benzoate, gallic acid, and hydroquinone, except that gallic acid has no solubilizing effect on terbinafine hydrochloride, salicylic acid, sodium benzoate, and hydroquinone all have a certain degree of solubilizing effect on terbinafine hydrochloride, but their solubilizing effects are not as good as that of phenylalanine. The reason why gallic acid containing a benzene ring has no solubilizing effect may be related to the molecular structure of gallic acid. There are three hydroxyl groups and one carboxyl group connected to the benzene ring of gallic acid, and the large steric hindrance causes the benzene ring of gallic acid to be unable to undergo a p-p interaction with the naphthalene ring of terbinafine.

[0060] II. Adding water-soluble nonionic amphiphilic molecules to the dispersion Water-soluble nonionic amphiphilic molecules are added to dispersion 1 (phenylalanine-terbinafine conjugate), dispersion 2 (salicylic acid-terbinafine conjugate), dispersion 3 (sodium benzoate-terbinafine conjugate), and dispersion 5 (hydroquinone-terbinafine conjugate) respectively. Under the shearing action of high-pressure homogenization, the water-soluble molecule-terbinafine conjugate containing a benzene ring is completely dissolved in water to form a stable aqueous solution of terbinafine hydrochloride.

[0061] In this specific embodiment, the water-soluble nonionic amphiphilic molecules selected are: polysorbate-80, PEG-40 hydrogenated castor oil.

[0062] Example 6

[0063] To the dispersion liquid 1 (50 mL, containing phenylalanine - terbinafine conjugate) was added 0.5 g of polysorbate - 80, and homogenized under a pressure of 1000 bar (which can be increased to 1500 bar) for 5 min (which can be extended to 10 min) to obtain an aqueous solution of terbinafine hydrochloride, denoted as aqueous solution 1.

[0064] The state of aqueous solution 1 is shown in Figure 1 . From Figure 1 it can be seen that: all of the phenylalanine - terbinafine conjugate dissolved in water, forming a clear and transparent solution, and no particles adhered to the bottle wall.

[0065] Example 7

[0066] To the dispersion liquid 2 (50 mL, containing salicylic acid - terbinafine conjugate) was added 0.5 g of polysorbate - 80, and homogenized under a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, denoted as aqueous solution 2.

[0067] The state of aqueous solution 2 is shown in Figure 3 . From Figure 3 it can be known that: the white particles originally adhered to the bottle wall were completely dispersed in water, and finally formed a translucent emulsion.

[0068] Example 8

[0069] To the dispersion liquid 3 (50 mL, containing sodium benzoate - terbinafine conjugate) was added 0.5 g of polysorbate - 80, and homogenized under a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, denoted as aqueous solution 3.

[0070] The state of aqueous solution 3 is shown in Figure 3 . From Figure 3 it can be known that: the white particles originally adhered to the bottle wall were completely dispersed in water, and finally formed a translucent emulsion.

[0071] Example 9

[0072] To the dispersion liquid 4 (50 mL, containing hydroquinone - terbinafine conjugate) was added 0.5 g of polysorbate - 80, and homogenized under a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, denoted as aqueous solution 4.

[0073] The state of aqueous solution 4 is shown in Figure 3 : the white particles originally adhered to the bottle wall were completely dispersed in water, and finally formed a translucent emulsion.

[0074] Example 10

[0075] To the dispersion 1 (50 mL, containing phenylalanine - terbinafine conjugate), 0.5 g of PEG - 40 hydrogenated castor oil was added, and homogenization treatment was carried out at a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, denoted as aqueous solution 5.

[0076] The state of aqueous solution 5 is shown in Figure 3 . It can be seen from Figure 3 that: all of the phenylalanine - terbinafine conjugate is dissolved in water, forming a clear and transparent solution, and no particles adhere to the bottle wall.

[0077] By comparing the states of the dispersion and the aqueous solution, it can be known that: after adding a small amount (1 wt%) of water - soluble non - ionic amphiphile to the dispersion, the dissolution performance of the conjugate becomes better, and the concentration of the aqueous solution of terbinafine hydrochloride can reach 60 mg / mL (6 wt%).

[0078] The particle size distributions of the dispersion 1 prepared in Example 1 and the aqueous solution 1 prepared in Example 6 were respectively detected.

[0079] The detection result of the particle size distribution of dispersion 1 is shown in Figure 6 , and the detection result of the particle size distribution of aqueous solution 1 is shown in Figure 7 .

[0080] It can be seen from Figure 6 that: there are mainly two kinds of particle size distributions in dispersion 1. Among them, the peak located at 5 - 10 nm can be attributed to the particle size distribution of the phenylalanine - terbinafine conjugate, and the peak located at 200 - 1000 nm can be attributed to the large aggregation structure formed by the conjugate.

