A photo-glycyrrhizin salicylate and application thereof
By synthesizing glycyrrhizin salicylate via covalent bonding, the stability and irritation issues of the combination of glycyrrhizin and salicylic acid were resolved, achieving highly effective whitening and antioxidant effects in skin care products, and making it suitable for a variety of skin care products.
Patent Information
- Application Number
- CN202610168269.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-02-05
- Publication Date
- 2026-06-26
AI Technical Summary
The physical combination of glycyrrhizin and salicylic acid has problems such as poor stability, high irritation and poor synergistic effect, and cannot achieve the synergistic effect of whitening and keratin metabolism.
By covalently combining glycyrrhizin and salicylic acid to form glycyrrhizin salicylate, the instability of glycyrrhizin is solved, and the strong acidity of salicylic acid is masked, thus achieving the synergistic effect of the active molecules.
Glycyrrhizin salicylate has significantly improved light and heat stability and reduced skin irritation, achieving synergistic effects of whitening, anti-oxidation, anti-inflammation and keratin regulation, and is suitable for a variety of skin care products.
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Abstract
Description
Technical Field
[0001] This invention relates to the fields of cosmetics and pharmaceutical chemistry, specifically to a glycyrrhizin salicylate and its applications. Background Technology
[0002] In the fields of skin whitening and problem skin care, achieving multi-target high-efficiency effects while maintaining good safety has always been a goal pursued by researchers. Glycyrrhizin, a precious flavonoid compound extracted from licorice root, is hailed as "whitening gold" due to its highly effective inhibition of tyrosinase activity. Its outstanding whitening effect, combined with antioxidant and anti-inflammatory properties, makes it highly sought after in high-end skincare products. However, the inherent molecular structure of glycyrrhizin presents significant application bottlenecks: First, its chemical stability is poor, making it sensitive to light, heat, and oxygen. It is prone to discoloration and inactivation during formulation and storage, affecting not only the product's appearance and shelf life but also significantly reducing its actual efficacy. Second, its high production cost, often requiring a high concentration in formulations to ensure effectiveness, further increases the product's cost burden.
[0003] On the other hand, salicylic acid, as a classic active skin ingredient, is remarkably effective in improving acne, pimples, and dull skin tone. Its exfoliating properties effectively unclog pores and promote the shedding of melanin-containing keratinocytes, thus aiding in skin whitening. However, salicylic acid's strong acidity is an unavoidable drawback, easily damaging the skin barrier and causing problems such as dryness, flaking, stinging, and redness, deterring many people with sensitive skin. Furthermore, salicylic acid has limited solubility in oil-based formulations, which to some extent restricts the diversification of its dosage forms.
[0004] Currently, in pursuit of synergistic effects between whitening and keratin metabolism, the industry commonly employs a simple physical combination strategy of glycyrrhizin and salicylic acid. However, this simple mixing not only fails to overcome their respective drawbacks but may also introduce new problems. In the same formulation system, the acidic environment created by salicylic acid may accelerate the chemical degradation of unstable glycyrrhizin, while the oxidation products of glycyrrhizin may also affect the stability of the system. More importantly, the irritant risks of both may have a cumulative effect, resulting in poor overall tolerability of the formulation. This simple physical combination cannot fundamentally achieve synergistic efficacy or complementary deficiencies.
[0005] Therefore, there is an urgent need to provide a new technical solution that organically combines the advantages of glycyrrhizin and salicylic acid, while avoiding the defects of the combination of glycyrrhizin and salicylic acid, such as poor stability, high irritation, limited dosage form and poor synergistic effect. Summary of the Invention
[0006] To address the aforementioned problems in the existing technology, this application provides a glycyrrhizin salicylate ester and its application, which combines two active molecules into one through covalent bonds. This prodrug design fundamentally solves the defects of poor stability, high irritation, and poor synergistic efficacy when glycyrrhizin and salicylic acid are physically combined.
