Aroyl-containing ceramide analogs, methods of synthesis and use thereof

Abstract

This invention discloses an aromatic acyl-containing ceramide analogue, its synthesis method, and its applications. The analogue is synthesized using ceramide C2 as a template by introducing alkyl chains of different lengths and aromatic rings via Henry reaction, reduction reaction, and acylation reaction. This type of compound exhibits excellent gelling ability in rapeseed oil, petroleum ether, and ethanol, rapidly forming stable gels. After self-assembling with borneol in petroleum ether or ethanol to form a gel, a small-molecule gelling agent-borneol assembly is obtained by freeze-drying. This assembly possesses a fibrous, three-dimensional network structure. Through hydrogen bonding, alkyl entanglement, and π-π interactions, the assembly significantly reduces borneol volatilization loss, and at safe borneol dosages, the assembly does not increase toxicity, demonstrating good biocompatibility. This invention offers a simple preparation method, strong gelling ability, and high drug loading capacity, providing a new approach for the stability control of volatile drug components and showing broad application prospects in borneol-containing traditional Chinese medicine preparations.

Description

Technical Field

[0001] This invention belongs to the field of small molecule gelling agent technology, specifically relating to an aromatic acyl ceramide analog and its synthesis method, as well as the application of the ceramide analog as a small molecule gelling agent in the preparation of assemblies for stabilizing borneol. Background Technology

[0002] Borneol, a bicyclic monoterpene chemically named 2-borneol, is a traditional Chinese medicine with a history of medicinal use spanning 1500 years. It possesses properties that awaken the mind, clear heat, and relieve pain. Modern research indicates that borneol exhibits excellent pharmacological effects, acting as a natural penetration enhancer to promote drug absorption across the blood-brain barrier, mucous membranes, gastrointestinal tract, and skin. Therefore, it is widely used in the composition of over 170 kinds of traditional Chinese medicine preparations and is commonly used to treat cardiovascular and cerebrovascular diseases and skin diseases.

[0003] However, borneol is highly volatile and easily sublimates and is lost during formulation and storage, leading to a gradual decrease in its content. This not only affects the stability and efficacy of the drug but also poses a significant challenge to the formulation and quality control of borneol-containing drugs. Currently, methods to improve borneol stability mainly include microencapsulation, β-cyclodextrin inclusion complexation, and solid dispersion. However, these methods all have certain limitations: microencapsulation is complex and costly; β-cyclodextrin inclusion complexation has low drug loading and introduces a large amount of excipients; and solid dispersion requires high temperatures or special equipment, making it unsuitable for highly volatile borneol. Furthermore, coating tablets and pills has not fundamentally solved the problem of borneol volatility and increases the number of processes and costs.

[0004] Small molecule organic gelling agents, as novel drug carriers, can self-assemble into three-dimensional network structures through non-covalent interactions such as hydrogen bonding, π-π stacking, and van der Waals forces, thus immobilizing solvent molecules within them. Previously, our research group prepared a small molecule gelling agent-borneol assembly (CN118949051 A), finding that this assembly effectively reduced borneol volatilization loss. However, the small molecule gelling agent used was costly to prepare, and the gelation time was long (over 1 hour), requiring further improvement in the stability and borneol retention rate of the assembly. Therefore, developing a novel small molecule gelling agent that is simple to prepare, lower in cost, has stronger gelling ability, and can more effectively stabilize borneol is of significant practical importance.

[0005] Ceramide C2 is a short acyl chain analog of ceramide, possessing cell permeability and bioactivity. Studies have found that ceramide C2 can form supramolecular self-assembly systems through hydrogen bonding and other forces, thus exhibiting certain gelling capabilities. Using it as a template for structural modification and alteration holds promise for obtaining novel small-molecule gelling agents with superior performance. Summary of the Invention

[0006] The present invention aims to provide an aromatic acyl ceramide analog that has good gelling ability and can self-assemble with borneol to form stable assemblies, thereby significantly reducing the volatility of borneol.

[0007] The present invention also provides a method for synthesizing the aryl ceramide analogue and its application in stabilizing borneol.

[0008] The aromatic acyl-containing ceramide analogue of the present invention has the following structural formula:

[0009]

[0010] Among them, R1 is selected from C3 to C4. 14 The straight-chain alkyl group; R2 is selected from any one of phenyl, benzyl, phenethyl, naphthyl, C1-C3 alkoxy-substituted phenyl, C1-C3 alkoxy-substituted benzyl, benzyloxyphenyl, benzyloxybenzyl, benzyloxynaphthyl, halophenyl, halobenzyl, hydroxy-substituted phenyl, hydroxy-substituted benzyl, and hydroxy-substituted naphthyl.

[0011] Furthermore, the aryl acyl ceramide analog is preferably any one of the following structural formulas:

[0012]

[0013] The synthetic routes and methods for the above-mentioned aryl ceramide analogs are as follows:

[0014]

[0015] Step 1: Using the aliphatic aldehyde shown in Formula A and 2-nitroethanol shown in Formula B as starting materials, the nitro alcohol compound shown in Formula C is synthesized via the Henry reaction in the presence of an alkaline catalyst.

[0016] Step 2: The nitro alcohol compound obtained in Step 1 is subjected to a nitro reduction reaction to reduce its nitro group to an amino group, thereby obtaining the amino alcohol compound shown in Formula D.

[0017] Step 3: The amino alcohol compound obtained in Step 2 is subjected to an acylation reaction with an aromatic acyl chloride compound of Formula E under the catalysis of an organic base to obtain the target compound F, wherein R3 is selected from any one of phenyl, benzyl, phenethyl, naphthyl, C1-C3 alkoxy-substituted phenyl, C1-C3 alkoxy-substituted benzyl, benzyloxyphenyl, benzyloxybenzyl, benzyloxynaphthyl, halophenyl, and halobenzyl.

[0018] In the above synthetic method, the target compound F obtained in step 3, representing benzyloxyphenyl, benzyloxybenzyl or benzyloxynaphthyl, can be further subjected to a debenzylation reaction to obtain an aromatic acyl ceramide analog, representing hydroxy-substituted phenyl, hydroxy-substituted benzyl or hydroxy-substituted naphthyl.

[0019] Furthermore, the Henry reaction in step 1 uses triethylamine as a catalyst and tetrahydrofuran as a solvent, and reacts for 2 to 4 days at 10°C to room temperature; the nitro reduction reaction in step 2 uses palladium on carbon as a catalyst and tetrahydrofuran as a solvent, and reacts for 20 to 24 hours at room temperature under nitrogen protection; the acylation reaction in step 3 uses triethylamine as a catalyst and dichloromethane as a solvent, and reacts for 3 to 5 hours at -25 to -15°C.

