Preparation method of high-concentration terbinafine hydrochloride aqueous solution

Abstract

The present invention discloses a method for preparing a high-concentration terbinafine hydrochloride aqueous solution, belonging 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 and stirring evenly, and performing a homogenization treatment to obtain a dispersion of a water-soluble molecule-terbinafine conjugate containing a benzene ring; and (2) adding a water-soluble non-ionic amphiphilic molecule to the dispersion, and continuing the homogenization treatment to obtain a terbinafine hydrochloride aqueous solution. The present invention is beneficial in that: 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 terbinafine hydrochloride aqueous solution is as high as 6wt%, which solves the problem that terbinafine is difficult to dissolve in water without adding a solubilizer.

Description

Technical Field

[0001] The invention relates to a method for preparing a terbinafine hydrochloride aqueous solution, in particular to a method for preparing a high-concentration terbinafine hydrochloride aqueous solution, and belongs to the technical field of pharmaceutical preparations. Background Art

[0002] Terbinafine is a highly effective anti-dermatophyte drug widely used to treat fungal infections. Terbinafine is available in tablets, capsules, creams, ointments, gels, and solutions.

[0003] Terbinafine solutions are highly hydrophobic and poorly soluble in water (less than 1 mg / mL at room temperature), but readily soluble in organic solvents. Therefore, the terbinafine content in water-based solutions is very low. Currently available terbinafine liquid preparations are typically made primarily with ethanol (95% content, a good solvent for terbinafine) and small amounts of 1,2-propylene glycol and water, containing approximately 1% terbinafine. However, these products should not be used by those allergic to ethanol or for the treatment of fungal infections in ethanol-sensitive areas such as the eyes and mucous membranes. They are also flammable and pose a safety risk. Furthermore, ethanol's strong irritating odor makes them unsuitable for use as a pet anti-ringworm spray.

[0004] Chinese invention patent CN 1883475A discloses a kind of veterinary compound terbinafine hydrochloride solution, and this solution is made up of terbinafine hydrochloride, metronidazole, thiabendazole, cypermethrin and organic solvent, wherein, organic solvent is any one or more of chloroform, benzene, dimethylbenzene, acetone, propylene glycol, butanone, ethanol and dimethyl sulfoxide.Although the content of terbinafine in this solution is up to 10wt%, because organic solvent majority there is toxicity or has stimulation to skin, so it is not suitable for animal use, more not suitable for human use.And these organic solvent majority are all easily flammable, there is large potential safety hazard.

[0005] In order to improve the solubility of terbinafine in water, the main methods currently used are:

[0006] 1. Make hydrochloride or malate

[0007] (1) Terbinafine is reacted with hydrochloric acid to prepare a hydrochloric acid addition salt of terbinafine. The solubility of terbinafine hydrochloride in water at room temperature increases to 6.7 mg / mL.

[0008] (2) Terbinafine is reacted 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 in the synthesis of terbinafine malate.

[0009] 2. Preparation of cyclodextrin inclusion compound

[0010] (1) Chinese invention patent CN 1843342A discloses an eye drop for treating fungal keratitis, which uses terbinafine as an active ingredient, hydroxypropyl β-cyclodextrin as a solubilizer, and water as a solvent to prepare terbinafine eye drops, wherein the concentration of terbinafine is 0.25wt% (2.5mg / mL), and the concentration of hydroxypropyl β-cyclodextrin is 3-3.5wt% (30-35 mg / mL). The amount of hydroxypropyl β-cyclodextrin used is 12-14 times that of terbinafine.

[0011] (2) Chinese invention patent CN 105687196A discloses an itraconazole-terbinafine compound injection for dogs and cats and its preparation method, wherein terbinafine is first completely dissolved in ethanol and then added dropwise to an aqueous solution of hydroxypropyl β-cyclodextrin to form a terbinafine / cyclodextrin inclusion complex, wherein the concentration of terbinafine is 2 wt% (20 mg / mL) and the concentration of hydroxypropyl β-cyclodextrin is 70 wt%, and the amount of hydroxypropyl β-cyclodextrin used is 35 times that of terbinafine.