[0007] To address the above problems, the present invention provides the following technical solution: In a first aspect, this application provides a glycyrrhizin salicylate ester, the structural formula of which is shown in Formula I: .
[0008] Secondly, this application provides a method for preparing glycyrrhizin salicylate, the synthetic route of which is as follows: .
[0009] In one embodiment of this application, glycyrrhizin and salicylic acid are used as starting materials, and glycyrrhizin salicylate is obtained by dehydration ester condensation.
[0010] In one embodiment of this application, the esterification reaction is carried out in the presence of an organic solvent, a dehydrating agent, and a catalyst.
[0011] In one embodiment of this application, the dehydrating agent may be selected from N,N'-dicyclohexylcarbodiimide.
[0012] In one embodiment of this application, the catalyst may be selected from 4-dimethylaminopyridine.
[0013] In one embodiment of this application, salicylic acid and dichloromethane are added to a reaction flask, followed by the addition of N,N'-dicyclohexylcarbodiimide and 4-dimethylaminopyridine, and then glycyrrhizin is added. The reaction is monitored by TLC until the reactants are completely reacted. The reaction is then quenched with saturated ammonium chloride, extracted with dichloromethane, concentrated, and then obtained by column chromatography as glycyrrhizin salicylate.
[0014] In one embodiment of this application, the molar ratio of salicylic acid to glycyrrhizin is 2-4:1.
[0015] In one embodiment of this application, the molar ratio of salicylic acid to glycyrrhizin is 3:1.
[0016] In one embodiment of this application, the molar ratio of the dehydrating agent to glycyrrhizin is 3.5-4:1.
[0017] In one embodiment of this application, the molar ratio of the catalyst to glycyrrhizin is 0.2-0.3:1.
[0018] In one embodiment of this application, the molar ratio of the catalyst to glycyrrhizin is 0.25:1.
[0019] Thirdly, a composition comprising at least glycyrrhizin salicylate or a pharmaceutically acceptable salt thereof, and a dermatologically or pharmaceutically acceptable excipient or carrier.
[0020] In one embodiment of this application, the composition includes a skin care composition and a pharmaceutical composition.
[0021] In one embodiment of this application, the composition may be formulated as a topical dosage form.
[0022] In one embodiment of this application, the topical dosage form includes cream, lotion, gel, serum, solution, ointment, mask, or patch.
[0023] In one embodiment of this application, the mass percentage of glycyrrhizin salicylate in the composition is 0.000001%-20%.
[0024] In one embodiment of this application, the mass percentage of glycyrrhizin salicylate in the composition is 0.0001%-1%.
[0025] In one embodiment of this application, the mass percentage of glycyrrhizin salicylate in the composition is 0.001%-0.1%.
[0026] In one embodiment of this application, the mass percentage of glycyrrhizin salicylate in the composition is 0.001%-0.01%.
[0027] In one embodiment of this application, the application of glycyrrhizin salicylate as an active ingredient in the preparation of daily chemical products includes: (1) Prepare daily chemical products with whitening effects; (2) Prepare daily chemical products with spot-fading effects; (3) Prepare daily chemical products with anti-aging effects; (4) Prepare daily chemical products with anti-photoaging effects; (5) Prepare daily chemical products with anti-inflammatory and soothing effects; (6) To prepare daily chemical products with anti-acne effects; and / or, (7) Prepare daily chemical products with antioxidant effects.
[0028] Fifthly, the application of glycyrrhizin salicylate as an active ingredient in the preparation of drugs that improve skin or repair the skin barrier.
[0029] Compared with the prior art, the present invention has the following beneficial effects: (1) The glycyrrhizin salicylate of this application uses glycyrrhizin and salicylic acid as starting materials, and combines the two active molecules into one through covalent bonds, which fundamentally solves the inherent instability problem of glycyrrhizin and greatly improves its tolerance to light and heat. At the same time, the structure cleverly masks the strong acidic carboxyl group of salicylic acid, which significantly reduces the skin irritation of the final product, making it much milder than physical mixtures, more tolerable, and suitable for a wider range of skin types.
