Tuber penetrating oil for treating pain

Abstract

The invention relates to the technical field of external pharmaceutical preparations, and discloses a pain-treating garden balsam stem oil, which is prepared from the following raw materials: peppermint oil, natural borneol, fatty acid, propylene glycol dicaprylate / caprate, ginger oil, blumea oil, lavender oil, rose oil, olive fruit oil, simmondsia chinensis seed oil, ceramide 3, bisabolol and the like. Wherein menthol in the peppermint oil, natural borneol and fatty acid are assembled through hydrogen bonds to form a ternary eutectic solvent system, and propylene glycol dicaprylate / caprate is used as a low-temperature stabilizer. By constructing a ternary eutectic solvent system, the problem that high-concentration borneol is easy to crystallize at low temperature is solved, and the antioxidant stability of gingerol is remarkably improved by utilizing a hydrogen bond clamping process. Meanwhile, by adding ceramide 3 and bisabolol, the synergism of a powerful transdermal effect and skin barrier repair is realized, the irritation of the preparation is reduced to a non-irritation level, and the drug effect, stability and safety are effectively improved.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of external drug preparation, in particular to a bone-penetrating oil for treating pain. BACKGROUND

[0002] Bone-penetrating oil or external essential oil for transdermal administration is a common way to relieve local muscle soreness, joint pain and neuralgia. Such products directly apply to the affected area to play a role by dissolving active ingredients with analgesic, anti-inflammatory or blood circulation promoting effects in lipophilic carrier oil. Common active ingredients such as menthol, natural borneol and gingerol are widely used due to their exact biological activity.

[0003] However, such oily preparations in the prior art still face technical bottlenecks in development and application. One major technical challenge is the effective loading and stability of high-melting solid active ingredients. For example, natural borneol, as a highly effective penetration enhancer and anti-inflammatory ingredient, has a melting point as high as 203℃, and its solubility in conventional carrier oil is very limited. In order to increase its concentration, heating or adding alcohol solubilizers is usually required, but this method is prone to cause the recrystallization of borneol after the product cools down or the solubilizer evaporates, which not only affects the appearance and uniformity of the product, but also makes it difficult to control the effective dose.

[0004] In addition, some plant-derived active ingredients are chemically unstable and prone to degradation in oily matrices. For example, gingerol, the main active ingredient in ginger oil, is sensitive to light, heat and oxygen due to the phenolic hydroxyl and β-hydroxy ketone functional groups in its molecular structure, and is prone to oxidation or dehydration during storage, resulting in a significant decrease in the efficacy of the preparation over time and a shortening of the effective shelf life of the product.

[0005] In order to improve the transdermal absorption efficiency of active ingredients, chemical penetration enhancers are often introduced in the prior art. These penetration enhancers can effectively disrupt the stratum corneum structure, but they often cause redness, stinging and other adverse reactions due to excessive damage to the skin barrier. Balancing the improvement of efficacy and the safety of the skin is a technical problem that continues to be concerned in this field. Therefore, it is of great practical value to develop a bone-penetrating oil product that can stably carry high-concentration, easily-degradable active ingredients and achieve efficient transdermal absorption while being gentle and non-irritating to the skin. SUMMARY

[0006] The technical problem solved by the present application is that existing bone-penetrating oil or external essential oil preparations usually use physical mixing process, which leads to the easy crystallization of high-melting active ingredients (such as natural borneol) at low concentrations, and the transdermal absorption efficiency depends on passive diffusion, resulting in low bioavailability. At the same time, strong penetration enhancers often cause skin irritation, and phenolic active ingredients (such as gingerol) are prone to oxidation in oil and lose efficacy.

[0007] To solve the above problems, the present application provides the following technical solutions:

[0008] In a first aspect, the present application provides a bone-penetrating oil for treating pain, which is made from raw materials comprising the following weight parts:

[0009] 12-18 parts of peppermint oil, 4-6 parts of natural borneol, 10-14 parts of fatty acid, and 2-5 parts of propylene glycol dicaprylate / caprate;

[0010] 4-6 parts of ginger oil, 3-5 parts of mugwort leaf oil, 1-2 parts of lavender oil, and 0.5-1.0 parts of rose oil;

[0011] 30-40 parts of olive fruit oil, 20-25 parts of jojoba seed oil, 0.05-0.2 parts of ceramide 3, and 0.1-0.5 parts of farnesol;

[0012] The menthol in the peppermint oil, the natural borneol, and the fatty acid form a ternary eutectic solvent system through hydrogen bonding.

[0013] 1. The ternary supramolecular solvent system realizes the liquid state of high-melting-point components:

[0014] The present application is different from the physical dissolution of traditional oils and fats relying on the similar phase solubility principle. The menthol in the peppermint oil and the natural borneol are used as hydrogen bond acceptors, and the fatty acid is used as a hydrogen bond donor. The three form an associated structure through intermolecular hydrogen bonding force in a specific molar ratio range, destroy the original lattice arrangement of natural borneol (melting point about 203℃) and fatty acid (melting point about 44℃-54℃), reduce the melting point of the system to below room temperature, and form a stable liquid ternary eutectic solvent (NADES). The system can realize the liquid stable existence of high-concentration natural borneol at room temperature without using a large amount of organic solvent, and solves the problem of drug precipitation caused by solvent volatilization in traditional preparations.

[0015] 2. Utilize the steric hindrance effect to strengthen the low-temperature stability:

[0016] Propylene glycol dicaprylate / caprate has suitable polarity and molecular volume, and can fill the gap between the supramolecular network of the ternary eutectic solvent system. In a low-temperature environment, propylene glycol dicaprylate / caprate hinders the ordered accumulation and crystal nucleus growth of borneol molecules through the steric hindrance effect, maintains the disordered structure of the system in a supercooled state, and thus endows the bone-penetrating oil with the anti-crystallization performance of maintaining a uniform and transparent liquid state in a cold environment (such as-15℃), overcoming the technical defects of low-temperature instability of oil-based preparations containing high-concentration borneol.

[0017] 3. Utilize the steric hindrance effect to strengthen the low-temperature stability:

[0018] The propylene glycol dicaprylate / caprate has suitable polarity and molecular volume, and can fill the gap between the supramolecular network of the ternary eutectic solvent system. In a low temperature environment, the propylene glycol dicaprylate / caprate hinders the ordered accumulation and crystal nucleus growth of the menthol molecules by the steric hindrance effect, maintains the disordered structure of the system in the supercooled state, and thus endows the bone-penetrating oil with the anti-crystallization performance of keeping uniform and transparent liquid state in a cold environment (such as -15℃), and overcomes the technical defect of the low temperature instability of the oil-based preparation containing high concentration of menthol.

