Bifunctional naproxen choline gel as well as preparation method and application thereof

Abstract

The invention belongs to the technical field of medicinal gel, and particularly relates to bifunctional naproxen choline gel as well as a preparation method and application thereof. The preparation method of the bifunctional naproxen choline gel comprises the following steps: S1, preparing naproxen sodium salt; s2, preparation of naproxen choline; s3, preparing blank gel; and S4, preparing the bifunctional naproxen choline gel. According to the method, naproxen sodium salt and naproxen choline which are relatively high in purity are prepared by adopting an alcohol system, and then the naproxen choline gel is prepared. Under the condition of the same drug loading capacity, compared with naproxen raw drug gel, the prepared naproxen choline gel shows a better transdermal effect and a faster transdermal rate. The ionic liquid is added into the naproxen choline gel, so that the penetration enhancing performance is improved, meanwhile, the green and low-toxicity choline lactate ionic liquid is synthesized, the toxic and side effects can be remarkably reduced, and the naproxen choline gel has higher application potential.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical gel technology, specifically relating to a bifunctional naproxen choline gel, its preparation method, and its application. Background Technology

[0002] Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs in the world, possessing anti-inflammatory, antirheumatic, anticoagulant, and analgesic effects. Clinically, they are widely used to relieve pain symptoms caused by osteoarthritis, rheumatoid arthritis, and various other conditions. Naproxen, a classic NSAID, is widely used as an antipyretic, anti-inflammatory, and analgesic to treat rheumatoid arthritis and osteoarthritis. However, naproxen has extremely low solubility in water, almost insoluble, which significantly affects its bioavailability and thus its therapeutic efficacy. Furthermore, traditional oral formulations have various limitations, including a significant first-pass effect, strong gastrointestinal irritation, and low bioavailability. Naproxen's half-life is approximately 12-14 hours, requiring frequent dosing to maintain blood drug concentration, easily leading to peak-and-trough effects. This increases the patient's medication burden, causing gastrointestinal irritation such as nausea, vomiting, and gastric ulcers. It may also affect the nervous system, causing symptoms such as mental confusion and dizziness.

[0003] Transdermal drug delivery systems (TDDS) refer to novel drug delivery systems where drugs are absorbed through the skin and enter the systemic circulation, thereby achieving systemic or local therapeutic effects and preventing or treating diseases. These systems allow for transdermal absorption, avoiding gastrointestinal metabolism and the first-pass effect of the liver, directly entering the systemic circulation, reducing systemic side effects, and providing stable blood drug concentrations. This is particularly suitable for patients with chronic inflammation requiring long-term medication. Hydrogels, as a typical representative of semi-solid formulations, occupy an important position in transdermal drug delivery systems due to their excellent morphological stability, controllable drug release characteristics, and good biocompatibility. Loading naproxen into a gel system not only avoids gastrointestinal irritation, unstable blood drug concentrations, and the first-pass effect of the liver caused by oral administration, but also allows for higher drug concentrations in the local tissues at the site of inflammation, improving the therapeutic effect on inflammation. Therefore, preparing naproxen gel can significantly improve adverse drug reactions, thus protecting patients' health. Studies have shown that medium-to-high concentration naproxen gels have significantly better analgesic activity, and among medium-to-high concentration naproxen gels, those containing 4% naproxen by mass exhibit the best analgesic activity.

[0004] Therefore, in order to avoid the drawbacks of naproxen's inherent properties and dosage form, developing a naproxen topical formulation that can reduce systemic toxicity, improve therapeutic efficacy and bioavailability is of great clinical significance. Summary of the Invention

[0005] The purpose of this invention is to provide a bifunctional naproxen-choline gel, its preparation method, and its application. First, high-purity naproxen sodium salt and naproxen-choline were prepared using an alcohol system, and then the naproxen-choline gel was prepared. Under the same drug loading conditions, the prepared naproxen-choline gel exhibits superior transdermal effect and a faster transdermal rate, thus possessing higher clinical pharmaceutical value.

[0006] To achieve the above objectives, the present invention provides the following technical solution:

[0007] A method for preparing a bifunctional naproxen choline gel includes the following steps:

[0008] S1. Preparation of naproxen sodium salt;

[0009] S2. Preparation of naproxen choline;

[0010] S3. Preparation of blank gel;

[0011] S4. Preparation of naproxen choline gel.

[0012] The specific steps of step S1 are as follows: Sodium hydroxide and anhydrous ethanol are mixed and stirred to dissolve, then naproxen is added while stirring until a solid is formed; the mixture is filtered, purified with ethyl acetate, and the filter cake is collected to obtain crude naproxen sodium; the crude naproxen sodium is vacuum dried to constant weight to obtain naproxen sodium salt.

[0013] The specific steps of step S1 are as follows: Sodium hydroxide and anhydrous ethanol are mixed and stirred to dissolve, then naproxen is added while stirring until a solid is formed; the mixture is filtered, purified with ethyl acetate, and the filter cake is collected to obtain crude naproxen sodium; the crude naproxen sodium is vacuum dried to constant weight to obtain naproxen sodium salt.