[0020] The present invention also provides a small molecule gelling agent-borneol assembly, which uses the aryl acyl ceramide analog described in the present invention as a small molecule gelling agent, and assembles with borneol in an organic solvent to form a gel, and then obtains it by freeze drying; the organic solvent is petroleum ether or ethanol.

[0021] Further, the preparation method of the assembly is as follows: the acyl-containing ceramide analog and borneol are added to an organic solvent at a mass ratio of 1:1 to 3, heated under sealed conditions until completely dissolved, and then allowed to stand at 0 to 5°C for 10 to 30 minutes to form a gel. The gel is then pre-frozen at -25 to -15°C for 4 to 6 hours and freeze-dried under vacuum to obtain the small molecule gelling agent-borneol assembly.

[0022] Preferably, when the mass ratio of the aryl ceramide analog to borneol is 1:1, the mass of the aryl ceramide analog added per milliliter of organic solvent is 88-100 mg; when the mass ratio is 1:2-3, the mass of the aryl ceramide analog added per milliliter of organic solvent is 130-200 mg.

[0023] Preferably, the solution is dissolved by heating at 60–90°C under sealed conditions; the vacuum freeze-drying temperature is -80–-20°C, the pressure is 5–100 Pa, and the drying time is 20–24 h.

[0024] The present invention further provides the application of the aromatic acyl-containing ceramide analogue or the small molecule gelling agent-borneol assembly in the preparation of pharmaceutical formulations that improve the stability of borneol and reduce its toxicity.

[0025] Compared with the prior art, the beneficial effects of the present invention are as follows:

[0026] 1. The aryl acyl-containing ceramide analogs synthesized in this invention form gels in only 10-30 minutes at a dosage of 2 wt% in rapeseed oil, significantly shorter than the more than one hour required in existing technologies. Compound F-6 exhibits the best gelling ability, forming a dry gel with a tightly interwoven three-dimensional network structure. Structure-activity relationship studies revealed that compounds containing oxygen (such as methoxy groups) in the aryl group exhibit stronger gelling ability than those with a single aryl structure; the closer the carbonyl group is to the aryl group in the structure, the stronger the gelling ability; and the longer the alkyl chain, the better the gelling performance.

[0027] 2. The compound of this invention is combined with borneol to form an assembly through hydrogen bonding, alkyl entanglement, and π-π interactions. In an accelerated volatilization experiment at 50°C, the loss of borneol alone reached 21.60% after 4 hours, while the borneol loss rate of the assembly (1:1) of this invention was only 0.88%, significantly better than existing technologies. In a 30-day stability study under temperature, light, and humidity, the borneol retention rates of the assembly (1:1) of this invention reached 85.38%, 58.37%, and 92.04%, respectively, far exceeding those of borneol alone.

[0028] 3. This invention confirms, through acute toxicity experiments on zebrafish, the median lethal concentration (LC50) of compound F-6. 50 The concentration was 448.3 µM, which is higher than that of borneol (LC). 50 =725.3 µM), but after F-6 and borneol were prepared into an assembly according to a safe dosage ratio, its LC... 50 The value (based on borneol concentration) increased to 761.3 µM, higher than the LC50 of borneol alone. 50 This indicates that under safe dosage conditions, the formation of assemblages does not increase toxicity and demonstrates good biocompatibility.

[0029] 4. The synthetic route of the present invention starts with inexpensive and readily available raw materials, the steps are simple, the operation is convenient, the yield is high, it is environmentally friendly, and it is conducive to industrial production. Attached Figure Description

[0030] Figure 1 This is a scanning electron microscope (SEM) image of compound F-6 (A) and its dry gel (B).

[0031] Figure 2 This is a differential scanning calorimetry (DSC) analysis chromatogram of compound F-6 and its dry gel.

[0032] Figure 3 This is a polarized light micrograph of compound F-6 after it has been cooled to 40°C using a polarizing microscope.

[0033] Figure 4 This is the Fourier Transform Infrared (FT-IR) spectrum of compound F-6 and its dry gel.

[0034] Figure 5 This is a microstructure (SEM) image of the borneol-small molecule gelling agent assembly, where A is borneol, B is F-6 dry gel, and C, D, and E are dry gels of compound F-6 and borneol in mass ratios of 1:1, 1:2, and 1:3, respectively.

[0035] Figure 6 These are DSC analysis chromatograms of compound F-6, its dry gel, and assemblies in different proportions.

[0036] Figure 7 These are the FT-IR spectra of compound F-6, its dry gel, and assemblies in different proportions.

[0037] Figure 8 It is a borneol-small molecule gelling agent assembly in solution and gel states. 1 Comparison of hydrogen shifts in the benzene ring under 1H NMR.

[0038] Figure 9 It is a borneol-small molecule gelling agent assembly in solution and gel states. 1 Comparison of hydrogen shifts in alkyl chains in 1H NMR.

[0039] Figure 10 It is a borneol-small molecule gelling agent assembly in solution and gel states. 1 Comparison of hydroxyl hydrogen shifts in 1H NMR.

[0040] Figure 11 It is a borneol-small molecule gelling agent assembly in solution and gel states. 1 Comparison of the hydrogen shifts of the hydroxyl group and the adjacent hydrogen shifts of the carbonyl group in 1H NMR.

[0041] Figure 12 This is a comparison chart of the loss of borneol and borneol-small molecule gelling agent assembly in a 50℃ hot air circulation system.

[0042] Figure 13 The graph shows the effects of temperature, light, and humidity on the loss rate of borneol and borneol-small molecule gelling agent assemblies.

[0043] Figure 14 This is a line graph showing the effects of borneol, compound F-6, and the assembly on the mortality rate of adult zebrafish, where A represents borneol, B represents compound F-6, and C represents the assembly.

[0044] Figure 15 This is a graph showing the effects of borneol, compound F-6, and their assembly on the aspartate aminotransferase (AST) content in adult zebrafish.

[0045] Figure 16 The graph shows the effects of borneol, compound F-6, and their assembly on the alanine aminotransferase (ALT) content in adult zebrafish (n=10). Detailed Implementation

[0046] The present invention will be further described in detail below with reference to the accompanying drawings and embodiments, but the scope of protection of the present invention is not limited to these embodiments.