[0019] Preferably, the weight parts of the raw materials are as follows:

[0020] 15 parts of peppermint oil, 5 parts of natural borneol, 12 parts of fatty acid, 3.5 parts of propylene glycol dicaprylate / caprate, 5 parts of ginger oil, 4 parts of mugwort leaf oil, 1.5 parts of lavender oil, 0.8 part of rose oil, 35 parts of olive fruit oil, 22.5 parts of jojoba seed oil, 0.1 part of ceramide 3, and 0.3 part of bisabalol.

[0021] By adopting the technical scheme, the proportion is near the eutectic point formed by the ternary eutectic solvent, the thermodynamic stability of the system is high, and the synergistic effect among the components is remarkable.

[0022] Preferably, the fatty acid is one or a mixture of two of lauric acid and myristic acid. More preferably, the fatty acid is lauric acid.

[0023] By adopting the technical scheme, the hydrogen bond network density formed by lauric acid (C12), menthol and borneol is moderate, the viscosity of the obtained system at room temperature is suitable, and the transdermal penetration rate is better than that of the long carbon chain fatty acid system.

[0024] Preferably, in the ternary eutectic solvent system, the menthol provided by the peppermint oil and the natural borneol act as the hydrogen bond acceptor, the fatty acid acts as the hydrogen bond donor, and the propylene glycol dicaprylate / caprate fills the intermolecular gap of the ternary eutectic solvent system as a low temperature stabilizer.

[0025] By adopting the technical scheme, the micro-assembly mode inside the system is limited, the formation of the supramolecular structure is ensured, and thus the expected heat-sensitive variable viscosity characteristics and solubilization effect are obtained.

[0026] Preferably, the raw materials are divided into A-phase components and B-phase components; the A-phase components include peppermint oil, natural borneol, fatty acid, propylene glycol dicaprylate / caprate, ginger oil, mugwort leaf oil, lavender oil and rose oil, and the dynamic viscosity of the A-phase components at 25℃ is 780-1150 mPa·s; the B-phase components include olive fruit oil, jojoba seed oil, ceramide 3 and bisabalol.

[0027] By adopting the technical scheme, the A-phase component is used as a high-viscosity active ingredient concentrated carrier, which limits the diffusion movement of active molecules at a storage temperature, reduces the oxidation rate and volatile loss; after being mixed with the B-phase carrier oil and contacting the skin (37℃), the viscosity is reduced by using the temperature-sensitive rheological properties of the NADES, which is conducive to the release and penetration of the active ingredients. The B-phase is used as a skin-softening carrier to improve the spreading and moisturizing properties of the preparation.

[0028] In a second aspect, the present application provides a preparation method of the above-mentioned bone-penetrating oil for treating pain, comprising the following steps:

[0029] S1, preparing a ternary eutectic solvent precursor: mixing peppermint oil and natural borneol, heating to be clear, adding fatty acid to be constant-temperature stirred to be a molten homogeneous phase, and then adding propylene glycol dioctanoate / caprylate to obtain a ternary eutectic solvent precursor;

[0030] S2, loading active ingredients: cooling the precursor obtained in step S1, adding ginger oil to constant-temperature stir and age, locking gingerols by using hydrogen bond clamping, and then sequentially adding leaf of wormwood oil, lavender oil and rose oil to mix uniformly to obtain an A-phase mixture;

[0031] S3, preparing a carrier oil: mixing olive fruit oil and jojoba seed oil, preheating, adding ceramide 3 and bisabolol to stir and dissolve to obtain a B-phase carrier oil;

[0032] S4, homogenizing and forming: injecting the A-phase mixture into the B-phase carrier oil, homogenizing and stirring, and then cooling and defoaming to obtain the product.

[0033] 1. Ensuring the formation of supramolecular structure by step-by-step in-situ assembly:

[0034] Step S1 is not simply a mixture of raw materials, but a thermodynamic construction process of a ternary eutectic solvent (NADES). First, the hydrogen bond acceptors (menthol and borneol) are made to be mutually soluble, and then the hydrogen bond donors (fatty acids) are introduced to provide activation energy at a specific temperature to promote the establishment of stable hydrogen bond network among the components. This step avoids the problem that the components cannot form a dense supramolecular structure due to dispersion in a large amount of solvent.

[0035] 2. Using the "hydrogen bond clamping aging" process to improve the stability of phenolic components:

[0036] Step S2 is the core process of the present application. The active ingredient 6-gingerol in ginger oil contains unstable phenolic hydroxyl and β-hydroxy ketone structures, which are prone to oxidation or dehydration. In the present application, the ginger oil is first introduced into a high-concentration NADES system for "aging" treatment before mixing the NADES precursor with a large amount of carrier oil. In this process, the gingerol molecules diffuse into the supramolecular grid of the NADES, and the phenolic hydroxyl group acts as a proton donor to participate in the hydrogen bond network to form intermolecular complexes. This "clamping" effect reduces the reactivity of the phenolic hydroxyl group on the one hand, and on the other hand, the steric hindrance effect of the NADES network blocks the contact of oxygen, thereby significantly inhibiting the oxidative degradation of gingerol during subsequent storage.

[0037] 3. Phase separation preparation strategy ensures system homogeneity:

[0038] The high-viscosity functional phase (A phase) and the low-viscosity carrier phase (B phase) are prepared separately, and then homogenized. This strategy ensures that the poorly soluble solid ingredients such as ceramide 3 are fully dissolved in the B phase, while the supramolecular structure in the A phase is not destroyed, finally obtaining a macroscopically uniform, microscopically stable bone-penetrating oil system.

[0039] Preferably, the specific implementation of step S1 is as follows: add peppermint oil and natural borneol into a sealed reaction kettle, control the temperature at 40-45°C, and stir until the solids disappear; keep the temperature unchanged, add fatty acids, and increase the stirring speed to 200-300 rpm, and stir for 30-45 minutes until a single homogeneous liquid is formed; finally add propylene glycol dicaprylate / caprate and mix for 5-10 minutes.

[0040] By using the above technical solution, the temperature range of 40-45°C can ensure that the solid components (borneol, fatty acids) have sufficient molecular kinetic energy to overcome the lattice energy, and can also avoid the loss of volatile components in the peppermint oil. Higher stirring speed helps to increase the molecular collision frequency, promote the orientation arrangement of hydrogen bond donors and acceptors, and accelerate the formation of eutectic.

[0041] Preferably, in step S2, the temperature of the cooled system is controlled at 30-35°C; and the time for constant temperature stirring and aging of the added ginger oil is 20-30 minutes.