[0030] (2) Compared with the physical mixture of glycyrrhizin and salicylic acid, the glycyrrhizin salicylate obtained by dehydration ester condensation in this application achieves a true synergistic effect in terms of efficacy: after the compound is absorbed through the skin, it can be decomposed by enzymes in the skin to release the original drug, thereby achieving precise synchronization of glycyrrhizin (inhibiting melanin production from the source) and salicylic acid (promoting the exfoliation of pigmented keratin) in terms of action time and space, producing a superior whitening and skin-renewing effect of "1+1>2".
[0031] (3) The glycyrrhizin salicylate of this application organically combines the advantages of glycyrrhizin and salicylic acid, possessing both the excellent whitening and antioxidant effects of glycyrrhizin and the excellent keratin regulation and anti-inflammatory capabilities of salicylic acid. It has broad application prospects in the preparation of topical products for skin whitening, spot fading, anti-inflammation, anti-acne and anti-photoaging. Detailed Implementation
[0032] The technical solutions in the embodiments of this application will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of this application, and not all embodiments.
[0033] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of the particular range. The range defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range.
[0034] Unless otherwise stated, when this invention relates to percentages between liquids, it is volume / volume percentage; when this invention relates to percentages between liquids and solids, it is volume / weight percentage; when this invention relates to percentages between solids and liquids, it is weight / volume percentage; the rest are weight / weight percentage.
[0035] For experimental methods in the following examples where specific conditions are not specified, follow conventional methods and conditions, or select according to the product instructions.
[0036] Example 1 Synthesis of glycyrrhizin salicylate .
[0037] At 20-30℃, salicylic acid (1.278 g) and dichloromethane (10.0 mL) were added to a reaction flask, followed by N,N'-dicyclohexylcarbodiimide (2.416 g) and 4-dimethylaminopyridine (0.096 g), and then glycyrrhizin (1.000 g). The mixture was stirred for 24.0 hours, and the reaction was confirmed to be complete by TLC. The reaction was quenched by adding saturated ammonium chloride (5.0 mL), and the mixture was extracted three times with dichloromethane (10.0 mL × 3). The organic phases were combined and concentrated under reduced pressure at 40-45℃ until no fraction remained. Column chromatography yielded 1.446 g of glycyrrhizin salicylate, with a yield of 83%. 1 H NMR (400 MHz, DMSO) δ 7.98 (dd, J = 8.0,1.6 Hz, 2H), 7.41 – 7.52 (m, 2H), 7.21 (dd, J = 8.7, 0.7 Hz, 1H), 7.07 – 6.89(m, 7H), 6.67 (d, J = 10.1 Hz, 1H), 6.46 (d, J = 8.2 Hz, 1H), 5.51 – 5.62 (m,1H), 4.37 (dd, J = 11.1, 5.0 Hz, 1H), 4.11 (dd, J = 11.1, 5.0 Hz, 1H), 3.59 –3.49 (m, 1H), 3.07 –3.17 (m, 1H), 2.87 –2.99 (m, 1H), 1.48 (d, J = 1.0 Hz,6H). ESI-MS: m / z 565.2 [M+H] + .
[0038] Example 2: Stability test of glycyrrhizin salicylate Light stability test: Glycyrrhizin salicylate and methanol solutions of glycyrrhizin (both at a concentration of 100 μg / mL) were placed in a light chamber and continuously irradiated at an illuminance of 4500 Lux for 5 days. Samples were taken on days 1, 3, and 5, and the remaining percentage of each main component was determined by high performance liquid chromatography (HPLC). The content of the sample without irradiation on day 0 was used as a baseline of 100%.
[0039] Thermal stability test: Glycyrrhizin salicylate and glycyrrhizin solid powder were placed in a constant temperature oven at 40°C for an accelerated test for 4 weeks. Samples were taken at weeks 1, 2 and 4, and after dissolution, the remaining percentage of each main component was determined by HPLC. The content of the sample at week 0 (without heating) was used as 100% baseline for calculation.