[0047] Example 1

[0048] Step 1: 5.00 g (20.83 mmol) of hexadecaldehyde, 2.09 g (22.92 mmol) of 2-nitroethanol, and 15 mL of tetrahydrofuran were added to a three-necked flask. Under nitrogen protection, the temperature was lowered to 10 °C and 5 mL of tetrahydrofuran solution containing 1.47 g (14.58 mmol) of triethylamine was slowly added dropwise. After the addition was complete, the reaction was continued at room temperature for 4 days. After the reaction was completed, the solvent was removed under reduced pressure at room temperature. After washing with water, the mixture was separated by silica gel column chromatography (the eluent was a mixture of petroleum ether and ethyl acetate in a volume ratio of 4:1) to obtain compound C-1 in 80% yield.

[0049] Replacing the above-mentioned hexadecaldehyde with equimolar amounts of n-decanal, n-heptaldehyde, and n-pentanaldehyde in the reaction with 2-nitroethanol, while keeping other conditions unchanged, yielded compounds C-2, C-3, and C-4, respectively.

[0050]

[0051] The structural characterization data of compound C-1 are as follows: 1 H NMR (400 MHz, CDCl3) δ: 4.62-4.49 (m,1H), 4.33-4.02 (m, 3H), 2.45-1.90 (m, 1H), 1.66-1.56 (m, 1H), 1.24 (s, 26H), 0.86 (t, J = 6.7 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ: 92.33, 90.91, 71.62,70.41, 61.85, 60.40, 33.95, 33.66, 32.00, 29.75, 29.57, 29.35, 25.67, 25.37,22.77, 14.23; FT-IR (cm -1 , KBr) 3404, 2921, 2847, 1716, 1552.

[0052] The structural characterization data of compound C-2 are as follows: 1H NMR (400 MHz, CDCl3) δ: 4.67-4.00 (m,2H), 2.51 (d, J = 153.6 Hz, 6H), 1.25 (s, 19H), 0.86 (s, 3H).

[0053] The structural characterization data of compound C-3 are as follows: 1 H NMR (400 MHz, CDCl3) δ: 4.58 (ddd, J =7.7, 5.7, 3.7 Hz, 2H), 4.54-4.42 (m, 2H), 4.28-4.20 (m, 3H), 4.19 (s, 1H),4.13 (s, 1H), 4.11 (s, 1H), 4.10 (s, 1H), 4.02 (s, 1H), 4.00 (s, 1H), 3.22(s, 8H), 3.01 (s, 3H), 1.49 (s, 1H), 1.39-1.35 (m, 11H), 1.30 (s, 1H), 1.26(s, 8H), 1.22 (d, J = 7.7 Hz, 4H), 0.84 (s, 3H).

[0054] The structural characterization data of compound C-4 are as follows: 1 H NMR (400 MHz, CDCl3) δ: 4.60-4.33 (m,1H), 4.22 (dd, J = 20.4, 6.9 Hz, 1H), 4.12 (dd, J = 13.1, 5.7 Hz, 1H), 4.08-3.96 (m, 2H), 1.39 (d, J = 77.9 Hz, 1H), 1.19 (s, 1H), 0.85 (s, 3H).

[0055] Step 2: 1.00 g (3.021 mmol) of compound C-1, 2.14 g (18.13 mmol) of palladium on carbon, and 10 mL of tetrahydrofuran were added to a three-necked flask and reacted under nitrogen protection and at room temperature for 24 hours. After the reaction was completed, the solvent was recovered by filtration and separated by silica gel column chromatography (the eluent was a mixture of dichloromethane and methanol in a volume ratio of 10:1) to obtain compound D-1 with a yield of 92%.

[0056] By replacing compound C-1 with equimolar amounts of compounds C-2, C-3, and C-4, respectively, under the same conditions, compounds D-2, D-3, and D-4 were obtained.

[0057]

[0058] The structural characterization data of compound D-1 are as follows: 1 H NMR (400 MHz, CDCl3) δ: 3.73-3.64 (m,2H), 3.63-3.43 (m, 2H), 2.85-2.71 (m, 1H), 1.56-1.41 (m, 4H), 1.37-1.29 (m,7H), 1.28 (s, 18H), 0.95-0.85 (t, J=6.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ:74.96, 72.64, 65.68, 63.87, 55.73, 34.53, 33.86, 32.01, 29.78, 29.70, 29.45,22.77, 14.20; FT-IR (cm -1 , KBr) 3359, 3148, 3047, 2915, 2847.

[0059] Step 3: 1.00 g (33.22 mmol) of compound D-1, 0.34 g (33.22 mmol) of triethylamine, and 10 mL of dichloromethane were added to a three-necked flask. Under nitrogen protection and at -20°C, 5 mL of a dichloromethane solution containing 0.51 g (36.54 mmol) of benzoyl chloride was slowly added dropwise. After the addition was complete, the mixture was reacted at -20°C for 4 hours. After the reaction was completed, the mixture was washed with water and extracted. The solvent was recovered under reduced pressure, and the mixture was separated by silica gel column chromatography (eluent was a mixture of dichloromethane and methanol in a volume ratio of 50:1) to obtain compound F-1 in 52% yield.

[0060] Replacing the above benzoyl chloride with equimolar amounts of phenylacetyl chloride, phenylpropionyl chloride, 1-naphthoyl chloride, phenoxyacetyl chloride, 4-methoxyphenylacetyl chloride, 4-benzyloxyphenylacetyl chloride, and p-chlorophenylacetyl chloride respectively in the reaction with compound D-1, while keeping other conditions unchanged, yielded compounds F-2, F-3, F-4, F-5, F-6, F-7, and F-8 respectively.

[0061] 0.3 g (58.62 mmol) of compound F-7, 0.11 g (58.62 mmol) of palladium on carbon, and 5 mL of methanol were added to a three-necked flask and reacted at room temperature under a hydrogen atmosphere for 2 hours. After the reaction was completed, the mixture was filtered, and the solvent was recovered from the filtrate under reduced pressure. The filtrate was then separated by silica gel column chromatography (using a mixture of dichloromethane and methanol in a volume ratio of 80:1 as the eluent) to obtain compound F-9.

[0062] Replacing compound D-1 with 4-methoxyphenylacetyl chloride in equimolar amounts with compounds D-2, D-3, and D-4 respectively, under the same conditions, yielded compounds F-10, F-11, and F-12.