[0042] By using the above technical solution, 30-35°C is a suitable temperature window for hydrogen bond formation, and too high a temperature will cause the hydrogen bond to break, and too low a temperature will hinder molecular diffusion. The aging time of 20-30 minutes provides sufficient thermodynamic equilibrium time for gingerol molecules to enter the NADES lattice cavity. If the time is too short, the gingerol has not completely entered the network inside and is diluted by the subsequent addition of oil phase, which will cause the "clamping" effect to weaken and the stability to decrease.

[0043] Preferably, in step S4, the rotation speed of the homogenizing stirring is 300-500 rpm, and the time is 10-15 minutes; and the cooling method is natural cooling to 20-25 DEG C while stirring.

[0044] By adopting the technical scheme, moderate shearing force promotes micro-mixing of the A phase and the B phase, and avoids local concentration gradient. The operation mode of cooling while stirring prevents local supersaturation precipitation caused by solubility change during the cooling process, and ensures the physical stability of the finished product at room temperature.

[0045] In summary, the present application has at least one of the following beneficial technical effects:

[0046] 1. The present application constructs a ternary eutectic solvent system by menthol in peppermint oil, natural borneol and fatty acid, uses hydrogen bond association to destroy the crystal lattice structure of high melting point components, realizes the liquid loading of high concentration natural borneol at room temperature; fills propylene glycol dioctanoate / decanoate in the intermolecular gap, uses steric hindrance effect to inhibit the crystal nucleus growth at low temperature, ensures that the product still maintains uniform transparent liquid state at-15 DEG C environment, avoids the solid-liquid separation or precipitation phenomenon of traditional oily preparation in cold environment.

[0047] 2. The present application uses hydrogen bond clamping aging process, disperses ginger oil in high concentration ternary eutectic solvent precursor in advance, promotes unstable 6-gingerol molecules into supramolecular grid, and the phenolic hydroxyl group as a proton donor participates in hydrogen bond network construction; this intermolecular interaction reduces the reaction activity of the phenolic hydroxyl group, and uses the steric hindrance of the network structure to block the contact of oxygen, effectively delays the oxidative degradation of the active ingredient, and improves the shelf life stability of the preparation.

[0048] 3. The present application uses the extraction and rearrangement of the ternary eutectic solvent system on the stratum corneum lipid to greatly improve the transdermal flux of the active ingredient; in view of the risk of weakening of the barrier function caused thereby, by compounding ceramide 3 and bisabolol for synergistic repair, ceramide 3 replenishes endogenous lipids extracted by the solvent to restore the barrier structure, and bisabolol inhibits the release of local inflammatory factors, so that the skin irritation of the preparation is reduced to the non-irritating level. DETAILED DESCRIPTION

[0049] In order to more clearly express the present application, the following will be further described by specific examples.

[0050] The main raw materials and reagents used in the following examples and comparative examples are as follows, and the reagents not specifically described are commercially available analytical pure or higher grade products.

[0051] Peppermint oil (CAS No. 8006-90-4, containing L-menthol > 50%), natural borneol (CAS No. 464-43-7, purity > 96%), lauric acid (CAS No. 143-07-7), myristic acid (CAS No. 544-63-8) and propylene glycol dicaprylate / caprate (CAS No. 68583-51-7) are all commercially available as technical grade; ginger oil (CAS No. 8007-08-7), mugwort leaf oil (CAS No. 8008-93-3), lavender oil (CAS No. 8000-28-0), rose flower oil (CAS No. 8007-01-0), olive fruit oil (CAS No. 8001-25-0) and jojoba seed oil (CAS No. 61789-91-1) are all commercially available as cosmetic grade; ceramide 3 (CAS No. 100403-19-8) and farnesol (CAS No. 515-69-5) are both commercially available as high purity grade.

[0052] Preparation Example 1:

[0053] The present preparation example provides a ternary eutectic solvent precursor, and the preparation process thereof comprises the following steps:

[0054] (1) 150 g of peppermint oil and 50 g of natural borneol were added to a sealed reaction kettle equipped with a temperature control and mechanical stirring device, the temperature of the system was controlled at 42°C, the stirring speed was set at 80 rpm, and stirring was continued for 20 minutes until the solids completely disappeared to form a clear liquid mixture;

[0055] (2) The temperature was kept at 42°C, 120 g of lauric acid was slowly added to the reaction kettle, the stirring speed was increased to 250 rpm, and constant temperature stirring was continued for 40 minutes until the lauric acid solids completely melted and the system changed to a single homogeneous viscous liquid;

[0056] (3) 35 g of propylene glycol dicaprylate / caprate was added to the above system, the stirring speed was kept at 200 rpm, and mixing was carried out for 8 minutes to obtain the ternary eutectic solvent precursor.

[0057] Preparation Example 2:

[0058] The present preparation example provides a ternary eutectic solvent precursor, and the preparation process thereof comprises the following steps:

[0059] (1) 120 g of peppermint oil and 40 g of natural borneol were added to a sealed reaction kettle equipped with a temperature control and mechanical stirring device, the temperature of the system was controlled at 40°C, the stirring speed was set at 50 rpm, and stirring was continued for 15 minutes until the solids completely disappeared to form a clear liquid mixture;

[0060] (2) Keep the temperature at 40 °C, slowly add 100 g of lauric acid into the reactor, increase the stirring speed to 200 rpm, and keep constant temperature stirring for 30 min until the lauric acid solid completely melts and the system turns into a single homogeneous viscous liquid;

[0061] (3) Add 20 g of propylene glycol dicaprylate / caprate into the above system, keep the stirring speed at 200 rpm, and mix for 5 min to obtain the ternary eutectic solvent precursor.

[0062] Preparation Example 3:

[0063] The preparation example provides a ternary eutectic solvent precursor, and the preparation process comprises the following steps:

[0064] (1) Add 180 g of peppermint oil and 60 g of natural menthol into a sealed reactor equipped with a temperature control and mechanical stirring device, control the system temperature at 45 °C, start the stirring at a speed of 100 rpm, and continuously stir for 20 min until the solids completely disappear to form a clear liquid mixture;

[0065] (2) Keep the temperature at 45 °C, slowly add 140 g of lauric acid into the reactor, increase the stirring speed to 300 rpm, and keep constant temperature stirring for 45 min until the lauric acid solid completely melts and the system turns into a single homogeneous viscous liquid;

[0066] (3) Add 50 g of propylene glycol dicaprylate / caprate into the above system, keep the stirring speed at 200 rpm, and mix for 10 min to obtain the ternary eutectic solvent precursor.