[0014] Preferably, step S1 is as follows: sodium hydroxide and anhydrous ethanol are mixed and stirred continuously at 800-1000 rpm until the sodium hydroxide is completely dissolved. Naproxen is then added in batches at 25-30°C while stirring at 800-1000 rpm for 1-1.5 hours. The mixture is then filtered. The filter cake is dissolved in ethyl acetate. The mixture is filtered, and the filter cake is collected to obtain crude naproxen sodium. The crude naproxen sodium is then dried under vacuum at 45°C and -0.08 to -0.09 MPa until constant weight is obtained to obtain naproxen sodium salt (CAS No. 26159-34-2).

[0015] Preferably, the solid-liquid ratio of sodium hydroxide to anhydrous ethanol is 1g:(10-15)mL.

[0016] Preferably, the molar ratio of naproxen to sodium hydroxide is 1:(1-1.1).

[0017] Preparing naproxen sodium salt in an alcohol system can improve its yield and purity. This is because naproxen is almost insoluble in water, and preparing naproxen sodium salt in an aqueous system often results in insufficient dissolution and reaction with sodium hydroxide, leading to a decreased yield. Furthermore, the reaction time required is long, and freeze-drying is necessary to remove the solvent water, which is also time-consuming. In contrast, naproxen has high solubility in alcohol, allowing for the rapid preparation of large quantities of naproxen sodium salt, thus improving both yield and purity.

[0018] The specific steps of step S2 are as follows: choline chloride and anhydrous ethanol are mixed and stirred to dissolve, naproxen sodium salt is added, stirred and naturally cooled to room temperature, the filtrate is collected by filtration, anhydrous ethanol is removed by rotary evaporation under reduced pressure, acetone is added, the filtrate is collected by filtration, and residual sodium chloride is removed; the collected filtrate is dried under reduced pressure to remove acetone, and a pale yellow oily substance is obtained, which is dried under vacuum at 40°C to constant weight to obtain naproxen choline.

[0019] Preferably, step S2 is as follows: choline chloride and anhydrous ethanol are mixed and stirred at 800-1000 rpm until completely dissolved. Then, naproxen sodium is added, and the mixture is stirred at 35-40℃ and 800-1000 rpm for 10-15 hours. After naturally cooling to room temperature, the mixture is filtered through a sintered glass funnel, and the filtrate is collected. The anhydrous ethanol is removed by rotary evaporation under reduced pressure at 55℃ and -0.07 to -0.09 MPa. Acetone is added, and the mixture is filtered again through a sintered glass funnel, and the filtrate is collected. The collected filtrate is dried under reduced pressure at 45℃ and -0.07 to -0.09 MPa to remove acetone, yielding a pale yellow oily substance. This substance is placed in a vacuum drying oven and dried under vacuum at 40℃ and -0.08 to -0.09 MPa until constant weight is achieved, yielding naproxen choline.

[0020] Preferably, the solid-liquid ratio of choline chloride to anhydrous ethanol is 1 g:(10-20) mL.

[0021] Preferably, the molar ratio of naproxen sodium salt to choline chloride is 1:1.

[0022] The specific steps of step S3 are as follows: after mixing the solvent raw materials, stir at 300-500 rpm for 4-5 minutes, add carbomer-940, and allow it to swell naturally for 24 hours to obtain the final product.

[0023] Preferably, the solvent raw material is glycerol, distilled water, and purified water in a volume ratio of (2-4):1:1.

[0024] Preferably, the solid-liquid ratio of the carbomer-940 and the solvent raw material is 1:(70-85).

[0025] The specific steps of step S4 are as follows: add naproxen choline and distilled water to the blank gel while stirring until the system is evenly dispersed.

[0026] Preferably, the amount of distilled water added is 75%-85% of the volume of distilled water in the blank gel.

[0027] In preparing naproxen-choline gel, reserving some distilled water and adding it along with naproxen-choline in step S4 reduces or eliminates the need for triethanolamine, resulting in a system pH of approximately 7.0. This improves the transdermal effect of naproxen while enhancing the safety of the gel. This is likely because in systems without ionic liquids, triethanolamine primarily prevents localized pH jumps that could lead to gel precipitation. The reserved distilled water allows for rapid and uniform dispersion of naproxen-choline, reducing precipitation and achieving a pH of around 7 even without added triethanolamine. This significantly improves safety and addresses the potential harm of triethanolamine to the human body. However, in systems with added ionic liquids, triethanolamine also has a neutralizing effect, so a suitable amount needs to be added to achieve the optimal transdermal pH. Overall, reducing the amount of triethanolamine added lowers the probability of skin irritation and improves the safety of the gel.

[0028] Preferably, the naproxen-choline gel contains 3.9%-4.1% naproxen by mass.

[0029] In some preferred embodiments, in step S4, after the system is evenly dispersed, an ionic liquid can be added, followed by the addition of triethanolamine to adjust the pH to 6.9-7.3.

[0030] In some preferred embodiments, after adding the ionic liquid, the quality of naproxencholine needs to be increased simultaneously to ensure that the mass fraction of naproxen in the final naproxencholine gel is 3.9%-4.1%.

[0031] Preferably, the molar ratio of naproxen choline to the ionic liquid is 1.59:1.

[0032] Preferably, the ionic liquid includes one or more of alkylimidazolium ionic liquids and lactic choline ionic liquids ([Lac][Ch]).