[0063]

[0064] The structural characterization data of compound F-1 are as follows: 1 H NMR (400 MHz, CDCl3) δ: 7.80 (s, 1H),7.50 (d, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 4.12 (d, J = 11.3 Hz,1H), 4.08-4.00 (m, 1H), 3.96-3.83 (m, 1H), 2.46 (s, 3H), 1.61 (s, 1H), 1.52(s, 1H), 1.25 (s, 14H), 1.23 (s, 6H), 0.87 (s, 3H); 13 C NMR (151 MHz, CDCl3)δ: 168.08, 134.23, 131.71, 128.62, 127.10, 74.35, 73.12, 65.50, 62.41, 54.10,53.65, 34.61, 34.51, 31.94, 29.69, 29.60, 29.54, 29.38, 26.02, 25.64, 22.71,14.13.

[0065] The structural characterization data of compound F-2 are as follows: 1 H NMR (600 MHz, CDCl3) δ: 7.34 (t, J = 5.8Hz, 2H), 7.28 (s, 2H), 7.27 (s, 1H), 6.28 (dt, J = 109.1, 6.2 Hz, 1H), 5.10(s, 0H), 3.94 (d, J = 11.8 Hz, 1H), 3.87 (dd, J = 15.0, 7.7 Hz, 1H), 3.77 (d,J = 12.3 Hz, 1H), 3.70 (d, J = 9.9 Hz, 1H), 3.60 (s, 1H), 2.68 (s, 1H), 1.33(s, 1H), 1.26(s, 24H), 0.88 (q, J = 6.2 Hz, 3H); 13C NMR (151 MHz, CDCl3) δ:171.51, 134.88, 134.80, 129.26, 129.22, 129.00, 128.98, 127.37, 127.36,73.81, 72.63, 65.09, 62.26, 54.17, 53.55, 43.87, 43.83, 34.40, 34.29, 31.94,29.69, 29.61, 29.54, 29.37, 22.70, 14.13.

[0066] The structural characterization data of compound F-3 are as follows: 1 H NMR (600 MHz, CDCl3) δ: 7.29 (d, J = 6.9Hz, 2H), 7.22 (t, J = 6.6 Hz, 3H), 6.17 (dd, J = 108.4, 8.0 Hz, 1H), 3.94-3.84 (m, 1H), 3.84-3.72 (m, 1H), 3.70 (s, 1H), 3.62 (d, J = 10.2 Hz, 1H), 2.98 (d, J = 7.7 Hz, 2H), 2.54 (q, J = 8.9, 7.9 Hz, 2H), 1.46 (d, J = 10.0Hz, 1H), 1.30 (dd, J = 15.3, 8.2 Hz, 6H), 1.26 (s, 19H), 0.88 (q, J = 7.2,5.2 Hz, 3H); 13 C NMR (151 MHz, CDCl3) δ: 172.81, 140.69, 140.63, 128.57,128.51, 126.36, 74.09, 72.83, 65.33, 62.20, 53.64, 53.23, 38.56, 38.50,34.32, 34.15, 31.93, 31.89, 31.83, 29.71, 29.67, 29.62, 29.59, 29.55, 29.50,29.37, 25.98, 25.59, 22.70, 14.12.

[0067] The structural characterization data of compound F-4 are as follows: 1H NMR (400 MHz, CDCl3) δ: 8.29 (s, 1H), 7.86 (d, J = 16.3 Hz, 2H), 7.62 (s, 1H), 7.52 (d, J = 2.2 Hz, 2H), 7.41 (s,1H), 4.08 (s, 1H), 3.92 (d, J = 13.5 Hz, 2H), 2.63 (s, 3H), 1.65-1.46 (m,3H), 1.25 (s, 26H), 0.87 (s, 3H); 13 C NMR (151 MHz, CDCl3) δ: 169.91, 134.06,133.68, 130.81, 130.09, 128.37, 127.22, 126.46, 125.36-125.17 (m), 125.09,124.70, 74.18, 72.98, 65.36, 62.40, 54.29, 53.69, 34.61, 31.94, 29.72, 29.59,29.38, 26.01, 25.62, 22.71, 14.14.

[0068] The structural characterization data of compound F-5 are as follows: 1 H NMR (600 MHz, CDCl3) δ: 7.35-7.30 (m,1H), 7.19 (d, J = 3.8 Hz, 1H), 6.97-6.94 (m, 1H), 6.90-6.85 (m, 2H), 4.61 (d,J = 24.3 Hz, 0H), 4.48-4.45 (m, 2H), 3.97 (d, J = 11.8 Hz, 1H), 3.89 (t, J =5.4 Hz, 1H), 3.83 (dt, J = 7.3, 3.6 Hz, 1H), 3.78 (d, J = 5.1 Hz, 1H), 3.72(t, J = 8.0 Hz, 1H), 2.57 (s, 2H), 1.60 (d, J = 52.4 Hz, 1H), 1.51-1.39 (m,2H), 1.32-1.29 (m, 1H), 1.21 (s, 1H), 1.18 (s, 18H), 0.81 (dd, J = 7.8, 4.6Hz, 3H); 13C NMR (151 MHz, CDCl3) δ: 167.59, 156.13, 128.78, 121.20, 113.75,72.78, 71.62, 66.36, 64.06, 61.17, 52.70, 52.13, 33.40, 33.26, 30.91, 28.68,28.66, 28.64, 28.57, 28.54, 28.52, 28.46, 28.34, 24.90, 24.53, 21.67, 13.10,-1.03.

[0069] The structural characterization data of compound F-6 are as follows: 1 H NMR (600 MHz, CDCl3) δ: 7.19 (s, 1H), 7.11 (s, 2H), 6.80 (s, 2H), 6.20 (d, J = 108.2 Hz, 1H), 3.81 (s, 1H), 3.73 (s, 3H), 3.69 (s, 1H), 3.64 (s, 1H), 3.47 (s, 2H), 2.65 (s, 1H), 1.39 (s,1H), 1.27 (s, 1H), 1.18 (s, 24H), 0.81 (s, 3H); 13 C NMR (151 MHz, CDCl3) δ:171.44, 170.96, 157.83, 129.32, 125.75, 113.39, 72.77, 71.61, 64.07, 61.26,54.24, 53.18, 52.55, 41.90, 33.38, 33.28, 30.91, 28.67, 28.59, 28.53, 28.35,24.88, 24.49, 21.68, 13.10.