[0067] Preparation Example 4:

[0068] The preparation example provides a ternary eutectic solvent precursor, and the preparation process comprises the following steps:

[0069] (1) Add 150 g of peppermint oil and 50 g of natural menthol into a sealed reactor equipped with a temperature control and mechanical stirring device, control the system temperature at 45 °C, start the stirring at a speed of 80 rpm, and continuously stir for 20 min until the solids completely disappear to form a clear liquid mixture;

[0070] (2) Keep the temperature at 45 °C, slowly add 120 g of myristic acid into the reactor, increase the stirring speed to 250 rpm, and keep constant temperature stirring for 45 min until the myristic acid solid completely melts and the system turns into a single homogeneous viscous liquid;

[0071] (3) Add 35 g of propylene glycol dicaprylate / caprate into the above system, keep the stirring speed at 200 rpm, and mix for 8 min to obtain the ternary eutectic solvent precursor.

[0072] Example 1:

[0073] The present embodiment provides a preparation method of the bone-penetrating oil for treating pain, comprising the following steps:

[0074] (1) Take 35.5 g of the ternary eutectic solvent precursor prepared in Preparation Example 1, and place it in a stirring kettle, and adjust the system temperature to 33°C;

[0075] (2) Under the condition of keeping the temperature at 33°C and the stirring speed at 180 rpm, add 5.0 g of ginger oil to the precursor, and continue to stir for 25 minutes to hydrogen bond clamping aging, then sequentially add 4.0 g of leafy oil, 1.5 g of lavender oil and 0.8 g of rose oil, and continue to stir for 5 minutes until the mixture is uniform, to obtain an A-phase mixture loaded with active ingredients;

[0076] (3) Mix 35.0 g of olive fruit oil and 22.5 g of jojoba seed oil, and preheat to 33°C, then add 0.1 g of ceramide 3 and 0.3 g of bisabolol to the mixture, and stir until the solids are completely dissolved, to obtain a clear B-phase carrier oil;

[0077] (4) Slowly inject the A-phase mixture prepared in step (2) into the B-phase carrier oil in step (3), and start homogenizing stirring at a speed of 400 rpm, and mix for 12 minutes;

[0078] (5) Stop heating, and naturally cool to 25°C while stirring, then stop stirring, and stand for 3 hours to remove bubbles, to obtain the bone-penetrating oil for treating pain.

[0079] Example 2:

[0080] The present embodiment provides a preparation method of the bone-penetrating oil for treating pain, comprising the following steps:

[0081] (1) Take 28.0 g of the ternary eutectic solvent precursor prepared in Preparation Example 2, and place it in a stirring kettle, and adjust the system temperature to 30°C;

[0082] (2) Under the condition of keeping the temperature at 30°C and the stirring speed at 150 rpm, add 4.0 g of ginger oil to the precursor, and continue to stir for 20 minutes to hydrogen bond clamping aging, then sequentially add 3.0 g of leafy oil, 1.0 g of lavender oil and 0.5 g of rose oil, and continue to stir for 5 minutes until the mixture is uniform, to obtain an A-phase mixture loaded with active ingredients;

[0083] (3) Mix 40.0 g of olive fruit oil and 25.0 g of jojoba seed oil, and preheat to 30°C, then add 0.2 g of ceramide 3 and 0.5 g of bisabolol to the mixture, and stir until the solids are completely dissolved, to obtain a clear B-phase carrier oil;

[0084] (4) slowly inject the A-phase mixture prepared in step (2) into the B-phase carrier oil of step (3), start homogenizing stirring, set the rotation speed at 300 rpm, and mix for 10 minutes;

[0085] (5) stop heating, naturally cool to 20°C while stirring, stop stirring, and stand for 2 hours to remove bubbles, thereby obtaining the bone-penetrating oil for treating pain.

[0086] Example 3:

[0087] The present example provides a preparation method of a bone-penetrating oil for treating pain, comprising the following steps:

[0088] (1) take 43.0 g of the ternary eutectic solvent precursor prepared in Preparation Example 3, and place it in a stirring kettle, and adjust the system temperature to 35°C;

[0089] (2) under the conditions of maintaining 35°C constant temperature and 200 rpm stirring rotation speed, add 6.0 g of ginger oil to the precursor, continue stirring for 30 minutes for hydrogen bond clamping aging, and then sequentially add 5.0 g of wormwood leaf oil, 2.0 g of lavender oil, and 1.0 g of rose flower oil, continue stirring for 10 minutes until mixed uniformly, thereby obtaining an A-phase mixture loaded with active ingredients;

[0090] (3) take another 30.0 g of olive fruit oil and 20.0 g of jojoba seed oil, mix them, preheat to 35°C, add 0.05 g of ceramide 3 and 0.1 g of bisabalol to the mixture, and stir until the solids are completely dissolved, thereby obtaining a clear B-phase carrier oil;

[0091] (4) slowly inject the A-phase mixture prepared in step (2) into the B-phase carrier oil of step (3), start homogenizing stirring, set the rotation speed at 500 rpm, and mix for 15 minutes;

[0092] (5) stop heating, naturally cool to 25°C while stirring, stop stirring, and stand for 4 hours to remove bubbles, thereby obtaining the bone-penetrating oil for treating pain.

[0093] Example 4:

[0094] The present example provides a preparation method of a bone-penetrating oil for treating pain, comprising the following steps:

[0095] (1) take 35.5 g of the ternary eutectic solvent precursor prepared in Preparation Example 4, and place it in a stirring kettle, and adjust the system temperature to 32°C;

[0096] (2) Under the condition of keeping 32℃ constant temperature and 180 rpm stirring speed, 5.0 g of ginger oil was added into the precursor, and hydrogen bond clamping aging was carried out by continuously stirring for 25 minutes, then 4.0 g of moxa oil, 1.5 g of lavender oil and 0.8 g of rose oil were sequentially added, and stirring was continued for 8 minutes until the mixture was uniformly mixed, to obtain an A-phase mixture loaded with active ingredients;

[0097] (3) 35.0 g of olive fruit oil and 22.5 g of jojoba seed oil were mixed, and preheated to 32℃, then 0.15 g of ceramide 3 and 0.3 g of bisabalol were added, and stirring was continued until the solids were completely dissolved, to obtain a clear B-phase carrier oil;

[0098] (4) The A-phase mixture prepared in step (2) was slowly injected into the B-phase carrier oil of step (3), and homogenizing stirring was started, with a stirring speed of 400 rpm, and mixing was carried out for 12 minutes;

[0099] (5) The heating was stopped, and the mixture was naturally cooled to 23℃ while stirring, then the stirring was stopped, and the mixture was left to stand for 3 hours to remove bubbles, to obtain the bone-penetrating oil for treating pain.