[0033] Preferably, the alkylimidazolium-type ionic liquid includes one or more of 1-ethyl-3-methylimidazolium bromide ([EMIM]Br), 1-butyl-3-methylimidazolium bromide ([BMIM]Br), 1-hexyl-3-methylimidazolium bromide ([HMIM]Br), and 1-octyl-3-methylimidazolium bromide ([OMIM]Br).

[0034] The specific steps for obtaining the lactic acid choline ionic liquid are as follows: Choline chloride and anhydrous ethanol are mixed and stirred at 800-1000 rpm until completely dissolved. Sodium lactate, along with choline chloride and other substances, is added. The mixture is stirred at 40°C for 4-5 hours, then filtered through a sintered glass funnel. The filtrate is collected and evaporated under reduced pressure at 55°C and -0.07 to -0.09 MPa to remove the solvent. Acetone is added, and the mixture is filtered again through a sintered glass funnel. The filtrate is collected and dried under reduced pressure at 45°C and -0.07 to -0.09 MPa to obtain a pale yellow oily substance. This substance is placed in a vacuum drying oven and dried under vacuum at 40°C and -0.08 to -0.09 MPa until constant weight is achieved, thus obtaining the lactic acid choline ionic liquid.

[0035] Preferably, the solid-liquid ratio of choline chloride to anhydrous ethanol is 1 g:(10-20) mL.

[0036] Preferably, the molar ratio of choline chloride to sodium lactate is 1:1.

[0037] Adding specific ionic liquids to standard naproxen choline gel can increase its permeability, thereby enhancing the transdermal effect of naproxen. This is likely because the specific ionic liquids enhance the interaction with the stratum corneum, promoting naproxen choline penetration and leading to a sharp increase in the transdermal rate. Simultaneously, the permeability increases almost linearly with prolonged transdermal time. This may be because the drug, under the influence of the ionic liquid, penetrates the dense stratum corneum, allowing naproxen to pass through the epidermis more smoothly and stably, while also increasing skin retention. Furthermore, the longer the alkyl chain of the alkylimidazolium-type ionic liquid, the greater the cumulative permeability of the ionic liquid gel, resulting in better transdermal efficacy. However, most alkylimidazolium-type ionic liquids exhibit varying degrees of biotoxicity, which may affect the safety of the ionic liquid gel. This application prepares a lactic acid choline ionic liquid, which has high biocompatibility, is green and non-toxic, and can replace azone and imidazole ionic liquids, reducing the toxic side effects caused by auxiliary ionic liquids. It is a better penetration enhancer and surfactant. At the same time, as the concentration gradient of lactic acid choline in the system increases, the porosity of the skin also increases significantly, improving the skin's porosity and thus increasing the permeability of naproxen.

[0038] Preferably, the mass fraction of naproxen in the bifunctional naproxen-choline gel is 2%-5%.

[0039] The bifunctional naproxen choline gel was prepared by the method described above.

[0040] Application of the bifunctional naproxen choline gel in the field of clinical pharmaceuticals.

[0041] Compared with the prior art, the advantages and beneficial effects of the present invention are as follows:

[0042] 1. This invention provides a bifunctional naproxen choline gel. Under the same drug loading conditions, the prepared naproxen choline gel exhibits superior transdermal effect and faster transdermal rate compared to the original naproxen gel. Adding an ionic liquid to the naproxen choline gel improves its permeability, and simultaneously synthesizes a green, low-toxicity lactic acid choline ionic liquid, which can significantly reduce toxic side effects and has greater application potential.

[0043] 2. The present invention prepares naproxen sodium salt in an alcohol system, which can improve the yield and purity of naproxen sodium salt.

[0044] 3. This invention improves the purity of naproxen choline by limiting the molar ratio of naproxen sodium salt and choline chloride.

[0045] 4. In preparing naproxen choline gel, this invention reserves some distilled water and adds it together with naproxen choline in step S4, which can reduce or even eliminate the need for triethanolamine, making the pH of the system approximately 7.0. This improves the transdermal effect of naproxen while enhancing the safety of the gel.

[0046] 5. This invention adds a specific ionic liquid to ordinary naproxen choline gel, which can increase the permeability of naproxen choline gel, thereby improving the transdermal effect of naproxen.

[0047] 6. This invention analyzes the transdermal gelation results of the 1-alkyl-3-methylimidazolium ionic liquid system and finds that as the alkyl chain of the side chain of the 1-alkyl-3-methylimidazolium bromide ionic liquid lengthens, the cumulative permeation at the same sampling point increases sequentially.

[0048] 7. This invention uses ionic liquids based on a lactic choline system to prepare the gel, providing a greener and safer skin penetration enhancement capability, reducing the toxic side effects caused by auxiliary ionic liquids, exhibiting high bioavailability, and with higher concentrations of lactic choline, stronger penetration enhancement capability, and increased cumulative penetration and skin retention, achieving optimal results at 5%. The naproxen-choline gel containing 5% lactic choline has significant research value and clinical significance. Attached Figure Description

[0049] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0050] Figure 1 This is a standard curve diagram of naproxen;

[0051] Figure 2 The Qt curves are for Control Example 1 (naproxen gel) and Example 1 (naproxen choline gel);

[0052] Figure 3 The Qt curves of naproxen choline gels from Examples 2-6 and Control Example 2 are shown.