[0040] The results of the light stability test of glycyrrhizin salicylate are shown in Table 1.
[0041] Table 1 ; The results of the thermal stability test of glycyrrhizin salicylate are shown in Table 2.
[0042] Table 2 ; Example 3 Cytotoxicity test of glycyrrhizin salicylate HaCat cells were used in the experiment. Cells were removed from liquid nitrogen, revived, and passaged 2-3 times until good cell viability was achieved. Then, they were injected with 5 × 10⁻⁶ cells / mL. 4 Cells were seeded at a density of 100 μL / mL in 96-well plates. After 24 hours, the cells adhered, the old culture medium was discarded, fresh PBS was added, and the cells were cultured for another 24 hours. Then, 100 μL of MTT (0.5 mg / mL, diluted in basal culture medium) was added to each well, the cells were wrapped in aluminum foil, and incubated in an incubator for 4 hours. The supernatant was discarded, 100 μL of DMSO was added to each well, and the plates were shaken for 10 min. The absorbance was measured at 570 nm using a microplate reader, and the cell viability was calculated. The experimental results are shown in Table 3.
[0043] Table 3 ; Example 4: Antioxidant Activity Test of Glycyrrhizin Salicylate The antioxidant capacity of glycyrrhizin salicylate was evaluated using a H2O2-induced oxidative damage model of HaCaT cells. HaCaT cells in logarithmic growth phase were divided into groups of 8 × 10⁻⁶ cells. 3Cells were seeded at a density of 100 μL per well in 96-well plates. After 24 hours of culture until complete cell adhesion, the medium was replaced with a solution containing 20 μg / mL glycyrrhizin salicylate (diluted with DMEM), and cultured for another 24 hours. The medium was then discarded, and 100 μL of H2O2 solution diluted to 800 μM with DMEM was added to each well. The plates were incubated for 4 hours to establish oxidative damage. The model included a blank control group without H2O2 damage, a hydrogen peroxide model group without drug administration, a control group with glycyrrhizin, and a control group with a physical mixture of glycyrrhizin and salicylic acid. Immediately after the treatment, cell viability was assessed using the CCK-8 assay to evaluate the cellular antioxidant capacity of glycyrrhizin salicylate.
[0044] Example 5: Anti-inflammatory activity test of glycyrrhizin salicylate The anti-inflammatory effect was evaluated using an LPS-induced inflammation model in RAW264.7 cells. Logarithmically growing RAW264.7 cells were harvested and treated at a concentration of 2.5 × 10⁻⁶ cells. 5 Cells were seeded at a density of 0.5 mL / well in 24-well plates and incubated for 24 hours. The supernatant was then discarded, and the following groups were established: solvent control group (DMEM medium), LPS inflammation model group (1 μg / mL LPS), glycyrrhizin-salicylate experimental group (1 μg / mL LPS + 20 μg / mL glycyrrhizin-salicylate), glycyrrhizin control group (1 μg / mL LPS + 20 μg / mL glycyrrhizin), and control group for a physical mixture of glycyrrhizin and salicylic acid (1 μg / mL LPS + 20 μg / mL physical mixture of glycyrrhizin and salicylic acid). All groups were treated for 24 hours. After treatment, the cell supernatant was collected, centrifuged at 1000 r / min for 5 minutes, and the supernatant was used to detect changes in inflammatory factors in the supernatant using a TNF-α and IL-6 inflammatory factor assay kit. The detection method strictly followed the instructions on the assay kit.