[0100] Comparative Example 1:

[0101] This comparative example provides a preparation method of a bone-penetrating oil, which is different from Example 1 in that the ternary eutectic solvent precursor is not prepared by hot melting, but all raw materials (mint oil, natural borneol, lauric acid, PGD, ginger oil and other essential oils, carrier oil, etc.) are directly physically mixed at room temperature of 25℃, and the types and amounts of the remaining raw materials are the same.

[0102] Comparative Example 2:

[0103] This comparative example provides a preparation method of a bone-penetrating oil, which is different from Example 1 in that natural borneol is not added in Example 1, and only a binary eutectic solvent is formed from mint oil and lauric acid under the same conditions, and the rest is the same.

[0104] Comparative Example 3:

[0105] This comparative example provides a preparation method of a bone-penetrating oil, which is different from Example 1 in that propylene glycol dicaprylate / caprate (PGD) is not added in Example 1, and the rest is the same.

[0106] Comparative Example 4:

[0107] This comparative example provides a preparation method of a bone-penetrating oil, which is different from Example 1 in that the ginger oil is not added in step (2) for 25 minutes of hydrogen bond clamping aging, but the subsequent moxa oil, lavender oil and rose oil are immediately added and directly mixed in the next step, and the rest is the same.

[0108] Comparative Example 5:

[0109] The comparative example provides a preparation method of bone-penetrating oil, which is different from example 1 in that no ceramide 3 and farnesol is added in step (3), and the rest is the same.

[0110] Test example 1:

[0111] The experimental method is as follows:

[0112] The ternary eutectic solvent precursor prepared in preparation examples 1-4 is selected as the sample to be tested, and the following physical and chemical properties are characterized:

[0113] (1) Observation of appearance: place each group of samples in a transparent clean erlenmeyer flask, and stand for 24 hours in a constant temperature environment of 25°C. Observe the material state, color, transparency and uniformity of the sample by visual method, and focus on checking whether there are visible crystals or stratification.

[0114] (2) Viscosity-temperature characteristic test: use a digital rotary viscometer to control the sample temperature by a constant temperature water bath, and measure the dynamic viscosity value of the sample at the storage temperature (25°C) and the human body surface temperature (37°C). The rotation speed is set to 30 rpm (25°C) and 60 rpm (37°C), each group of sample is measured three times and the arithmetic mean value is taken. Calculate the decrease rate of viscosity with the increase of temperature to characterize the temperature-sensitive characteristics of the system.

[0115] The physical characterization data of each preparation example sample is recorded in table 1.

[0116] Table 1 Physical property data of ternary eutectic solvent precursor obtained in preparation examples 1-4:

[0117]

[0118] According to the data in table 1, the ternary eutectic solvent system constructed by the technical scheme is analyzed as follows:

[0119] Preparation examples 1-4 all present a uniform and transparent liquid state at room temperature of 25°C, and no solid particle suspension or phase separation phenomenon is observed. The menthol (melting point about 42°C) in peppermint oil, natural menthol (melting point about 203°C) and lauric acid (melting point about 44°C) or myristic acid (melting point about 54°C) are all solid or semi-solid in single component state, but form a stable liquid system after mixing. This confirms that the interaction between components through hydrogen bond donor and acceptor destroys the original crystal lattice arrangement of each component, resulting in a significant reduction in the melting point of the system below room temperature, and successfully forming a supramolecular eutectic solvent. The addition of propylene glycol dioctanoate / caprate further fills the intermolecular gap and maintains the liquid phase stability of the system at room temperature.

[0120] The viscosity test data show that the ternary system has significant heat-sensitive viscosity characteristics. At 25°C, the system viscosity is maintained in a higher interval of 780-1100 mPa·s. This higher viscosity is beneficial to the physical stability of the product during storage and transportation, limiting the Brownian motion of active molecules, reducing oxidation and volatilization. When the temperature rises to 37°C (close to the temperature of human skin), the viscosity of each group of samples decreases sharply, with a value of 160-260 mPa·s, a decrease of more than 75%.

[0121] The mechanism of this rheological behavior is that as the temperature rises, the intermolecular hydrogen bonding force maintaining the supramolecular network structure of the NADES weakens, the intermolecular distance increases, and the free volume increases, resulting in a significant decrease in internal friction of the fluid.

[0122] As can be seen from Comparative Preparation Example 1 and Preparation Example 4, after using myristic acid (C14) instead of lauric acid (C10), the viscosity of the system at 25°C and 37°C increases. This is because myristic acid has a longer hydrophobic carbon chain, and the intermolecular van der Waals force is enhanced, resulting in an increase in the degree of entanglement within the fluid. This result shows that by adjusting the carbon chain length of the fatty acid, the basic rheological properties of the solvent system can be fine-tuned to meet the needs of different application scenarios.

[0123] In summary, the ternary eutectic system not only realizes the liquid loading of high-melting-point components (borneol), but also has the significant temperature-sensitive rheological characteristics of high viscosity stability during storage and low viscosity and rapid penetration during use, providing a thermodynamic and kinetic basis for the efficient penetration of bone oil.

[0124] Test Example 2:

[0125] The experimental method is as follows:

[0126] The bone oil samples prepared in Examples 1-4 and Comparative Examples 1 and 3 were selected as test objects.

[0127] (1) Sample pretreatment: The samples prepared and defoamed in each group were divided into transparent borosilicate glass bottles with a specification of 20 mL, sealed with bottle caps, and each group was prepared in triplicate.

[0128] (2) Low-temperature destructive test: All samples were placed in a low-temperature constant temperature test chamber, set to -15°C, and left for 48 hours. This temperature setting aims to simulate the transportation and storage environment in extreme cold climates and to investigate the phase stability of the system under supercooling conditions.

[0129] (3) Observation index: After reaching the set time, the samples were quickly removed and observed under a standard light source box.

[0130] Clarity: Observe whether there are white flocculent precipitates, needle-shaped crystals, or turbidity in the bottle;

[0131] Flowability: Invert the sample bottle by 90 degrees, observe the flow behavior of the liquid and whether there is solid deposition at the bottom.

[0132] The physical state of each group of samples after being subjected to low temperature treatment at -15°C for 48 hours is recorded in Table 2.

[0133] Table 2: Low temperature stability test results of example and comparative sample:

[0134]

[0135] According to the data in Table 2, the phase behavior and stability mechanism of each group of formulations in a low temperature environment are analyzed as follows:

[0136] Examples 1-4 all remained macroscopically homogeneous liquid state at an extreme low temperature of -15°C, without solid-liquid separation or visible crystal precipitation. Although the viscosity of the samples generally increased (manifested as slow flow) due to the decrease in molecular thermal motion caused by temperature reduction, the internal supramolecular structure remained intact. This result shows that the menthol-menthane-fatty acid ternary eutectic system formed by hydrogen bonding assembly has a solid-liquid phase transition point significantly lower than -15°C. Although there are slight differences in low temperature viscosity (flowability) between the examples due to differences in the ratio, none of them have undergone phase transition, confirming the low temperature adaptability of the technical solution in a wide range of ratios.