[0012] 3. Make oil-in-water emulsions, micelles, etc.

[0013] (1) Chinese invention patent CN 1927181A discloses a method for preparing an oil-in-water terbinafine nanoemulsion, wherein terbinafine is first dissolved in ethanol and then 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, Tween 80, Span 80), mixed evenly, and then water is added and stirred to emulsify to obtain the final product. However, in order to obtain an emulsion with an effective content of 2% terbinafine, the amount of surfactant used is as high as 40%-62.5%, and 4.4%-15% of oil is also used.

[0014] (2) Chinese invention patent CN 102600192A discloses a compound terbinafine nanoparticle drug for treating skin diseases and its preparation method, which 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), cosolvents (anhydrous ethanol, ethylene glycol, 1,2-propylene glycol, glycerol, PEG 200, PEG 400, PEG 600) and a large amount of surfactants (Tween-80, Tween-60, Tween-20, RH-40, EL-40 and Span-80) to solubilize terbinafine and prepare a nanodispersion system.

[0015] (3) Chinese invention patent CN 105012235A discloses an ophthalmic antifungal nanomicelle solution containing terbinafine hydrochloride. The nanomicelle solution uses nanomicelles to solubilize terbinafine. Specifically, terbinafine is first dissolved in glycerol, and then a solubilizer (15-hydroxystearate polyethylene glycol, polyoxyethylene ether 40 hydrogenated castor oil) is added. After mixing evenly, an aqueous phase containing a thickener is added, and the mixture is stirred and emulsified to obtain a nanomicelle solution. However, the terbinafine content in the nanomicelle solution prepared by this method is only 1 wt%.

[0016] (4) Chinese invention patent CN 113440483A discloses a terbinafine hydrochloride spray for dogs and its preparation method, which uses up to 50% ethylene glycol and 10% non-ionic surfactant (polyoxyethylene stearate and polyoxyethylene alkyl ether) to solubilize terbinafine, and the maximum terbinafine content can reach 3wt%.

[0017] (5) Chinese invention patent CN 113786382A discloses a terbinafine hydrochloride gel and its preparation method, wherein 2 parts of terbinafine, 20-60 parts of Tween 20, and 5-15 parts of an oil phase are used to prepare a terbinafine microemulsion, wherein the effective content of terbinafine in the microemulsion is 2 wt%.

[0018] (6) Chinese invention patent CN 115531312A discloses a process for preparing terbinafine hydrochloride spray, which uses 10 times the mass of solubilizer polyethylene glycol 15-hydroxystearate (HS15) and laurocapram to prepare terbinafine hydrochloride spray, with an effective content of terbinafine of about 0.88 wt%.

[0019] (7) Chinese invention patent CN 119564596A discloses a needle-free injection of terbinafine hydrochloride, a transdermal injection for treating superficial fungal infections, and a drug delivery device thereof, which utilizes ethanol to solubilize terbinafine, so that the concentration of terbinafine dissolved in water can reach 0.1-0.5 wt%.

[0020] However, these methods do not produce terbinafine aqueous solutions, but rather oil-in-water emulsions containing terbinafine. Not only are these technologies complex to prepare, but the long-term stability of the emulsions remains to be verified. More importantly, after the water evaporates, terbinafine primarily dissolves in the oil phase, and the skin permeability of this oil phase determines how easily terbinafine reaches the lesions. These issues remain to be verified.

[0021] 4. Dissolve terbinafine in a good solvent first, then add water to obtain a mixed solution

[0022] Chinese invention patent CN 105395484A discloses a compound terbinafine spray and its preparation method. Terbinafine and other antibiotics are first dissolved in a mixture of ethylene glycol and dimethyl sulfoxide, and then water is added. This method can produce a terbinafine solution with a maximum solids content of 2% by weight, but the total amount of ethylene glycol and dimethyl sulfoxide used is as high as 50-90%.