[0053] Figure 4 Qt curves for Example 6 (naproxen-choline gel of lactic choline) with different concentration gradients;

[0054] Figure 5 HE staining images (40×) of rat skin of Control Example 1 (naproxen gel) and Example 1 (naproxen choline gel), where A is blank gel, B is Control Example 1, and C is Example 1;

[0055] Figure 6 HE staining images (40×) of rat skin in Examples 2-6 and Control Example 2, where A is blank gel, B is Control Example 2, and CG are Examples 2-6 respectively;

[0056] Figure 7 HE staining images (40×) of rat skin at different concentration gradients in Example 6, where A is blank gel, B is lactic choline with a mass fraction of 2.13%, C is lactic choline with a mass fraction of 3%, and D is lactic choline with a mass fraction of 5%. Detailed Implementation

[0057] The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0058] Preparation Example 1

[0059] The preparation method of naproxen sodium salt according to Preparation Example 1 is as follows: S1. Preparation of naproxen sodium salt: 3.9932g of sodium hydroxide and 50mL of anhydrous ethanol were mixed and stirred continuously at 900rpm until the sodium hydroxide was completely dissolved. Then, 22.3973g of naproxen was added in batches at 28℃ while stirring at 400rpm for 1h. The mixture was then filtered. The filter cake was washed with ethyl acetate. After filtration, the filter cake was collected to obtain crude naproxen sodium. The crude naproxen sodium was placed at 45℃ and -0.085MPa vacuum dried to constant weight to obtain naproxen sodium salt.

[0060] Preparation Example 2

[0061] The preparation method of naproxen sodium salt according to Preparation Example 2 is as follows:

[0062] The method of Preparation Example 1 is the same, except that anhydrous ethanol is replaced with distilled water.

[0063] Preparation Example 3

[0064] The preparation method of naproxencholine according to Preparation Example 1 is as follows: S2. Preparation of naproxencholine: 18.9046g of naproxen sodium salt prepared in Example 1 was mixed with 400mL of anhydrous ethanol and stirred at 900rpm until completely dissolved. Then, 10.4648g of choline chloride was added. After stirring at 37℃ and 900rpm for 12h, the mixture was naturally cooled to room temperature. The mixture was filtered through a sintered glass funnel, and the filtrate was collected. The anhydrous ethanol was removed by rotary evaporation under reduced pressure at 55℃ and -0.08MPa. Acetone was added, and the mixture was filtered again through a sintered glass funnel. The filtrate was collected. The collected filtrate was dried under reduced pressure at 45℃ and -0.08MPa to remove acetone, and a pale yellow oily substance was obtained. The substance was placed in a vacuum drying oven and dried under vacuum at 40℃ and -0.085MPa to constant weight to obtain naproxencholine.

[0065] Preparation Example 4

[0066] The preparation method of naproxen choline according to Preparation Example 4 is as follows:

[0067] The method of preparation example 3 is the same, except that the amount of choline chloride added is 8.3772 g, that is, the molar ratio of naproxen sodium salt to choline chloride is 5:4.

[0068] Performance Test 1: Purity and Yield Investigation of Naproxen Sodium Salt and Naproxencholine

[0069] The purity and yield of naproxen sodium salt prepared in Preparation Examples 1-2 were tested; the purity and yield of naproxen choline prepared in Preparation Examples 3-4 were tested, and the results are shown in Table 1.

[0070] Table 1 Purity and yield of naproxen choline

[0071] Naproxen sodium salt purity / % Naproxen sodium salt yield / % Naproxen choline purity / % Naproxen choline yield / % Preparation Example 1 99.3 91.2 - - Preparation Example 2 98.5 89.7 - - Preparation Example 3 - - 99.5 93.5 Preparation Example 4 - - 95.3 85.9

[0072] As can be seen from Table 1, by controlling the preparation solvent of naproxen sodium salt and limiting the molar ratio of naproxen sodium salt to choline chloride, the purity and yield of the prepared naproxen sodium and naproxen choline can be improved.

[0073] Examples 1-6

[0074] The formulations of naproxen choline gel according to Examples 1-6 are shown in Table 2.

[0075] Table 2. Naproxen-choline gel formulations from Examples 1-6

[0076]

[0077] The preparation method of the naproxen choline gel is as follows:

[0078] S3. Preparation of blank gel: Add 3.2 mL of glycerol, 10 mL of distilled water and 10 mL of purified water to a beaker, stir at 400 rpm for 4.5 min until the system is mixed and transparent; slowly add carbomer-940 to the above system and allow it to swell naturally for 24 h to obtain the blank gel.

[0079] S4. Preparation of naproxen choline gel: Add naproxen choline and 8 mL of distilled water to the blank gel while stirring until the system is evenly dispersed. Then add the ionic liquid and triethanolamine (in Example 1, the ionic liquid and triethanolamine do not need to be added).

[0080] The preparation method of [Lac][Ch] is as follows: 15.0247g of choline chloride and anhydrous ethanol are mixed and stirred at 900rpm until completely dissolved. Then, 11.6644g of sodium lactate is added and stirred at 40℃ until the layers are separated. The mixture is filtered through a sintered funnel, and the filtrate is collected. The solvent is removed by rotary evaporation under reduced pressure at 55℃ and -0.08MPa. An appropriate amount of acetone is added, and the mixture is filtered again through a sintered funnel. The filtrate is collected to remove residual sodium chloride. The collected filtrate is dried under reduced pressure at 45℃ and -0.08MPa to obtain a pale yellow oily substance. The substance is placed in a vacuum drying oven and dried under vacuum at 40℃ and -0.085MPa to constant weight to obtain lactic choline ionic liquid ([Lac][Ch]).