[0081] It can be seen from Figure 7 that: the average particle diameter of aqueous solution 1 is about 10 nm, indicating that the large aggregation structure formed by the conjugate disappears. This shows that a small amount of water - soluble non - ionic amphiphile has a significant inhibitory effect on the aggregation of the phenylalanine - terbinafine conjugate.

[0082] The aqueous solution 1, aqueous solution 2, aqueous solution 3, aqueous solution 4 and aqueous solution 5 were stored at room temperature, and after 3 months, it was observed whether there was precipitation or phase separation in each aqueous solution.

[0083] After observation, after storing at room temperature for 3 months, there was neither precipitation nor phase separation in each aqueous solution. This shows that each aqueous solution has good stability.

[0084] The particle size distribution of aqueous solution 1 was detected again. The detection result is shown in Figure 8 .

[0085] It can be seen from Figure 8It can be known that after being stored at room temperature for 3 months, the average particle size of Aqueous Solution 1 is about 10 nm, which is the same as that 3 months ago. This shows that Aqueous Solution 1 has good stability.

[0086] The reason why the aqueous solution has good stability is that water-soluble nonionic amphiphilic molecules such as polysorbate-80 and PEG-40 hydrogenated castor oil can form micelles to encapsulate the conjugate, further increasing the energy barrier for the rebinding of terbinafine molecules, thereby improving the stability of the conjugate in the aqueous phase.

[0087] In addition, using healthy male mice as model animals, the Franz diffusion cell method was used to test the transdermal performance of the terbinafine hydrochloride aqueous solutions (Aqueous Solution 1, Aqueous Solution 2, Aqueous Solution 3, Aqueous Solution 4, Aqueous Solution 5) prepared above.

[0088] The results of the transdermal performance test showed that the 24-hour cumulative skin permeation rates of Aqueous Solution 1, Aqueous Solution 2, Aqueous Solution 3, Aqueous Solution 4, and Aqueous Solution 5 were 68.33%, 47.62%, 52.67%, 35.91%, and 67.43% respectively.

[0089] As a control, a commercially available terbinafine hydrochloride spray (containing 1 wt% terbinafine hydrochloride, and the excipients are ethanol, 1,2-propanediol, etc.) was purchased. The results of its transdermal performance test showed that the 24-hour cumulative skin permeation rate was 43.08%.

[0090] As is well known, for terbinafine hydrochloride, ethanol and 1,2-propanediol are excellent penetration enhancers and solubilizers. However, the terbinafine hydrochloride aqueous solution prepared in the present invention still has skin penetration performance equivalent to or better than that of the spray without adding these two substances.

[0091] It should be noted that the above embodiments are merely examples given to clearly illustrate the present invention, rather than limitations on the embodiments of the present invention. For those of ordinary skill in the art, other different forms of changes or modifications can be made based on the above description. It is impossible to list all the embodiments here. Any obvious changes or modifications derived from the technical solutions of the present invention still fall within the protection scope of the present invention.

Claims

1. A method for preparing a high-concentration terbinafine hydrochloride aqueous solution, characterized in that, It includes the following steps: (1) Mix a water-soluble molecule containing a benzene ring with terbinafine hydrochloride, add deionized water, stir evenly, and perform homogenization treatment to obtain a dispersion of the water-soluble molecule-terbinafine conjugate containing a benzene ring; (2) Add a water-soluble non-ionic amphiphilic molecule to the dispersion of the water-soluble molecule-terbinafine conjugate containing a benzene ring, and continue to perform homogenization treatment to obtain an aqueous solution of terbinafine hydrochloride.

2. The preparation method according to claim 1, wherein In step (1), the water-soluble molecule containing a benzene ring selected is: phenylalanine, salicylic acid, sodium benzoate or hydroquinone.

3. The preparation method according to claim 1, characterized in that, In step (1), the mass ratio of the water-soluble molecule containing a benzene ring to terbinafine hydrochloride is 1:1, and the concentration of the water-soluble molecule containing a benzene ring is 6 wt%.

4. The preparation method according to claim 1, wherein, In step (1), the process parameters of the homogenization treatment are: homogenization treatment at a pressure of 500-1500 bar for 10-15 min.

5. The preparation method according to claim 1, wherein In step (2), the water-soluble non-ionic amphiphilic molecule selected is: polysorbate-80 or PEG-40 hydrogenated castor oil.

6. The preparation method according to claim 1, wherein In step (2), the concentration of the water-soluble non-ionic amphiphilic molecule is 1 wt%.

7. The preparation method according to claim 1, characterized in that, In step (2), the process parameters of the homogenization treatment are: homogenization treatment at a pressure of 500-1500 bar for 5-10 min.

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