[0045] Example 6: Whitening effect test of glycyrrhizin salicylate The inhibitory effect of glycyrrhizin salicylate on tyrosinase was evaluated using an in vitro enzyme reaction system. In a 96-well plate, 80 μL of PBS buffer (pH 6.8), 40 μL of sample diluents at different concentrations, 40 μL of tyrosinase solution, and 80 μL of L-tyrosine substrate solution were added sequentially. After mixing, the plate was incubated at 25°C in the dark for 20 minutes, and the absorbance was immediately measured at 475 nm using a microplate reader. The tyrosinase inhibition rate was calculated using the formula: Inhibition rate (%) = [1 - (B0 - B1) / (A0 - A1)] × 100%, where A0 is the absorbance of the negative control and the reaction system, A1 is the absorbance of the negative control blank group (without enzyme), B0 is the absorbance of the sample and the reaction system, and B1 is the absorbance of the sample blank group (without enzyme). The inhibitory effects of glycyrrhizin and a physical mixture of glycyrrhizin and salicylate on tyrosinase were also evaluated as controls.
[0046] Example 7: Anti-aging effect test of glycyrrhizin salicylate The anti-aging efficacy was evaluated using a UV-induced HDF cell damage model. Logarithmically growing HDF cells were seeded at a density of 8 × 10³ cells / well in 96-well plates. After cell adhesion, the medium was replaced with complete medium containing a final concentration of 10 μg / mL glycyrrhizin salicylate, and the cells were cultured for another 24 hours. Subsequently, the cells were irradiated with UV light for 5 minutes and cultured for another 24 hours. Cell viability was then assessed using the CCK-8 assay. The experiment included a blank control group without UV irradiation, a model group irradiated with UV light but without drug administration, and control groups supplemented with glycyrrhizin and a physical mixture of glycyrrhizin and salicylate.
[0047] The results of the tests on the antioxidant activity, anti-inflammatory effect, whitening effect and anti-aging effect of glycyrrhizin salicylate are shown in Table 4.
[0048] Table 4 ; As shown in Tables 1, 2, 3, and 4, the glycyrrhizin salicylate ester of this application exhibits significant synergistic effects in terms of stability, antioxidant properties, anti-inflammatory properties, whitening, and anti-aging. Its chemical stability is greatly improved, effectively solving the problem of easy oxidation and inactivation of glycyrrhizin. Simultaneously, this structure masks the strongly acidic carboxyl group of salicylic acid, significantly reducing skin irritation and improving tolerability. This compound combines the excellent whitening and antioxidant effects of glycyrrhizin with the superior keratin-regulating and anti-inflammatory capabilities of salicylic acid.
[0049] The present application has been described in detail above with reference to specific embodiments and exemplary examples. However, these descriptions should not be construed as limiting the present application. Those skilled in the art will understand that various equivalent substitutions, modifications, or improvements can be made to the technical solutions and implementation methods of the present application without departing from the spirit and scope of the present application, and all such modifications and improvements fall within the scope of the present application.
Claims
1. A glycyrrhizin salicylate, the structural formula of which is shown in Formula I: 。 2. A composition, characterized in that, It includes at least the glycyrrhizin salicylate as described in claim 1 or a pharmaceutically acceptable salt thereof, as well as a dermatologically or pharmaceutically acceptable excipient or carrier.
3. The composition according to claim 2, characterized in that, The composition includes skin care compositions and pharmaceutical compositions.
4. The composition according to claim 2, characterized in that, The composition is in the form of a topical dosage form.
5. The application of the glycyrrhizin salicylate ester according to claim 1 as an active ingredient in the preparation of daily chemical products, characterized in that, The applications include: (1) Prepare daily chemical products with whitening effects; (2) Prepare daily chemical products with spot-fading effects; (3) Prepare daily chemical products with anti-aging effects; (4) Prepare daily chemical products with anti-photoaging effects; (5) Prepare daily chemical products with anti-inflammatory and soothing effects; (6) To prepare daily chemical products with anti-acne effects; and / or, (7) Prepare daily chemical products with antioxidant effects.
6. The use of the glycyrrhizin salicylate as an active ingredient in the preparation of a medicament for improving skin or repairing the skin barrier, as described in claim 1.