[0081] Comparative Example 1-Comparative Example 2

[0082] The formulations of naproxen gel based on Comparative Examples 1-2 are shown in Table 3.

[0083] Table 3 Naproxen Gel Formulation

[0084]

[0085] The preparation method of naproxen gel in Comparative Example 1 is as follows:

[0086] S3. Preparation of blank gel: Add 3.2 mL of glycerol, 10 mL of distilled water and 10 mL of purified water to a beaker, stir at 400 rpm for 4.5 min until the system is mixed and transparent; slowly add carbomer-940 to the above system and allow it to swell naturally for 24 h to obtain the blank gel.

[0087] S4. Preparation of naproxen gel: Add naproxen and 8 mL of distilled water to the blank gel while stirring. Then, add triethanolamine dropwise to the system (0.1 mL each time) and stir the gel thoroughly until the system is uniformly dispersed and stable.

[0088] The preparation method of naproxen gel in Comparative Example 2 is as follows:

[0089] The method is the same as in Comparative Example 1, except that: S4, preparation of naproxen gel: add naproxen and 8 mL of distilled water to the blank gel and disperse evenly, add laurocapram while stirring, then add triethanolamine dropwise to the system (0.1 mL each time), and then stir the gel thoroughly until the system is uniformly dispersed and stable.

[0090] Performance Test 2: Analysis of the transdermal properties of the prepared naproxen-choline gel and naproxen gel.

[0091] 1. Experimental Section

[0092] 1.1 Preparation of naproxen standard solution

[0093] Accurately weigh 12.5 mg of naproxen reference standard, place it in a 25 mL volumetric flask, dissolve and dilute to the mark with methanol, and shake well to prepare the naproxen reference standard stock solution (0.5 mg / mL). -1 Accurately pipette 12, 120, 240, 600, 1200, 3600, 4800, 6000, 8000, and 10000 μL of the reference stock solution into 10 mL volumetric flasks, and dissolve in methanol to prepare concentrations of 0.6, 6, 12, 30, 60, 180, 240, 300, 400, and 500 μg·mL, respectively. -1 Naproxen standard solution.

[0094] 1.2 Preparation of Sample Solution

[0095] 1.2.1 Preparation of isolated mouse skin

[0096] Take approximately 240g of SD rats, euthanize them by intoxication with ether, carefully remove the abdominal hair with a razor, peel off the entire abdominal skin, remove the fat, mucous membrane and tissue on the back of the skin, put it into the prepared physiological saline, wash it carefully and repeatedly, and keep it in physiological saline for later use.

[0097] 1.2.2 Preparation of the test solution

[0098] Take the rat skin that has been processed as described in 1.2.1, fix it on the transdermal diffusion apparatus, and place the rat skin in the diffusion chamber (diffusion area of ​​2.8 cm²). 2A PBS buffer solution was poured into the receiving cell between the stratum corneum and the diffusion cell, with the stratum corneum facing the diffusion cell. A small magnetic dot was placed inside the receiving cell, and 1.0 g of gel was spread onto the skin surface. The receiving cell was covered with plastic wrap to prevent external contamination of the gel. Small holes were pricked in the plastic wrap with a needle to prevent problems such as excessive pressure inside the system that could prevent sampling or the formation of air bubbles. The mixture was stirred at (37±1)℃ at 1000 rpm. Following a time gradient of 1, 2, 4, 6, 8, 10, 12, 20, and 24 h, 0.2 mL of PBS solution was transferred to the tissue culture plate each time, and the absorbance of the sample was immediately measured at 331 nm using a microplate reader. After each aspiration, an equal volume (0.2 mL) of PBS buffer was added to the system.

[0099] 1.2.3 Skin Retention Volume Q S Measurement

[0100] Prepare 50% anhydrous ethanol. Remove rat skin from the transdermal test. Use a cotton swab dipped in 50% anhydrous ethanol to wipe away any remaining gel inside and outside the skin. Remove excess skin around the skin with scissors. Cut the rat skin in half along the midline. Grind one half into small pieces and place it in a 10mL centrifuge tube. Soak in 10mL methanol for 8 hours, then sonicate for 30 minutes. Centrifuge at 9000rpm for 15 minutes. Transfer the supernatant to a 25mL volumetric flask. Add 5mL methanol to the same centrifuge tube, sonicate for 30 minutes, then centrifuge at 9000rpm for 15 minutes. Transfer the supernatant to a 25mL volumetric flask, then dilute to volume with methanol and filter through a 0.45μm filter membrane.

[0101] 1.3 HE staining treatment

[0102] The remaining half of the rat skin from step 1.2.3 was rinsed with physiological saline, preserved in polyoxymethylene tissue fixative, stained with hematoxylin and eosin (HE), and observed under an optical microscope to study the effects of different formulations of naproxen gel and naproxen-choline gel on the pathology of rat abdominal skin.