[0070] The structural characterization data of compound F-7 are as follows: 1H NMR (600 MHz, CDCl3) δ: 7.42 (s, 2H), 7.38 (d, J = 5.8 Hz, 2H), 7.33 (s, 1H), 6.95 (s, 1H), 5.04 (s, 2H), 3.88 (d,J = 44.6 Hz, 1H), 3.75 (s, 1H), 3.69 (s, 1H), 3.53 (s, 1H), 2.83 (d, J = 89.4Hz, 2H), 1.68 (dt, J = 39.8, 22.4 Hz, 0H), 1.46 (s, 2H), 1.34 (s, 1H), 1.25(s, 22H), 0.88(s, 3H); 13 C NMR (151 MHz, CDCl3) δ: 172.42, 171.95, 158.08,136.88, 130.37, 128.60, 128.02, 127.49, 127.12, 127.04, 115.37, 114.98,73.79, 72.56, 70.06, 65.04, 62.27, 54.21, 53.60, 42.95, 42.91, 34.41, 34.31,31.94, 29.72, 29.68, 29.64, 29.57, 29.38, 25.92, 25.53, 22.70, 14.13.

[0071] The structural characterization data of compound F-8 are as follows: 13 C NMR (151 MHz, CDCl3) δ: 167.58, 167.05,154.77, 128.70, 128.68, 126.24, 115.08, 72.90, 71.71, 66.68, 64.16, 61.16,52.58, 33.47, 33.33, 30.91, 28.68, 28.67, 28.64, 28.57, 28.54, 28.52, 28.47,28.34, 24.90, 24.53, 21.67, 13.10; 1H NMR (600 MHz, CDCl3) δ: 6.81 (t, J = 5.8Hz, 2H), 4.44 (dd, J = 10.1, 4.0 Hz, 2H), 4.02-3.67 (m, 2H), 2.47 (d, J =27.0 Hz, 2H), 1.75-1.36 (m, 3H), 1.36-1.29 (m, 1H), 1.18 (s, 24H), 0.81 (q, J= 6.2 Hz, 3H).

[0072] The structural characterization data of compound F-9 are as follows: 1 H NMR (600 MHz, CDCl3) δ 7.81 (s, 1H), 7.39 (s, 1H), 7.01 (s, 1H), 6.93 (s, 3H), 6.52 (d, J = 5.7 Hz, 1H), 5.07 (d, J =49.3 Hz, 2H), 3.96 (d, J = 6.7 Hz, 2H), 1.77 (d, J = 7.9 Hz, 2H), 1.55 (s,3H), 1.44 (q, J = 7.3 Hz, 2H), 1.33 (d, J = 25.6 Hz, 8H), 1.26 (d, J = 5.5Hz, 14H), 0.88 (d, J = 7.0 Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 172.4, 158.9,130.4, 126.8, 114.5, 73.9, 72.9, 65.4, 62.3, 55.3, 54.2, 53.5, 43.0, 34.11,34.0, 29.7, 28.0, 27.6, 22.6, 14.0.

[0073] The structural characterization data of compound F-10 are as follows: 1H NMR (600 MHz, CDCl3) δ 7.19 (d, J = 6.9Hz, 2H), 6.89 (t, J = 6.8 Hz, 2H), 6.19 (d, J = 103.0 Hz, 1H), 4.00 – 3.83(m, 1H), 3.81 (d, J = 5.1 Hz, 4H), 3.75 – 3.69 (m, 1H), 3.55 (d, J = 5.1 Hz, 2H), 1.45 (d, J = 28.8 Hz, 2H), 1.31 (d, J = 56.5 Hz, 4H), 0.89 (t, J = 7.1Hz, 3H). 13 C NMR (151 MHz, CDCl3) δ 172.4, 158.9, 130.4, 126.8, 114.5, 73.9, 65.4, 62.4, 55.3, 43.1, 34.0, 27.6, 22.6, 14.0.

[0074] The structural characterization data of compound F-11 are as follows: 13 C NMR (151 MHz, CDCl3) δ: 172.30, 171.90,158.87, 130.33, 126.83, 114.45, 72.86, 62.34, 55.27, 54.18, 42.96, 34.34,31.68, 29.15, 39.52-18.04 (m), 22.57, 14.05; 1 H NMR (600 MHz, CDCl3) δ: 7.19(t, J = 6.7 Hz, 2H), 6.88 (t, J = 6.5 Hz, 2H), 6.29 (s, 1H), 6.12 (s, 1H),3.98-3.83 (m, 3H), 3.80 (d, J = 4.4 Hz, 4H), 3.54 (d, J = 4.9 Hz, 2H), 1.46 (d, J = 10.2 Hz, 2H), 1.26 (s, 9H), 0.87 (d, J = 6.8 Hz, 3H).

[0075] The structural characterization data of compound F-12 are as follows: 13C NMR (151 MHz, CDCl3) δ: 171.92, 158.82,130.34 (d, J = 5.0 Hz), 126.74, 114.43 (d, J = 3.3 Hz), 73.84, 65.21, 62.31,55.27, 42.94, 40.64, 34.43, 31.89, 29.54, 29.31, 25.89, 25.49, 22.68, 14.11; 1 H NMR (600 MHz, CDCl3) δ: 7.20 (q, J = 7.2, 6.7 Hz, 2H), 6.88 (t, J = 6.1 Hz, 2H), 6.22 (dt, J = 103.8, 6.5 Hz, 1H), 3.90 (dd, J = 45.2, 16.0 Hz, 1H), 3.80(d, J = 4.5 Hz, 3H), 3.71 (d, J = 10.3 Hz, 1H), 3.55 (d, J = 11.8 Hz, 2H), 2.60 (s, 1H), 2.06 (dq, J = 103.6, 7.0 Hz, 1H), 1.68 (s, 1H), 1.46 (s, 1H), 1.34 (s, 1H), 1.26 (s, 11H), 0.88 (d, J = 6.4 Hz, 3H).

[0076] The purity of compounds F-1 to F-12 obtained above is all above 98.50%.

[0077] The gelling ability of compounds F-1 to F-12 in different solvents was evaluated using the stable-to-inversion method. Accurately weighed amounts of the compounds and a measured amount of solvent (such as rapeseed oil, petroleum ether, diethyl ether, dichloromethane, etc.) were added to a stoppered test tube and heated until the solid was completely dissolved. The test tube was then allowed to stand at room temperature or 4°C, and the state of the system was observed. If a homogeneous, transparent or opaque gel formed after cooling, and no liquid flowed when the test tube was inverted, it was recorded as a gel (G); if partial gelation occurred, it was recorded as (PG); if crystals precipitated, it was recorded as (P); if it remained a solution, it was recorded as (S); if it could not completely dissolve during heating, it was recorded as (I). The shortest time (t) required for gel formation was recorded. gel The gel-sol transition temperature (T0) and minimum gel concentration (MGC) were determined by differential scanning calorimetry (DSC). gelThe gelling ability of each compound was tested in rapeseed oil at a concentration of 2 wt%, and the results are shown in Table 1. The gelling ability evaluation results of each compound in different solvents are shown in Table 2.