[0023] 5. Loading terbinafine on nanoparticles

[0024] (1) Chinese invention patent CN 111629717A discloses nanoparticles formed from a polymer and terbinafine. Terbinafine and polyhexamethylene guanidine are mixed and formed into nanoparticles in an alcohol-water mixture. The maximum terbinafine content is 1 wt%, but 30% ethanol is required.

[0025] (2) Chinese invention patent CN 119405676A discloses a method for co-loading terbinafine with self-assembled Scutellaria baicalensis nanoparticles, as well as a preparation method and application thereof. Terbinafine is first loaded onto the Scutellaria baicalensis nanoparticles by ultrasound, and then filtered through a filter membrane to obtain a dispersion of Scutellaria baicalensis nanoparticles containing terbinafine. According to the examples provided, the mass percentage concentration of terbinafine is approximately 0.063 wt%.

[0026] In the aforementioned patent applications, the maximum terbinafine concentration is 3 wt% (CN 113440483A). However, to dissolve 3 wt% terbinafine, a mixed solution is required containing 50 wt% ethylene glycol and 10% nonionic surfactant to solubilize terbinafine. Similarly, in Chinese invention patent CN 105395484A, a combined amount of 50-90% of the solubilizing agents ethylene glycol and dimethyl sulfoxide is used to dissolve 2 wt% terbinafine. In addition, ethanol, glycerol, oils, surfactants, cyclodextrins, and other additives are also added in large quantities to solubilize terbinafine.

[0027] In summary, the preparation of high-concentration terbinafine aqueous dispersion systems (aqueous solutions, micelles, nanoparticles) remains a huge challenge. Summary of the Invention

[0028] To address the deficiencies of the prior art, the present invention aims to provide a method for preparing a high-concentration (6 wt %) aqueous solution of terbinafine hydrochloride by a simple process using only a small amount of surfactant (polysorbate 80, PEG-40 hydrogenated castor oil) without using organic solvents and solubilizers.

[0029] In order to achieve the above objectives, the present invention adopts the following technical solutions:

[0030] The preparation method of high-concentration terbinafine hydrochloride aqueous solution comprises the following steps:

[0031] (1) mixing a water-soluble molecule containing a benzene ring with terbinafine hydrochloride, adding deionized water, stirring evenly, and performing a homogenization treatment to obtain a water-soluble molecule containing a benzene ring-terbinafine conjugate dispersion;

[0032] (2) Adding a water-soluble nonionic amphiphilic molecule to the dispersion of the water-soluble molecule containing a benzene ring-containing terbinafine conjugate, and continuing the homogenization process to obtain an aqueous solution of terbinafine hydrochloride.

[0033] 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 minutes.

[0034] Preferably, in step (2), the water-soluble nonionic amphiphilic molecule is polysorbate 80 or PEG-40 hydrogenated castor oil; the concentration of the water-soluble nonionic amphiphilic molecule is 1 wt %; and the process parameters of the homogenization treatment are: homogenization treatment at a pressure of 500-1500 bar for 5-10 minutes.

[0035] The present invention is beneficial in that:

[0036] (1) Through the pp interaction between the benzene ring of the water-soluble molecule containing a benzene ring and the naphthalene ring in the terbinafine molecule, as well as the synergistic effect of the water-soluble non-ionic amphiphilic molecule, terbinafine is completely dissolved in water at the molecular level. The concentration of the prepared terbinafine hydrochloride aqueous solution is as high as 6wt%, which solves the problem of terbinafine being difficult to dissolve in water without the addition of a solubilizer;

[0037] (2) Terbinafine hydrochloride exists in aqueous solution as a small molecule, which significantly improves skin permeability and efficacy;

[0038] (3) High-pressure homogenization technology is used, which has simple process, low cost and is easy for industrial production;

[0039] (4) The obtained aqueous solution of terbinafine hydrochloride has good stability, which ensures the stability of the efficacy during long-term storage and use. BRIEF DESCRIPTION OF THE DRAWINGS

[0040] Figure 1 This is a state diagram of dispersion 6, dispersion 1, and aqueous solution 1. From left to right, it is dispersion 6, dispersion 1, and aqueous solution 1.