[0103] 2 Results and Discussion

[0104] 2.1 Examination of Linear Range

[0105] Take the 1.1 series of standard solutions and use an ELISA reader at λ = 331 nm and 25℃. Plot A as the ordinate and calculate the mass concentration (c, μg·mL). -1 Plot a graph with the x-axis as the horizontal axis, see... Figure 1 .from Figure 1 The linear equation for the standard curve was obtained as: A = 0.00458c + 0.26377 (r = 0.9995). This indicates that the naproxen standard solution exhibits good linearity within the range of 0.6-500 μg / mL.

[0106] 2.2 Transdermal analysis of naproxen gels

[0107] 2.2.1 Analysis of cumulative transdermal absorption

[0108] The transdermal permeability of naproxen gel, naproxen-choline gel, and naproxen-choline-ionic liquid gel was studied using cumulative permeation, expressed as Q in μg·cm³. -2 The formula for calculating Q is as follows: Formula (1).

[0109]

[0110] In the formula: A is the area of ​​the diffusion cell, 2.8 cm². 2 ;8 indicates the volume of the receiving pool, mL; c n The concentration at the nth sampling point is in μg·mL. -1 ; 0.2 indicates the sample volume per time, in mL.

[0111] Plot the cumulative permeation curve Qt with time t on the x-axis and Q on the y-axis. The steady-state permeation rate J is... s (μg·cm -2 ·h -1 ) is the slope of the cumulative permeation curve of Qt.

[0112] 2.2.2 Transdermal analysis of naproxen gel (Control Example 1) and naproxen-choline gel (Example 1)

[0113] Based on the absorbance of the absorbent solution at different time points obtained by the ELISA reader, the concentration c of the transdermal solution at different sampling points was calculated using the linear equation A = 0.00458c + 0.26377 (r = 0.9995). Then, the cumulative permeation Q was calculated using formula (1). The results of the transdermal experiments of naproxen choline gel containing different ionic liquids are shown in Tables 4-5. Figure 2 .

[0114] Table 4. Cumulative permeation of naproxen agglutination and naproxen choline gel ( n=3)

[0115]

[0116] Table 5 Transdermal absorption capacity of naproxen gel and naproxen choline gel ( n=3)

[0117]

[0118] From Table 4, Figure 2It is evident that the cumulative penetration of both Control Example 1 and Example 1 increases continuously with time t, indicating that naproxen continues to penetrate the skin with both gels over time. However, the cumulative penetration capacity of Example 1 is significantly superior to that of Control Example 1. This conclusion is consistent with the results presented by the Qt equation in Table 5; the greater the mass, the higher the slope (J) of this equation. s The larger the value, the greater the penetration rate and the better the transdermal effect.

[0119] Depend on Figure 2 It can be seen that after the mass of Example 1 exceeds a certain level, the transdermal rate (J) s The transdermal activity of Control Example 1 and Example 1 changed drastically in the first 12 hours. It is possible that in the first 12 hours, the effects of Control Example 1 and Example 1 on the skin were similar, so their transdermal activity was very similar.

[0120] Starting from the 12th hour, the cumulative penetration amount of Example 1 began to increase significantly, gradually widening the gap with Control Example 1. This may be because the ionic liquid enhances the effect on the stratum corneum of the skin, thereby promoting the penetration of naproxen choline and leading to a sharp increase in the transdermal rate. As the transdermal time increases, the linearity in the graph becomes increasingly better. This may be because the drug, under the action of the ionic liquid, breaks through the dense stratum corneum, allowing naproxen to penetrate the epidermis more smoothly and resulting in more stable transdermal penetration.

[0121] 2.2.3 Transdermal analysis of naproxen-choline gels containing different ionic liquids (Preparation Examples 6-10)

[0122] Based on the absorbance of the absorbent solution at different time points obtained by the ELISA reader, the concentration c of the transdermal solution at different sampling points was calculated using the linear equation A = 0.00458c + 0.26377 (r = 0.9995). Then, the cumulative permeation Q was calculated using equation (1). The data were processed to obtain the transdermal experimental results of naproxen choline gel containing different ionic liquids, as shown in Tables 6-7. Figure 3 The table uses Control Example 2 as a comparison.

[0123] Table 6. Cumulative permeation of naproxen choline gel with different ionic liquids ( n=3)

[0124]

[0125] Note: u represents the uncertainty.

[0126] Table 7. Transdermal permeability of naproxen choline gel with different ionic liquids ( n=3)

[0127]

[0128] From Tables 6-7, Figure 3It can be seen that the cumulative permeation of naproxen choline gels containing different ionic liquids increases continuously with time, and the cumulative permeation curves of Qt show good linearity (r is greater than 0.99 for all). As can be seen from Tables 6-7, the cumulative permeation of the naproxen choline gel in the [Lac][Ch] system (Example 6) is close to that of the naproxen gel in the azone system (Control Example 2). Compared with the transdermal permeability of the naproxen choline gel in the ionic liquid system, the cumulative permeation of the [Lac][Ch] system in Manufacturing Example 10 is in the middle.

[0129] As can be seen from Table 7, with the elongation of the alkyl chain in the 1-alkyl-3-methylimidazolium bromide ionic liquid, the slope of the Qt equation (J) increases. s The larger the number of molecules, the greater the penetration rate and the better the transdermal effect; naproxen choline gel in ionic liquid systems, J s The order of their sizes is [OMIM]Br > [HMIM]Br > laurocapram > [Lac][Ch] > [BMIM]Br > [EMIM]Br.