[0137] Comparative Example 1 (physical mixing) failed completely in the test. Since it did not undergo a hot melt eutectic process, the natural menthane (melting point ~203°C) and lauric acid (melting point ~44°C) in the raw materials failed to form a stable hydrogen bond network with menthol, and were only physically dispersed in the solvent in a supersaturated state. At low temperatures, the solubility decreases, and the high-melting-point components crystallize out of the oil phase rapidly, leading to the separation of the system and solidification. This confirms the necessity of in-situ assembly process for constructing liquid bone oil systems.

[0138] The test results of Comparative Example 3 (without PGD) reveal the key role of low temperature stabilizer. Although Comparative Example 3 underwent a eutectic preparation process, it appeared turbid and needle-shaped crystals precipitated at -15°C in the absence of propylene glycol dicaprylate / caprate (PGD). This shows that a simple ternary NADES system is in a metastable state at an extreme low temperature, and as the temperature decreases, the menthane molecules tend to break away from the hydrogen bond and rearrange into a crystal lattice (nucleation). The PGD introduced in Examples 1-4, as a cosolvent with appropriate polarity and molecular volume, inserts into the intermolecular space of NADES, hindering the ordered packing and crystal nucleus growth of menthane molecules through steric hindrance effect, thereby maintaining the liquid phase stability of the system under supercooling conditions.

[0139] In summary, this technical solution effectively solves the technical problem of easy crystallization in oily systems containing high concentrations of borneol by constructing a ternary eutectic framework and introducing a low-temperature stabilizer with a specific structure, thus ensuring the physical stability of the product during transportation and use in cold regions.

[0140] Test Example 3:

[0141] The experimental method is as follows:

[0142] The bone-penetrating oil samples prepared in Example 1, Comparative Example 1, and Comparative Example 4 were selected as test subjects.

[0143] (1) Accelerated aging treatment: The above three groups of samples were divided into transparent glass sample bottles, without nitrogen protection, and sealed with caps (leaving a certain amount of headspace air to simulate the actual storage oxidation environment). The sample bottles were placed in a constant temperature forced-air drying oven, with the temperature set at 45°C and the relative humidity at 60%, and subjected to continuous heat aging for 15 days. This condition is equivalent to storage at room temperature for about 3 to 6 months.

[0144] (2) Sampling and testing: Samples were taken out on day 0, day 5, day 10 and day 15 for testing.

[0145] 6-Gingerol Retention Determination: High-performance liquid chromatography (HPLC) was used. A C18 column (4.6 × 250 mm, 5 μm) was selected, and the mobile phase was acetonitrile-0.1% phosphoric acid aqueous solution (gradient elution). The detection wavelength was 280 nm. Samples were accurately measured, extracted with methanol after demulsification, and injected. The content of 6-gingerol was calculated using the external standard method. The retention rate was calculated using the formula: R... t =(C t / C0)×100%.

[0146] Color difference analysis: Color parameters of the samples before and after aging were measured using a colorimeter (D65 light source, 10° field of view). , , According to the formula Calculate the total color difference value.

[0147] The chemical stability data of each group of samples during the accelerated test at 45℃ are recorded in Table 3.

[0148] Table 3. Retention rate and color difference data of 6-gingerol in the examples and comparative samples:

[0149]

[0150] Based on the data in Table 3, the chemical stability and "hydrogen bond clamping" mechanism of the active ingredient in this technical solution are analyzed as follows:

[0151] The comparative example 1 (physical mixing) showed the worst chemical stability during the accelerated aging process. By the 15th day, the retention rate of 6-gingerol was only 58.33%, and the total color difference value ΔE was as high as 8.95, and the macroscopic performance was that the sample color changed from yellowish to dark brown. The 6-gingerol molecular structure contains phenolic hydroxyl and β-hydroxy ketone structure, which is prone to oxidation to generate quinone substances or dehydration to generate 6-gingerenol, resulting in reduced efficacy and brown color change. In the physical mixing system, gingerol is directly exposed to oil and dissolved oxygen environment, lacking the protection of microstructure, and the oxidation kinetic reaction rate is fast.

[0152] The example 1 showed excellent stability, and the retention rate was still maintained at 94.73% by the 15th day, and the color difference change was very small (ΔE=1.24). This result proves the protection effect of the ternary eutectic solvent (NADES) system on the easily oxidized components. The mechanism is that the hydrogen bond acceptor (menthol / borneol) and the hydrogen bond donor (lauric acid) in the NADES system form a dense supramolecular network. When the ginger oil is introduced into the system, the phenolic hydroxyl group in the gingerol molecule acts as a proton donor and participates in the hydrogen bond network of the NADES, forming a stable intermolecular complex. This combination reduces the electron cloud density of the phenolic hydroxyl group on the one hand, and increases its oxidation potential; on the other hand, the huge supramolecular network forms a steric hindrance, hindering the diffusion of oxygen molecules to the active site.

[0153] The data of the comparative example 4 (no hydrogen bond clamping aging) (the retention rate was 75.81% by the 15th day) was significantly lower than that of the example 1, but better than that of the comparative example 1. This comparison result strongly proves the necessity of the “hydrogen bond clamping aging” step in the preparation process. Although the comparative example 4 has the material basis of NADES, it is directly dispersed in a large amount of oil phase carrier without giving the ginger oil enough thermodynamic equilibrium time (25-30 minutes of constant temperature stirring) in the preparation process. The gingerol molecules have not yet completely entered the hydrogen bond network cavity of the NADES, and are diluted, and most of the gingerol is still free outside the NADES structure, and cannot form an effective “clamping” effect, so its stability is better than that of the pure physical mixing, but far inferior to that of the example 1 treated by the special aging process.

[0154] In summary, the present application realizes the molecular level embedding and protection of phenolic heat-sensitive / light-sensitive active ingredients by constructing a specific ternary NADES system and cooperating with the “hydrogen bond clamping” process, and significantly prolongs the shelf life stability of the product.

[0155] Test example 4:

[0156] The experimental method is as follows:

[0157] The bone penetrating oil samples prepared by the example 1, the comparative example 1 and the comparative example 2 were selected as the test objects.

[0158] (1) Skin barrier preparation: The back skin of Bama miniature pigs was selected as the permeation barrier. The subcutaneous adipose tissue and connective tissue were removed, and only the stratum corneum, epidermis and dermis were retained. The skin was cut into a circular piece with a diameter of 2.5 cm. The skin pieces with a thickness of 1.0 ± 0.1 mm were selected using a thickness gauge, washed with normal saline and stored at -20°C for later use. Before use, the skin pieces were thawed at room temperature and hydrated for 1 hour.