[0078] Table 1. Evaluation results of gelling ability in rapeseed oil at 2 wt%.

[0079]

[0080] Table 2. Evaluation results of gelling ability in different solvents

[0081]

[0082] Table 1 shows that, compared with ceramide C2 (gelation time 1 hour), the gelation time of the aromatic acyl ceramide analogs of the present invention is significantly shortened (10-30 minutes). Among them, compounds F-1 to F-4 require only 10 minutes to gel, exhibiting rapid gelation characteristics. Table 2 shows that all compounds exhibit excellent gelling ability in petroleum ether (60-90℃), and can form stable gels at low concentrations. This lays the foundation for the subsequent preparation of assemblies with borneol in petroleum ether. Comparison revealed that, compared with F-2 (phenylacetyl), the closer the carbonyl group is to the aromatic ring in F-1 (benzoyl), the better the gelling ability (T). gel (Higher). F-4 (containing a naphthalene ring) exhibits stronger gelling ability than F-1 (containing a benzene ring). F-5 (containing phenoxymethyl) shows a significantly improved gelling ability compared to F-2 (containing phenethyl). F-6 (containing 4-methoxybenzyl) demonstrates superior gelling ability compared to F-7 (containing 4-benzyloxybenzyl), indicating that methoxy substitution is more beneficial for enhancing gelling ability. Comparing F-6, F-10, F-11, and F-12, whose R1 groups are tetraalkyl, octyl, pentyl, and propyl, respectively, the results show that the longer the alkyl chain, the better the gelling performance. In conclusion, compound F-6 exhibits the best overall gelling ability; therefore, it will be used as a representative for further in-depth characterization and application research.

[0083] like Figure 1 As shown, compound F-6 powder is in irregular block form. Figure 1 A), while the dry gel prepared from it exhibits a fibrous structure with a diameter of approximately 1.00 µm ( Figure 1 (B) These fibers are tightly interwoven to form a three-dimensional network structure, which is the microscopic basis for their ability to fix solvent molecules. For example... Figure 2 As shown, both compound F-6 and its dry gel exhibit two endothermic peaks, but at slightly different temperatures (69.17℃ / 84.22℃ vs. 67.66℃ / 85.04℃), indicating that a new phase or crystal transformation may have occurred after gel formation. Combined with polarized light microscopy (…), Figure 3The observation of a smectic liquid crystal state at 40°C explains the appearance of the double endothermic peaks. Figure 4 As shown, when compound F-6 is mixed with petrolatum (excluding intermolecular forces), it reaches a depth of 3610.4 cm⁻¹. -1 A free hydroxyl stretching vibration peak appears at [value missing]. However, the hydroxyl stretching vibration peak of the F-6 dry gel shifts to 3302.8 cm⁻¹. -1 A significant redshift occurred, indicating that intermolecular hydrogen bonding is an important driving force during gel formation.

[0084] Example 2

[0085] Using compound F-6, which has the best gelling ability, as an example, assemblies were prepared by combining it with borneol at different mass ratios, and the preparation process was optimized.

[0086] Accurately weigh compound F-6 (15 mg) and borneol, mix them at mass ratios of 1:1, 1:2, and 1:3, respectively, add different volumes of petroleum ether (60–90℃), seal, and heat at 65℃ until completely dissolved. Then, place the solution at 4℃ and observe gel formation, recording the time required for gel formation and the gelation state. The results are shown in Table 3.

[0087] Table 3 Results of optimization of assembly preparation conditions

[0088]

[0089] Table 3 shows that when the mass ratio of F-6 to borneol is 1:1, gelation occurs rapidly (within 10 min) at room temperature (26℃). When the borneol ratio increases to 1:2 or 1:3, a stable gel is formed after standing at 4℃ for 15–25 min. Considering the amount of gelling agent, drug loading, and gelation time, the optimal preparation conditions are determined to be: a mass ratio of F-6 to borneol of 1:3, 0.075 mL of petroleum ether, and standing at 4℃ for 20 min. Under these conditions, a stable gel is formed with the highest drug loading. The gel prepared under the optimized conditions is pre-frozen at -20℃ for 4 h, and then freeze-dried under vacuum at -80℃ and 0.01 MPa for 24 h to obtain the F-6-borneol assembly.

[0090] To observe the changes in microstructure after assembly formation, scanning electron microscopy was used to analyze the morphology of borneol, F-6 dry gel, and assemblies with different proportions of F-6-borneol. The results are as follows: Figure 5 As shown. By Figure 5 It can be seen that the raw materials for borneol ( Figure 5 A) It appears as irregular blocky crystals; F-6 dry gel ( Figure 5 B) exhibits a fibrous structure with a diameter of approximately 1.00 µm, with the fibers tightly interwoven to form a three-dimensional network structure. When F-6 and borneol are mixed at a mass ratio of 1:1 ( Figure 5 C), 1:2 Figure 5 D), 1:3 ( Figure 5 E) After being assembled, all components retained a three-dimensional network structure similar to that of F-6 dry gel. Notably, as the proportion of borneol increased, the fiber diameter gradually decreased, and the network structure became more compact. This phenomenon indicates that the borneol was effectively encapsulated and fixed within the network structure formed by the small-molecule gelling agent, resulting in a homogeneous composite system.

[0091] To investigate whether new phases are formed during assembly formation, differential scanning calorimetry (DSC) was used to perform thermal analysis on borneol, compound F-6, F-6 dry gel, and assemblies of different proportions of F-6-borneol. The results are as follows: Figure 6 As shown, the DSC curve of borneol shows a sharp endothermic peak at 204.89℃, corresponding to its melting process; compound F-6 shows an endothermic peak at 84.22℃; the endothermic peak of F-6 dry gel appears at 85.04℃, slightly higher than that of compound F-6. When F-6 and borneol form assemblies, assemblies of different mass ratios all exhibit thermal behaviors significantly different from the raw materials: the 1:1 assembly shows a new endothermic peak at 71.46℃, and the 1:2 and 1:3 assemblies show new endothermic peaks at 60.63℃ and 60.30℃, respectively. The appearance of these new peaks proves that a new phase is generated in the assembly, rather than a simple physical mixture of F-6 and borneol, indicating that the two form a stable composite structure through intermolecular interactions.