[0130] However, improper use of azone or in individuals with specific health conditions may lead to risks such as skin irritation, allergic reactions, and mucosal damage. Multiple studies have shown that most alkylimidazolium-based ionic liquids exhibit varying degrees of biotoxicity, further exacerbating concerns about their safety. Lactocholine, on the other hand, is biocompatible and possesses green and non-toxic properties. Therefore, lactocholine can serve as a superior alternative to azone and imidazolium-based ionic liquids as a penetration enhancer and surfactant.

[0131] 2.2.4 Cumulative permeation of naproxen-choline gels with different concentration gradients of lactic choline (Example 6)

[0132] Based on the absorbance of each group of transdermal absorption obtained by the ELISA reader, the concentration c was calculated by obtaining the linear equation A = 0.00458c + 0.26377 (r = 0.9995) from the standard curve. Then, the cumulative permeation Q was calculated by formula (1). The cumulative permeation of naproxen choline gel containing different concentration gradients of lactic choline was obtained, as shown in Tables 8-9. Figure 4 .

[0133] Table 8. Cumulative permeation of naproxen choline gel with different concentration gradients of lactic choline ( n=3)

[0134]

[0135] Table 9. Transdermal permeability of naproxen-choline gels containing different concentration gradients of lactic choline (n=3)

[0136]

[0137] From Tables 8-9, Figure 4 It can be seen that the cumulative permeation of naproxen-choline gels with different concentration gradients of lactic choline increases continuously with time, with a more rapid increase in the first 8 hours followed by a slower increase after 8 hours. This phenomenon may be related to the concentration difference across the skin; a larger concentration difference results in greater osmotic pressure and therefore a faster permeation rate. Before 8 hours, the concentration difference across the skin was significant. After 8 hours, the lactic choline in the skin and PBS buffer gradually approached saturation, causing the concentration difference to decrease, thus significantly reducing the permeation rate after 8 hours. Higher concentrations of lactic choline resulted in a more rapid transdermal permeation rate. Figure 4 (Table 8), this result is consistent with the result presented by the Qt equation (Table 9). The greater the mass, the steeper the slope of this equation (J). s The larger the value, the greater the penetration rate and the better the transdermal effect.

[0138] from Figure 4 It can be seen that the transdermal differences between naproxen choline gels with a [Lac][Ch] concentration of 2.13% and 3.0% are relatively small. However, the naproxen choline gel with a [Lac][Ch] concentration of 5% shows significant differences compared to both the gels with [Lac][Ch] concentrations of 2.13% and 3.0%, with a marked increase in permeation volume and rate over 5-12 hours. This may be because the 5.0% [Lac][Ch] concentration has a stronger effect on the skin, facilitating naproxen penetration.

[0139] Table 9 shows that, comparing naproxen choline gels with a [Lac][Ch] mass concentration of 2.13%, 3.0%, and 5%, the steady-state permeation rate J... s The differences were not significant, but the linearity of the gel Qt curve for naproxen and choline with a [Lac][Ch] mass concentration of 5% was not good. Figure 4 The analysis results showed that naproxen choline gel with a [Lac][Ch] mass concentration of 5% [Lac][Ch] could improve the permeability of naproxen.

[0140] 2.2.5 Skin Retention Volume Q S analyze

[0141] The absorbance of the skin retention sample solution obtained in 1.2.3 was measured at λ = 331 nm and 25 °C. The obtained data was then used to calculate the naproxen concentration (c) using the linear equation in 2.1, and finally the skin retention Q was calculated. S The calculation formula is shown in formula (2).

[0142] m = c × v (2)

[0143] Where: c, μg·mL -1 v, 25.00 mL; m, μg.

[0144] m is calculated according to equation (2), and m is the skin retention amount Q. S The results are shown in Tables 10-12.

[0145] Table 10. Retention analysis of naproxen gels

[0146]

[0147] Table 11 Retention analysis of naproxen-choline gels containing different ionic liquids

[0148]

[0149] Table 12 Retention analysis of naproxen-choline gels containing different concentration gradients of lactic choline

[0150]

[0151] Table 10 shows that the skin retention of naproxen choline gel is superior to that of naproxen gel. Combined with the transdermal analysis results in section 2.2.2, the transdermal effect of naproxen choline gel is also better than that of naproxen gel. This is because naproxen choline is a functional ionic liquid, possessing all the properties of ionic liquids, such as good surface activity and permeability enhancement. Therefore, naproxen choline not only has the effects of a drug but also acts as a good permeation enhancer.

[0152] As shown in Table 11, the skin retention of [Lac][Ch]-naproxen choline gel is greater than that of naproxen choline gel containing azone, and the difference in skin retention between [Lac][Ch]-naproxen choline gel and [RMIM]Br-naproxen choline gel is small. Combining the transdermal analysis results in section 2.2.3, the toxicity of [RMIM]Br, azone, and [Lac][Ch], [Lac][Ch] can be used as the best auxiliary ionic liquid to promote the penetration of naproxen in naproxen choline gel into the skin.

[0153] As shown in Table 12, with the increase of the mass of [Lac][Ch] added to the naproxen choline gel, the amount retained in the skin also increases. Combined with the transdermal analysis results in section 2.2.4, it can be seen that with the increase of the mass of [Lac][Ch], the permeation-enhancing ability of [Lac][Ch] is improved, which gradually increases the transdermal permeability of naproxen in the naproxen choline gel. When the amount of [Lac][Ch] added reaches 5.0%, the permeation and skin retention of naproxen reach the optimal levels.