[0041] Figure 2This is a state diagram of dispersion 2, dispersion 3, dispersion 4, and dispersion 5. From left to right, it is dispersion 2, dispersion 3, dispersion 4, and dispersion 5.

[0042] Figure 3 This is a 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.

[0043] Figure 4 Terbinafine hydrochloride, phenylalanine, phenylalanine-terbinafine conjugate, phenylalanine-terbinafine mixed powder at 1250-1850cm -1 Infrared spectrum within the range;

[0044] Figure 5 Terbinafine hydrochloride, phenylalanine, phenylalanine-terbinafine conjugate, phenylalanine-terbinafine mixed powder at 725-1050cm -1 Infrared spectrum within the range;

[0045] Figure 6 This is the particle size distribution test result of dispersion 1, which was measured three times in parallel;

[0046] Figure 7 This is the particle size distribution test result of aqueous solution 1, which was measured three times in parallel;

[0047] Figure 8 This is the particle size distribution test result of aqueous solution 1 after being stored at room temperature for 3 months, and the measurement was performed in parallel 3 times. DETAILED DESCRIPTION

[0048] The present invention will be described in detail below with reference to the accompanying drawings and specific embodiments.

[0049] 1. Preparation of water-soluble molecule-terbinafine conjugate containing a benzene ring

[0050] By utilizing the pp interaction between the benzene ring of the water-soluble molecule containing a benzene ring and the naphthalene ring in the terbinafine molecule, the water-soluble molecule containing a benzene ring is intercalated into the terbinafine crystal with the help of the strong shearing effect of high-pressure homogenization, thereby causing the terbinafine crystal to disintegrate and form a water-soluble molecule containing a benzene ring-terbinafine conjugate.

[0051] In this specific embodiment, the water-soluble molecules containing a benzene ring are selected from: phenylalanine, salicylic acid, sodium benzoate, gallic acid, and hydroquinone.

[0052] Example 1

[0053] Mix 3.0 g of phenylalanine and 3.0 g of terbinafine hydrochloride, add 50 mL of deionized water, and stir thoroughly to obtain a mixture. Place the mixture in a high-pressure homogenizer and homogenize at 500 bar (which can be increased to 1500 bar) for 10 minutes (which can be extended to 15 minutes) to obtain a phenylalanine-terbinafine conjugate dispersion, designated as Dispersion 1.

[0054] The state of dispersion 1 is shown in Figure 1 .Depend on Figure 1 It can be seen that most of the terbinafine hydrochloride is dissolved in water, the solution is clear and transparent, and only a small amount of particles adhere to the bottle wall.

[0055] Example 2

[0056] 3.0 g of salicylic acid and 3.0 g of terbinafine hydrochloride were mixed, 50 mL of deionized water was added, and the mixture was stirred uniformly to obtain a mixture. The mixture was placed in a high-pressure homogenizer and homogenized at a pressure of 1000 bar for 10 minutes to obtain a salicylic acid-terbinafine conjugate dispersion, which was recorded as Dispersion 2.

[0057] The state of dispersion 2 is shown in Figure 2 .Depend on Figure 2 It can be seen 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 wall of the bottle.

[0058] Example 3

[0059] 3.0 g of sodium benzoate and 3.0 g of terbinafine hydrochloride were mixed, 50 mL of deionized water was added, and the mixture was stirred uniformly to obtain a mixture. The mixture was placed in a high-pressure homogenizer and homogenized at a pressure of 1000 bar for 10 minutes to obtain a sodium benzoate-terbinafine conjugate dispersion, which was recorded as dispersion 3.

[0060] The state of dispersion 3 is shown in Figure 2 .Depend on Figure 2 It can be seen 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 wall of the bottle.