[0092] To investigate the intermolecular forces involved in the formation of the assemblies, FT-IR was used to characterize compound F-6, F-6 dry gel, and assemblies in different proportions. A mixture of F-6 and petrolatum (3:97, w / w) was used as a control to eliminate the influence of intermolecular forces on the hydroxyl absorption peak. The results are as follows: Figure 7 As shown. In the infrared spectrum of the F-6 and Vaseline mixture, at 3610.4 cm⁻¹. -1 A sharp absorption peak appears at 3294.7 cm⁻¹, attributed to the stretching vibration of the free hydroxyl group; simultaneously, at 3294.7 cm⁻¹... -1 A relatively broad absorption peak is observed, which may be due to the stretching vibration of intramolecularly associated hydroxyl groups. The hydroxyl stretching vibration peak of the F-6 dry gel shifts to 3302.8 cm⁻¹. -1 A significant redshift occurred, indicating that intermolecular hydrogen bonds played a crucial role in gel formation. Infrared spectra of F-6-borneol assemblies with different ratios showed that the hydroxyl stretching vibration peaks of the 1:1, 1:2, and 1:3 assemblies were located at 3312.2 cm⁻¹. -1 3314.4cm -1 and 3317.3 cm -1 All were significantly lower than the absorption position of the free hydroxyl group (3610.4 cm). -1This indicates that hydrogen bonding is also an important driving force for assembly formation. The slight blue shift of the hydroxyl absorption peak with increasing borneol content may be related to the competition of borneol molecules for hydrogen bond networks.

[0093] To further elucidate the intermolecular interactions in the formation of the assemblies, deuterated chloroform was used as the solvent to compare the ¹H NMR spectra of a 1:1 mixture of F-6 and borneol in both the solution state (tested immediately after heating and dissolving) and the gel state (tested after allowing the gel to form). The results are as follows: Figures 8-11 As shown. By Figure 8 As can be seen, the hydrogen signals on the benzene rings in the gel state shifted from 7.21 ppm and 6.82 ppm in the solution state to 7.22 ppm and 6.84 ppm, respectively, exhibiting a low-field shift (Δδ = +0.01~0.02 ppm), indicating that the π-π interactions between the benzene rings participated in the formation of the assembly. Figure 9 As can be seen, the hydrogen signal on the alkyl chain shifted from 1.24 ppm in the solution state to 1.23 ppm in the gel state, exhibiting a high-field shift (Δδ = -0.01 ppm), suggesting that the hydrophobic interaction between alkyl chains (alkyl entanglement) is also an important driving force for assembly formation. Figure 10 and Figure 11 It is evident that the hydrogen signals adjacent to the hydroxyl and carbonyl groups also underwent significant shifts. Specifically, the hydroxyl hydrogen signal at 3.51 ppm shifted to 3.71 ppm (Δδ = +0.20 ppm) in the gel state, further confirming the involvement of hydrogen bonding. Meanwhile, another signal at 3.51 ppm, attributed to the α-hydrogen of the carbonyl group, shifted to 3.67 ppm (Δδ = +0.16 ppm), which may be related to changes in the shielding effect caused by the ordered molecular arrangement after gel formation. Combined FT-IR and ¹H NMR analyses indicate that F-6 and borneol self-assembled into a stable three-dimensional network structure through multiple non-covalent interactions, including hydrogen bonding, π-π interactions, and alkyl entanglement, effectively encapsulating the borneol within it.

[0094] To evaluate the inhibitory effect of the assembly on the volatility of borneol, individual borneol and F-6-borneol assemblies with different mass ratios were placed in a 50℃ hot air circulating drying oven. Samples were taken and weighed at different time points, and the cumulative loss rate of borneol was calculated. The results are shown in Table 4 and 5. Figure 12 As shown.

[0095] Table 4. Loss rate variation of borneol and assemblies with different proportions in a 50℃ hot air circulation system (%)

[0096]

[0097] From Table 4 and Figure 12It was found that borneol alone volatilized rapidly at 50℃, with a loss rate as high as 21.60% after 4 hours. However, the volatilization loss of borneol in the F-6-borneol assembly was significantly reduced: the loss rate of the 1:1 assembly after 4 hours was only 0.88%, with an inhibition rate (relative to borneol alone) reaching 95.9%; the loss rates of the 1:2 and 1:3 assemblies were 1.20% and 3.16%, respectively, with inhibition rates of 94.4% and 85.4%, respectively. The results indicate that encapsulating borneol in the gel network formed by F-6 can greatly inhibit its volatilization, and the higher the proportion of gelling agent (i.e., the lower the proportion of borneol), the more significant the inhibition effect.

[0098] To further investigate the stability of the assemblies under different environmental conditions, individual borneol and assemblies of different proportions were placed under high temperature (50℃), light (4500 lx), and high humidity (25℃, relative humidity 40%±5%) conditions for 30 days. Samples were taken on days 0, 10, 20, and 30 to observe appearance changes and determine borneol retention. The results are shown in Table 5. Figure 13 As shown.

[0099] Table 5. Retention rate of borneol in borneol and assemblies under different conditions (30 days)

[0100]

[0101] From Table 5 and Figure 13 It was found that, under all three conditions, the retention rate of borneol in all proportion assemblies was significantly higher than that of borneol alone. Taking the 1:1 assembly as an example, after 30 days at high temperature, the retention rate of borneol was 85.38%, while that of borneol alone was only 44.37%. Under light conditions, the retention rate of the 1:1 assembly was 58.37%, while borneol alone almost completely evaporated (retention rate of only 0.68%). Under high humidity conditions, the retention rate of the 1:1 assembly was as high as 92.04%, while that of borneol alone was 53.19%. The results indicate that preparing borneol into F-6-borneol assemblies can significantly improve its stability under high temperature, light, and high humidity conditions.