[0154] 2.3 Analysis of the transdermal mechanism of naproxen gel

[0155] The skin has a unique structure, consisting of a hydrophobic stratum corneum (SC) rich in various lipids and hydrophilic regions. Only drugs with suitable solubility in both the oil and aqueous phases can penetrate the skin and enter the systemic circulation. The stratum corneum not only effectively slows down the loss of water from the body but also hinders the permeation of most topical drugs, serving as a key rate-limiting barrier in transdermal drug delivery. The presence or absence of structural or functional changes in the stratum corneum can be used to assess transdermal drug penetration. HE staining was performed on the mouse skin samples processed and preserved in section 1.3; the HE staining results are shown below. Figures 5-7 .

[0156] 2.3.1 Analysis of the transdermal mechanism of naproxen gel and naproxen-choline gel

[0157] Depend on Figure 5 It can be seen that the stratum corneum of the control group was almost unaffected and remained very tight. Both naproxen gel and naproxen-choline gel had some effect on the skin, making the stratum corneum looser. Naproxen-choline gel had a stronger loosening effect on the skin than naproxen gel, making the stratum corneum more porous and increasing the permeability of naproxen. This may be because ionic liquids (ILs), as cationic surfactants, interfere with the lipid bilayer and hydrophobic tails through the fluidization process of lipids, thus making the skin looser.

[0158] 2.3.2 Analysis of the transdermal mechanism of naproxen-choline gel containing different ionic liquids

[0159] Depend on Figure 6It can be seen that the stratum corneum of the skin in the control group was almost unaffected and remained very tight; all six ionic liquids had a strong effect on the skin, making it more porous to varying degrees. 1-alkyl-3-methylimidazolium bromide ionic liquids exhibited strong skin-poring ability and good porosity, which is beneficial to the permeability of naproxen. [Lac][Ch] showed weaker skin-poring ability compared to 1-alkyl-3-methylimidazolium bromide ionic liquids, but slightly stronger than azone. Combining the analytical results of 2.2.2 and 2.2.5 with the toxicity of azone and 1-alkyl-3-methylimidazolium bromide ionic liquids, lactic acid choline, due to its green and non-toxic properties and its skin-poring effect as a penetration enhancer, can promote the permeability of naproxen and improve its safety, thus holding significant research potential.

[0160] 2.3.3 Analysis of the transdermal mechanism of naproxen-choline gel containing different concentration gradients of lactate choline

[0161] Based on the analysis of the HE staining results in section 2.3.2, HE staining was performed on mouse skin after transdermal administration of naproxen choline gel containing different concentration gradients of lactate choline, as per procedure 1.3. The HE staining results are shown in [Figure 1]. Figure 7 .Depend on Figure 7 It can be seen that as the concentration gradient of lactic acid choline increases, the skin's porosity also increases significantly, with 5% lactic acid choline showing the best effect and the best degree of dispersion.

[0162] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. A process for the preparation of a bifunctional type of naproxen choline gel, characterized by, It comprises the following steps: S1. Preparation of naproxen sodium salt; S2. Preparation of naproxen choline; S3. Preparation of blank gel; S4. Preparation of naproxen choline gel; The specific steps of the step S1 are: after mixing and stirring sodium hydroxide and anhydrous ethanol to dissolve, adding naproxen, stirring while adding, until solid is generated; suction filtration, purification with ethyl acetate, collecting the filter cake, to obtain crude naproxen sodium; vacuum drying the crude naproxen sodium to constant weight, to obtain naproxen sodium salt.

2. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 1, wherein, The solid-liquid ratio of the sodium hydroxide and anhydrous ethanol is 1g: (10-15) mL.

3. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 2, wherein, The molar ratio of the naproxen and sodium hydroxide is 1: (1-1.1).

4. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 1, wherein, The specific steps of the step S2 are: after mixing and stirring choline chloride and anhydrous ethanol to dissolve, adding naproxen sodium salt, stirring and naturally cooling to room temperature, filtering to collect the filtrate, adding acetone after removing anhydrous ethanol by rotary evaporation under reduced pressure, filtering to collect the filtrate, removing residual sodium chloride; drying the collected filtrate under reduced pressure to remove acetone, to obtain light yellow oily material, vacuum drying to constant weight, to obtain naproxen choline.

5. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 4, wherein, The mass ratio of the naproxen sodium salt and choline chloride is 1:

1.

6. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 1, wherein, The specific steps of the step S3 are: after mixing solvent raw materials, stirring at 300-500 rpm for 4-5 min, slowly adding carbomer-940, naturally swelling for 24 h, to obtain the blank gel.

7. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 6, wherein, The solvent raw materials are glycerol, distilled water and pure water, with a volume ratio of (2-4):1:

1.

8. The process for the preparation of bifunctional type naproxen choline gel as claimed in claim 1, wherein, The specific steps of the step S4 are: adding naproxen choline and distilled water to the blank gel, stirring while adding, until the system is uniformly dispersed.

9. A bifunctional naproxen choline gel prepared by the preparation method of the bifunctional naproxen choline gel according to any one of claims 1-8.

10. Use of the bifunctional naproxen choline gel according to claim 9 in the field of clinical drugs.

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