[0061] Example 4

[0062] 3.0 g of gallic acid and 3.0 g of terbinafine hydrochloride were mixed, 50 mL of deionized water was added, and the mixture was stirred uniformly to obtain a mixture. The mixture was placed in a high-pressure homogenizer and homogenized at a pressure of 1000 bar for 10 minutes to obtain a gallic acid-terbinafine conjugate dispersion, which was recorded as Dispersion 4.

[0063] The state of dispersion 4 is shown in Figure 2 .Depend on Figure 2It can be seen that terbinafine hydrochloride is not dissolved in water, some particles agglomerate and settle at the bottom of the bottle, and some particles adhere to the bottle wall.

[0064] Example 5

[0065] 3.0 g of hydroquinone and 3.0 g of terbinafine hydrochloride were mixed, 50 mL of deionized water was added, and the mixture was stirred uniformly to obtain a mixture. The mixture was placed in a high-pressure homogenizer and homogenized at a pressure of 1000 bar for 10 minutes to obtain a hydroquinone-terbinafine conjugate dispersion, which was recorded as Dispersion 5.

[0066] The state of dispersion 5 is shown in Figure 2 .Depend on Figure 2 It can be seen that most of the terbinafine hydrochloride is dissolved in water, the solution is turbid, and a small amount of particles (slightly more than those in system 1) adhere to the wall of the bottle.

[0067] Comparative Example 1

[0068] 3.0 g of terbinafine hydrochloride was added to 50 mL of deionized water and stirred evenly. The mixture was then placed in a high-pressure homogenizer and homogenized at a pressure of 1000 bar for 10 min to obtain a terbinafine hydrochloride aqueous dispersion, which was designated as dispersion 6.

[0069] The state of dispersion 6 is shown in Figure 1 .Depend on Figure 1 It can be seen that terbinafine hydrochloride is not dissolved in water, some particles are aggregated and deposited at the bottom of the bottle, and some particles adhere to the bottle wall.

[0070] Comparative Example 2

[0071] 3.0 g of phenylalanine was dissolved in 50 mL of deionized water, followed by the addition of 3.0 g of terbinafine hydrochloride. The mixture was stirred vigorously at 80°C for 10 minutes. No dissolution of the terbinafine hydrochloride was observed, resulting in a suspension containing phenylalanine and terbinafine hydrochloride. The container containing the suspension was then placed in a 200 W ultrasonic cleaner and sonicated at room temperature for 10 minutes. No significant change in the state of the suspension was observed. This suspension was designated as Dispersion 7.

[0072] State of dispersion 7: Terbinafine hydrochloride was not dissolved in water and still existed in the state of suspension. Some particles aggregated and deposited at the bottom of the bottle, while some particles adhered to the bottle wall.

[0073] Comparative Example 3

[0074] 3.0 g of phenylalanine and 3.0 g of terbinafine hydrochloride were mixed and added to 50 mL of a mixed solvent of deionized water and ethanol (30 mL deionized water, 20 mL ethanol). The mixture was heated and stirred in a 75°C water bath for 10 minutes, completely dissolving the phenylalanine and terbinafine hydrochloride to obtain a clear, transparent mixed solution. The mixed solution was allowed to stand at room temperature. Once the temperature of the mixed solution cooled to room temperature, white particles precipitated, primarily adhering to the bottom and walls of the bottle. The container containing the mixed solution was then placed in a 90°C water bath with open heating and stirring, causing the white particles to redissolve. Heating and stirring were continued openly until the solvent evaporated completely, yielding white particles. The white particles were then remixed with 50 mL of deionized water and sonicated at room temperature for 10 minutes to obtain a suspension, designated as Dispersion 8.

[0075] State of dispersion 8: white particle suspension system. After standing, some particles settle at the bottom of the bottle, and some particles adhere to the bottle wall.