[0159] (2) Franz diffusion cell device setup: A vertical Franz diffusion cell was used, with an effective diffusion area of 1.77 cm 2 and a receiving chamber volume of 15 mL.

[0160] Donor chamber: 0.5 g of the sample to be tested was weighed and uniformly coated on the surface of the skin stratum corneum, and sealed with sealing film to prevent evaporation.

[0161] Receiving chamber: The receiving chamber was filled with a mixture of degassed phosphate buffer (PBS, pH 7.4) and ethanol (volume ratio 80:20) to ensure that the poorly soluble components met the sink conditions.

[0162] Operating conditions: The system temperature was maintained at 37 ± 0.5°C by turning on the circulating water bath, and the magnetic stirring speed in the receiving liquid was set to 300 rpm.

[0163] (3) Sampling and determination: 1.0 mL of the receiving liquid was sampled at 1, 2, 4, 8, 12 and 24 hours after administration, and immediately supplemented with an equal volume of fresh receiving liquid at the same temperature. The sample was filtered through a 0.45 μm microporous filter, and the concentrations of 6-gingerol and menthol in the sample were determined by HPLC.

[0164] (4) Data processing: The cumulative permeation amount Q n was calculated according to Fick's first diffusion law, and the formula is as follows:

[0165] ;

[0166] where C n is the measured concentration at the nth time point, V is the volume of the receiving chamber, V s is the sampling volume, and A is the effective diffusion area. The cumulative permeation amount Q n was calculated as the ordinate and the time t as the abscissa, and the total cumulative permeation amount Q 24 in 24 hours was calculated.

[0167] The in vitro transdermal permeation test data of the samples in each group are shown in Table 4.

[0168] Table 4 24-hour cumulative permeation amount Q 24 data of the sample of the examples and comparative examples:

[0169]

[0170] According to the data in Table 4, the transdermal penetration mechanism of the ternary supramolecular solvent system constructed according to the present technical solution is as follows:

[0171] The penetration effect of Comparative Example 1 (physical mixture) is the worst, and the 24-hour cumulative penetration amount of 6-gingerol is only 38.12 μg / cm 2 In the physical mixture system, the active ingredient mainly relies on the concentration gradient for passive diffusion. Since the stratum corneum is composed of dense keratinocytes and lipid bilayers, there is still a large resistance to 6-gingerol and menthol with certain lipophilicity. The physical mixture cannot change the microstructure of the stratum corneum, and the thermodynamic activity of the solute is limited by its solubility in the ordinary oil phase, resulting in low transmembrane transport efficiency.

[0172] Example 1 (ternary NADES) shows a significant penetration advantage, with a 6-gingerol penetration amount of 142.65 μg / cm 2 , which is about 3.7 times that of the physical mixture; the menthol penetration amount also reaches 895.34 μg / cm 2 . This improvement is attributed to the special physicochemical properties of the ternary eutectic solvent:

[0173] First, stratum corneum lipid extraction and rearrangement: the fatty acid (lauric acid) and terpene (menthol, borneol) components in the NADES system can penetrate the stratum corneum lipid bilayer, disrupt the ordered arrangement of endogenous lipids such as ceramides and cholesterol through hydrogen bond competition, and increase the lipid fluidity, thereby opening the drug penetration channel.

[0174] Second, carrier drag effect: in the present application, 6-gingerol is not simply dissolved in the solvent, but is "clamped" in the supramolecular network of NADES through hydrogen bonds. When the NADES components penetrate the skin, they will carry the active molecules across the barrier in a co-permeation manner, and this solvent drag effect significantly improves the flux of macromolecular drugs.

[0175] From the data of Comparative Example 1 and Comparative Example 2 (binary system, no borneol), it can be seen that the penetration efficiency of the ternary system is obviously better than that of the binary system (the capsaicin penetration amount is increased by about 50%). This confirms that natural borneol not only acts as a co-crystal former in the system, but also plays a key role in synergistically promoting penetration. Borneol has strong volatility and fat solubility, and is easy to form a high-concentration microenvironment on the surface of the skin. In the ternary system, the binary alcohol co-crystal skeleton formed by borneol and menthol has stronger affinity with the stratum corneum than single menthol. Borneol can specifically act on the skin keratin protein, change its conformation, and further reduce the diffusion resistance. In addition, the hydrogen bond network structure formed by the ternary system is more dense and stable than that of the binary system, which maintains a higher local thermodynamic activity, thereby driving the active ingredients to migrate to the subcutaneous tissue more efficiently.

[0176] In summary, the bone-penetrating oil of the present application is not simply a superposition of components, but a ternary supramolecular delivery system with high penetration driving force constructed by in-situ assembly technology, which effectively overcomes the bottleneck of poor transdermal absorption of traditional oil agents.

[0177] Test Example 5:

[0178] The experimental method is as follows:

[0179] Select the bone-penetrating oil samples prepared from Example 1 (containing ceramide 3 and bisabolol) and Comparative Example 5 (without ceramide 3 and bisabolol) as test objects. In order to follow the ethical standards and simulate skin irritation, the chicken embryo chorioallantoic membrane (HET-CAM) in vitro irritation evaluation model is used.

[0180] (1) Model preparation: 10-day-old SPF fertilized chicken embryos are selected and maintained at constant temperature and humidity in an incubator. The inner membrane is carefully removed by opening the top of the eggshell, exposing the chorioallantoic membrane (CAM) below, and maintaining the integrity of the CAM. Each test group has 6 replicates.

[0181] (2) Sample treatment: 0.3 g of Example 1 and Comparative Example 5 samples are weighed and uniformly added to the exposed CAM surface, while a negative control group (normal saline) and a positive control group (0.1 M NaOH) are set up.

[0182] (3) Observation and scoring of irritation response: At 0.5 minutes, 2 minutes and 5 minutes after adding the sample, the CAM blood vessel network is observed using a stereomicroscope. The time of occurrence of three kinds of irritation reactions, including bleeding, blood vessel lysis and coagulation, is recorded. According to the severity and occurrence time of the irritation reaction, the irritation score (IS) is calculated according to the ICH regulations of the European Union.

[0183] IS = 300 - (301 - L) x 0.5 - (301 - C) x 0.7 - (301 - H) x 0.9;

[0184] Wherein, L, C, H are the time of dissolution, coagulation and bleeding (seconds), if not occurred within 5 minutes (300 seconds), take 300 seconds. The higher the IS value, the stronger the irritation.

[0185] The irritation score data of each group of samples in the HET-CAM test are recorded in Table 5.