[0102] The acute toxicity of compound F-6 and its F-6-borneol assembly was evaluated using a zebrafish model. Wild-type AB strain zebrafish aged 3–6 months were randomly divided into a blank control group, a solvent control group (0.10% DMSO aqueous solution), borneol dose groups of 1300 µM, 900 µM, 750 µM, and 300 µM, compound F-6 dose groups of 900 µM, 430 µM, 216 µM, and 100 µM, and assembly groups of F-6:borneol at doses of 430:1300 µM, 250:750 µM, 216:650 µM, and 100:300 µM, respectively. Each group had three replicates, with 10 fish per replicate. Mortality was observed within 96 hours, and the median lethal concentration (LC50) was calculated. 50The levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were measured. Mortality data are shown in Table 6. Figure 14 As shown, the AST and ALT detection results are as follows: Figure 15 , Figure 16 As shown.

[0103] Table 6. Mortality rate of zebrafish in each group (n=10)

[0104]

[0105] Calculations show that the LC50 of borneol 50 The value was 725.3 μM; the LC50 of the F-6-borneol assembly was [value missing]. 50 The value was 761.3 μM. The results indicate that after F-6 forms an assembly with borneol, its LC50 value is... 50 The value was slightly higher than that of borneol alone, indicating that preparing the assembly at a safe dose of borneol would not increase its toxicity.

[0106] AST and ALT test results showed ( Figure 15 , Figure 16 Except for the highest dose group (430:1300 μM), the AST and ALT levels in the other dose groups were not significantly different from those in the blank control group, further confirming that within the safe dose range, the F-6-borneol assembly did not cause significant damage to the zebrafish liver.

[0107] In summary, compound F-6 exhibits excellent gelling ability, capable of self-assembling with borneol through hydrogen bonding, π-π interactions, and alkyl entanglement to form a stable three-dimensional network structure, effectively encapsulating borneol within it. This assembly significantly inhibits borneol volatilization, improves its stability under high temperature, light, and high humidity, and demonstrates good biocompatibility at effective doses. Therefore, the aryl ceramide analog provided by this invention, as a small molecule gelling agent, has significant application value in improving borneol stability.

Claims

1. A ceramide analog containing an aromatic acyl group, characterized in that: The structural formula of the analogue is shown below: Where R1 represents C3~C 14 The straight-chain alkyl group; R2 is selected from any one of phenyl, benzyl, phenethyl, naphthyl, C1-C3 alkoxy-substituted phenyl, C1-C3 alkoxy-substituted benzyl, benzyloxyphenyl, benzyloxybenzyl, benzyloxynaphthyl, halophenyl, halobenzyl, hydroxy-substituted phenyl, hydroxy-substituted benzyl, and hydroxy-substituted naphthyl.

2. The ceramide analog containing an aromatic acyl group according to claim 1, characterized in that: The analogue is any one of the following compounds with the following structural formulas: 。 3. A method for synthesizing the ceramide analog containing an aromatic acyl group as described in claim 1, characterized in that... Includes the following steps: Step 1: Using the aliphatic aldehyde shown in Formula A and 2-nitroethanol shown in Formula B as starting materials, the nitro alcohol compound shown in Formula C is synthesized by Henry reaction in the presence of an alkaline catalyst. Step 2: The nitro alcohol compound obtained in Step 1 is subjected to a nitro reduction reaction to reduce its nitro group to an amino group, thereby obtaining the amino alcohol compound shown in Formula D. Step 3: The amino alcohol compound obtained in Step 2 is subjected to an acylation reaction with an aromatic acyl chloride compound of formula E under the catalysis of an organic base to obtain the target compound F; the synthetic route is as follows: Where R1 represents C3~C 14 The straight-chain alkyl group, R3 is selected from any one of phenyl, benzyl, phenethyl, naphthyl, C1-C3 alkoxy-substituted phenyl, C1-C3 alkoxy-substituted benzyl, benzyloxyphenyl, benzyloxybenzyl, benzyloxynaphthyl, halophenyl, and halobenzyl.

4. The method for synthesizing ceramide analogs containing aromatic acyl groups according to claim 3, characterized in that: The Henry reaction in step 1 uses triethylamine as a catalyst and tetrahydrofuran as a solvent, and reacts for 2 to 4 days at 10°C to room temperature; the nitro reduction reaction in step 2 uses palladium on carbon as a catalyst and tetrahydrofuran as a solvent, and reacts for 20 to 24 hours at room temperature under nitrogen protection; the acylation reaction in step 3 uses triethylamine as a catalyst and dichloromethane as a solvent, and reacts for 3 to 5 hours at -25 to -15°C.

5. The method for synthesizing ceramide analogs containing aromatic acyl groups according to claim 3, characterized in that: The target compound F obtained in step 3, where R3 represents benzyloxyphenyl, benzyloxybenzyl or benzyloxynaphthyl, is further subjected to a debenzylation reaction to obtain an aryl ceramide analog containing an aromatic acyl group, where R2 in claim 1 represents a hydroxy-substituted phenyl, hydroxy-substituted benzyl or hydroxy-substituted naphthyl.

6. A small molecule gelling agent-borneol assembly, characterized in that: The ceramide analog containing aromatic acyl groups as described in claim 1 is used as a small molecule gelling agent. After self-assembly with borneol in an organic solvent to form a gel, the assembly is obtained by freeze-drying. The organic solvent is petroleum ether or ethanol.

7. The small molecule gelling agent-borneol assembly according to claim 6, characterized in that: The ceramide analog containing aromatic acyl groups and borneol were added to an organic solvent at a mass ratio of 1:1 to 3. The mixture was heated under sealed conditions until completely dissolved, and then allowed to stand at 0 to 5°C for 10 to 30 minutes to form a gel. The gel was then pre-frozen at -25 to -15°C for 4 to 6 hours and freeze-dried under vacuum to obtain a small molecule gelling agent-borneol assembly.

8. The small molecule gelling agent-borneol assembly according to claim 7, characterized in that: When the mass ratio of the aryl-containing ceramide analog to borneol is 1:1, the mass of the aryl-containing ceramide analog added per milliliter of organic solvent is 88-100 mg; when the mass ratio of the aryl-containing ceramide analog to borneol is 1:2-3, the mass of the aryl-containing ceramide analog added per milliliter of organic solvent is 130-200 mg.

9. The small molecule gelling agent-borneol assembly according to claim 7, characterized in that: The solution is dissolved by heating at 60–90°C under sealed conditions; the vacuum freeze-drying temperature is -80–-20°C, the pressure is 5–100 Pa, and the drying time is 20–24 h.

10. The use of the aryl ceramide analogue of claim 1 or the small molecule gelling agent-borneol assembly of any one of claims 6 to 9 in the preparation of pharmaceutical formulations that improve the stability of borneol and reduce its toxicity.

Images