[0076] Comparing the states of dispersions 1 to 8, we can see that:

[0077] (1) Without the addition of water-soluble molecules containing benzene rings, simple high-pressure homogenization has no significant effect on promoting the dissolution of terbinafine hydrochloride in water;

[0078] (2) When a water-soluble molecule containing a benzene ring (phenylalanine) was added, except for high-pressure homogenization, ultrasound and heating stirring had no significant effect on promoting the dissolution of terbinafine hydrochloride in water. Even by preparing an alcohol-water mixed solution of the two, so that terbinafine hydrochloride and phenylalanine were first mixed uniformly at the molecular level and then the solvent was evaporated and precipitated, it was still unable to promote the dissolution of terbinafine hydrochloride in water.

[0079] (3) When water-soluble molecules containing benzene rings were added, under the shearing action of high-pressure homogenization, phenylalanine, salicylic acid, sodium benzoate and hydroquinone all had a solubilizing effect on terbinafine hydrochloride, except for gallic acid. Among them, phenylalanine had the best solubilizing effect. This was mainly because the benzene rings of molecules such as gallic acid, salicylic acid, sodium benzoate and hydroquinone were directly connected to larger groups such as hydroxyl and carboxyl groups. The large steric hindrance effect resulted in weaker pp interactions between the benzene rings of these molecules and the naphthalene rings of the terbinafine molecule. In addition, phenylalanine molecules were more soluble in water than the above molecules, thus giving the phenylalanine-terbinafine conjugate better water solubility.

[0080] 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 were heated at 1250-1850 cm -1 Infrared detection is carried out within the range, and the test results are shown in Figure 4.

[0081] Aromatic compounds containing benzene rings can stack through pp interactions, which will cause the C=C skeleton and CH vibration absorption peaks related to the benzene ring in the infrared spectrum to broaden or shift. Figure 4 It can be seen that:

[0082] (1) Phenylalanine at 1460-1610 cm -1 There are two strong absorption peaks in the range of 1494 cm -1 and 1563cm -1 , which are typical characteristic absorption peaks of benzene ring, corresponding to symmetrical and asymmetrical C=C stretching vibration absorption. After high pressure homogenization shearing treatment, phenylalanine originally located at 1563cm -1 The absorption peak of -1 A shoulder peak appeared nearby, located at 1494cm -1 Although the absorption peak change of 1514cm is not as obvious as the former, -1 The shoulder peak near the 1563cm is still clearly visible. After heating and stirring, the infrared spectrum obtained is just a simple superposition of the infrared spectra of phenylalanine and terbinafine hydrochloride. -1 and 1494cm -1 The absorption peak did not broaden. This indicates that the high shear energy provided by high-pressure homogenization is a necessary condition for promoting the formation of a conjugate between phenylalanine and terbinafine through the PP interaction.

[0083] (2) Located at 1307cm -1 and 1409cm -1 The absorption peak corresponds to the carboxylate (COO - ) and the symmetrical stretching vibration of the carboxylate group. The vibrational absorption of the carboxylate group remained unchanged before and after high-pressure homogenization shearing, indicating that the bonding between terbinafine and phenylalanine is not via the carboxylate group. Possible esterification reactions and hydrogen bonding between the phenolic hydroxyl group in terbinafine and the carboxyl group of phenylalanine can be ruled out.

[0084] 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 were heated at 725-1050 cm -1 Infrared detection is carried out within the range, and the test results are shown in Figure 5 .

[0085] Depend on Figure 5 It can be seen that terbinafine hydrochloride is at 725-1050cm -1Four relatively strong absorption peaks appeared in the range of 777.3cm -1 、792.7cm -1 、808.6cm -1 and 959.2cm -1 These four absorption peaks can be attributed to the CH bending vibration on the naphthalene ring. After high-pressure homogenization shearing treatment, these four peaks are significantly broadened, especially at 792.7cm -1 and 808.6cm -1 The two absorption peaks are the most telling, because phenylalanine has no absorption peak in this wave number range, so the superposition interference of the vibration absorption peak of phenylalanine can be ruled out.