[0186] Table 5 HET-CAM irritation score results of example and comparative sample:

[0187]

[0188] According to the data in Table 5, the safety advantage of the "penetration-repair" mechanism in the technical solution is analyzed as follows:

[0189] The IS value of the positive control group (0.1M NaOH) is as high as 19.85, confirming the effectiveness of the HET-CAM model. The IS value of the negative control group (normal saline) is 0.00.

[0190] The average irritation score of Comparative Example 5 (without ceramide 3 and bisabolol) is 4.21, which is judged as mild irritation. This system has strong transdermal penetration ability (based on the conclusion of Test Example 4). Although this high penetration rate helps to deliver the active ingredients, it has the side effect that the lauric acid, menthol and borneol components in the ternary eutectic solvent (NADES) may over-extract endogenous skin lipids when destroying the lipid barrier of the stratum corneum, thereby triggering skin barrier dysfunction, release of inflammatory factors and local irritation (hyperemia, burning sensation, etc.). This result confirms the technical problem that penetration enhancers often cause irritation.

[0191] The average irritation score of Example 1 (containing ceramide 3 and bisabolol) is only 0.95, which is rated as non-irritating according to international standards. This result strongly proves the effectiveness of the "penetration and repair synergistic" strategy of the present application. Its mechanism is as follows:

[0192] First, ceramide 3: as a key structural component in the lipid bilayer of the stratum corneum, exogenous ceramide 3 can timely fill the gap of extracted endogenous lipids while the NADES system opens the skin barrier, accelerating the self-repair process of the stratum corneum barrier. This synchronous "penetration-repair" mechanism effectively offsets the short-term damage to the barrier structure caused by strong penetration enhancers.

[0193] Second, bisabolol: bisabolol has clear anti-inflammatory and anti-irritation activity. In this example, its synergistic effect is to quickly alleviate the local capillary dilation and inflammatory response that may be caused by borneol and high concentrations of essential oils, thereby reducing the subjective irritation of the skin during the penetration process.

[0194] In summary, the technical scheme integrates the powerful supermolecular penetration enhancer (ternary NADES), the stratum corneum biomimetic repair agent (ceramide 3), and the natural anti-inflammatory agent (bisabolol) to ensure efficient transdermal penetration while significantly reducing the biological irritation of the product, achieving a balance between efficacy and safety.

[0195] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely divergences, modifications, replacements and variations of the embodiments, and the scope of the application is defined by the appended claims and their equivalents.

Claims

1. A bone-penetrating oil for treating pain, characterized in that, Made from the following ingredients in parts by weight: Peppermint oil 12-18 parts, natural borneol 4-6 parts, fatty acids 10-14 parts, propylene glycol dioctanoic acid / capric acid ester 2-5 parts; 4-6 parts ginger oil, 3-5 parts mugwort oil, 1-2 parts lavender oil, and 0.5-1.0 parts rose oil; Olive fruit oil 30-40 parts, jojoba seed oil 20-25 parts, ceramide 3 0.05-0.2 parts, bisabolol 0.1-0.5 parts; In this process, menthol, natural borneol, and fatty acids in the peppermint oil are assembled through hydrogen bonds to form a ternary eutectic solvent system.

2. The bone-penetrating oil for treating pain according to claim 1, characterized in that, The weight parts of the raw materials are: 15 parts peppermint oil, 5 parts natural borneol, 12 parts fatty acids, 3.5 parts propylene glycol dicaprylic / capric acid ester; 5 parts ginger oil, 4 parts mugwort oil, 1.5 parts lavender oil, and 0.8 parts rose oil; Olive fruit oil 35 parts, jojoba seed oil 22.5 parts, ceramide 3 0.1 parts, bisabolol 0.3 parts.

3. The bone-penetrating oil for treating pain according to claim 1, characterized in that, The fatty acid is one or a mixture of two of lauric acid and myristic acid.

4. The bone-penetrating oil for treating pain according to claim 1, characterized in that, In the ternary eutectic solvent system, menthol provided by peppermint oil and natural borneol serve as hydrogen bond acceptors, fatty acids serve as hydrogen bond donors, and propylene glycol dioctanoic acid / decanoic acid ester fills the intermolecular gaps in the ternary eutectic solvent system as a low-temperature stabilizer.

5. The bone-penetrating oil for treating pain according to claim 1, characterized in that, The raw material is divided into phase A and phase B components; The A phase component includes peppermint oil, natural borneol, fatty acids, propylene glycol dicaprylic / capric acid ester, ginger oil, mugwort oil, lavender oil and rose oil, and the dynamic viscosity of the A phase component at 25°C is 780-1150 mPa·s. The B phase component includes olive fruit oil, jojoba seed oil, ceramide 3, and bisabolol.

6. The bone-penetrating oil for treating pain according to claim 3, characterized in that, The fatty acid is lauric acid.

7. A method for preparing a pain-relieving penetrating oil as described in any one of claims 1-6, characterized in that, Includes the following steps: S1. Preparation of ternary eutectic solvent precursor: Peppermint oil and natural borneol are mixed and heated until clear, fatty acids are added and stirred at a constant temperature until a homogeneous melt is formed, and then propylene glycol dioctanoic acid / decanoic acid ester is added and mixed to obtain ternary eutectic solvent precursor; S2, Loading active ingredients: Cool the precursor obtained in step S1, add ginger oil and stir and age at a constant temperature, lock gingerol by hydrogen bond clamping, then add artemisia oil, lavender oil and rose oil in sequence and mix evenly to obtain phase A mixture. S3. Preparation of carrier oil: Mix olive fruit oil and jojoba seed oil and preheat, add ceramide 3 and bisabolol and stir to dissolve to obtain phase B carrier oil; S4. Homogenization molding: Inject the A-phase mixture into the B-phase carrier oil, homogenize and stir, then cool and degas to obtain the final product.

8. The preparation method according to claim 7, characterized in that, The specific implementation method of step S1 is as follows: Add peppermint oil and natural borneol to a sealed reactor, control the temperature at 40-45°C, and stir until the solid disappears; keep the temperature constant, add fatty acids, increase the stirring speed to 200-300 rpm, and stir for 30-45 minutes until a single homogeneous liquid is formed; finally, add propylene glycol dioctanoic acid / decanoic acid ester and mix for 5-10 minutes.

9. The preparation method according to claim 7, characterized in that, In step S2, the temperature of the cooled system is controlled at 30-35℃; the time for adding ginger oil and stirring and aging at a constant temperature is 20-30 minutes.

10. The preparation method according to claim 7, characterized in that, In step S4, the homogenizing stirring speed is 300-500 rpm and the time is 10-15 minutes; the cooling method is to cool naturally to 20-25°C while stirring.

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