[0086] The above-mentioned infrared spectroscopy analysis shows that after high-pressure homogenization and shearing treatment, a pp interaction occurs between phenylalanine and terbinafine molecules. Through this pp interaction, the phenylalanine molecules are able to intercalate into the terbinafine molecular crystals. Under the action of the strong shear force provided by high-pressure homogenization, the originally highly hydrophobic terbinafine crystals are disintegrated and dispersed in water in the form of a phenylalanine-terbinafine conjugate (the highly polar functional groups amino and carboxyl groups in the phenylalanine molecule give the conjugate good water solubility).

[0087] Among phenylalanine, salicylic acid, sodium benzoate, gallic acid, and hydroquinone, gallic acid had no solubilizing effect on terbinafine hydrochloride. Salicylic acid, sodium benzoate, and hydroquinone all showed some solubilization, but none as good as phenylalanine. The lack of solubilization by gallic acid, which contains a benzene ring, may be related to its molecular structure. The benzene ring of gallic acid is connected to three hydroxyl groups and one carboxyl group, resulting in significant steric hindrance that prevents the benzene ring from interacting with the naphthalene ring of terbinafine.

[0088] 2. Add water-soluble nonionic amphiphilic molecules to the dispersion

[0089] Water-soluble non-ionic amphiphilic molecules were 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 containing a benzene ring-terbinafine conjugate was completely dissolved in water to form a stable aqueous solution of terbinafine hydrochloride.

[0090] In this specific embodiment, the water-soluble nonionic amphiphilic molecules selected are: polysorbate 80, PEG-40 hydrogenated castor oil.

[0091] Example 6

[0092] To dispersion 1 (50 mL, containing phenylalanine-terbinafine conjugate) was added 0.5 g of polysorbate 80, and the mixture was homogenized at 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, which was designated as aqueous solution 1.

[0093] The state of aqueous solution 1 is shown in Figure 1 .Depend on Figure 1 It can be seen that the phenylalanine-terbinafine conjugate is completely dissolved in water to form a clear and transparent solution, and no particles adhere to the bottle wall.

[0094] Example 7

[0095] 0.5 g of polysorbate 80 was added to dispersion 2 (50 mL, containing salicylic acid-terbinafine conjugate), and the mixture was homogenized at a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, which was recorded as aqueous solution 2.

[0096] The state of aqueous solution 2 is shown in Figure 3 .Depend on Figure 3 It can be seen that the white particles originally attached to the bottle wall are completely dispersed in the water, eventually forming a translucent emulsion.

[0097] Example 8

[0098] 0.5 g of polysorbate 80 was added to dispersion 3 (50 mL, containing sodium benzoate-terbinafine conjugate), and the mixture was homogenized at a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, which was designated as aqueous solution 3.

[0099] The state of aqueous solution 3 is shown in Figure 3 .Depend on Figure 3 It can be seen that the white particles originally attached to the bottle wall are completely dispersed in the water, eventually forming a translucent emulsion.

[0100] Example 9

[0101] 0.5 g of polysorbate 80 was added to dispersion 4 (50 mL, containing hydroquinone-terbinafine conjugate), and the mixture was homogenized at a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, which was recorded as aqueous solution 4.

[0102] The state of aqueous solution 4 is shown in Figure 3 : The white particles originally attached to the bottle wall are completely dispersed in the water, eventually forming a translucent emulsion.

[0103] Example 10

[0104] 0.5 g of PEG-40 hydrogenated castor oil was added to dispersion 1 (50 mL, containing phenylalanine-terbinafine conjugate), and the mixture was homogenized at a pressure of 1000 bar for 5 min to obtain an aqueous solution of terbinafine hydrochloride, which was designated as aqueous solution 5.

[0105] The state of aqueous solution 5 is shown in Figure 3 .Depend on Figure 3 It can be seen that the phenylalanine-terbinafine conjugate is completely dissolved in water to form a clear and transparent solution, and no particles adhere to the bottle wall.

[0106] Comparing the states of the dispersion and aqueous solution, it can be seen that after adding a small amount (1wt%) of water-soluble non-ionic amphiphilic molecules to the dispersion, the solubility of the conjugate becomes better, and the concentration of the terbinafine hydrochloride aqueous solution can reach 60mg / mL (6wt%).

[0107] The particle size distribution of the dispersion 1 prepared in Example 1 and the aqueous solution 1 prepared in Example 6 were respectively tested.

[0108] The particle size distribution test results of dispersion 1 are shown in Figure 6 The particle size distribution test results of aqueous solution 1 are shown in Figure 7 .

[0109] Depend on Figure 6 It can be seen that the particle size of dispersion 1 mainly has two distributions. Among them, the peak at 5-10 nm can be attributed to the particle size distribution of phenylalanine-terbinafine conjugate, and the peak at 200-1000 nm can be attributed to the large aggregate structure formed by the conjugate.

[0110] Depend on Figure 7 It can be seen that the average particle size of aqueous solution 1 is about 10 nm, indicating that the large aggregated structure formed by the conjugate has disappeared. This shows that a small amount of water-soluble nonionic amphiphilic molecules has a significant inhibitory effect on the aggregation of phenylalanine-terbinafine conjugates.

[0111] 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, each aqueous solution was observed to see whether there was precipitation or phase separation.

[0112] After 3 months of storage at room temperature, the aqueous solutions showed neither precipitation nor phase separation, indicating that the aqueous solutions had good stability.

[0113] The particle size distribution of aqueous solution 1 was tested again. The test results are shown in Figure 8 .

[0114] Depend on Figure 8It can be seen that after 3 months of storage at room temperature, 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.

[0115] The reason why the aqueous solution has good stability is that water-soluble non-ionic amphiphilic molecules such as polysorbate 80 and PEG-40 hydrogenated castor oil can form micelles, encapsulating the conjugate, further increasing the energy barrier for the recombination of terbinafine molecules, thereby improving the stability of the conjugate in the aqueous phase.

[0116] In addition, healthy male rats were used as model animals, and the Franz absorption 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.

[0117] The results of the transdermal performance test showed that the 24-h 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.

[0118] As a control, a terbinafine hydrochloride spray (terbinafine hydrochloride content 1wt%, excipients such as ethanol and 1,2-propylene glycol) was purchased from the market. The transdermal performance test results showed that the 24-hour cumulative skin permeability was 43.08%.

[0119] It is well known that ethanol and 1,2-propylene glycol are excellent penetration enhancers and solubilizers for terbinafine hydrochloride. However, the terbinafine hydrochloride aqueous solution prepared by the present invention still has skin penetration performance comparable to or better than that of the spray without the addition of these two substances.

[0120] It should be noted that the above embodiments are merely examples for the purpose of clearly illustrating the present invention and are not intended to limit the embodiments of the present invention. A person skilled in the art would be able to make other variations or modifications based on the above description. It is not possible to enumerate all embodiments here. Any obvious variations or modifications arising from the technical solution of the present invention remain within the scope of protection of the present invention.

Claims

1. A method for preparing a high-concentration terbinafine hydrochloride aqueous solution, characterized in that: The following steps are involved: (1) mixing a water-soluble molecule containing a benzene ring with terbinafine hydrochloride, wherein the water-soluble molecule containing a benzene ring is selected from phenylalanine, salicylic acid, sodium benzoate or hydroquinone, adding deionized water, stirring evenly, and homogenizing. The process parameters of the homogenization treatment are: homogenizing at a pressure of 500-1500 bar for 10-15 minutes to obtain a dispersion of a water-soluble molecule containing a benzene ring-terbinafine conjugate; (2) Adding a water-soluble nonionic amphiphilic molecule to the dispersion of the water-soluble molecule containing a benzene ring and the terbinafine conjugate, wherein the water-soluble nonionic amphiphilic molecule is polysorbate-80 or PEG-40 hydrogenated castor oil, and continuing the homogenization treatment to obtain an aqueous solution of terbinafine hydrochloride.

2. 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 %.

3. The preparation method according to claim 1, characterized in that In step (2), the concentration of the water-soluble nonionic amphiphilic molecule is 1 wt %.

4. 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 minutes.

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