Compound paeonol temperature-sensitive gel for treating allergic dermatitis and preparation process thereof

Abstract

The invention relates to the technical field of pharmaceutical preparations, in particular to preparation of compound paeonol temperature-sensitive gel and application of the compound paeonol temperature-sensitive gel in allergic dermatitis, and the main components of the compound paeonol temperature-sensitive gel are paeonol, menthol, blumea oil, clove oil, propylene glycol, a temperature-sensitive gel matrix and deionized water. The temperature-sensitive gel matrix is prepared from poloxamer 407 and poloxamer 188. The temperature-sensitive gel is selected as a drug delivery carrier of paeonol, the preparation process is mature and efficient, the compliance is good, the stability is high, the stability problem of a hydrophobic drug in a water-based matrix is solved, meanwhile, the defects in clinical application caused by poor water solubility, volatility and the like of paeonol are overcome, and the application prospect is wide. And a novel medicinal preparation is expected to be provided for the transdermal drug delivery treatment of allergic dermatitis.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical preparations, and in particular to a prescription and preparation process of a compound paeonol thermosensitive gel. Background Art

[0002] Allergic dermatitis (AD) is a chronic recurrent inflammatory skin disease, the main clinical manifestations of which are long-term severe itching, extensive skin erythema, desquamation and papules, which seriously affect the quality of life of patients. In recent years, the incidence of AD in my country has increased year by year. Relevant research data show that AD has become one of the most common allergic skin diseases in dermatology. However, the pathogenesis of AD is complex and the course of disease is long. In the past decade, drug treatment regimens have mainly been based on topical corticosteroids (TCSs), topical calcineurin inhibitors (TCIs) and systemic immunosuppressants such as cyclosporine, azathioprine, methotrexate and mycophenolate mofetil. However, topical hormone treatment regimens are difficult to implement in sensitive skin lesions such as the face, and are prone to increase the incidence of adverse skin reactions. The use of systemic immunosuppressants is effective but may lead to serious side effects. Therefore, it is of great significance to invent a new drug preparation that can safely and effectively eliminate or alleviate the clinical symptoms of AD.

[0003] Traditional medicine has unique advantages in treating skin diseases. According to traditional Chinese medicine theory, the pathogenesis of atopic dermatitis in traditional Chinese medicine is hyperactivity of heart fire, which is caused by the accumulation of external rheumatism in the body and the transformation of heat. Therefore, clearing away heat and detoxifying, dispelling wind and relieving itching are its main treatment principles. Paeonol (Pae), also known as peony alcohol, is an active ingredient extracted and separated from the root bark of Paeonia suffruticosa Andr., a plant of the Ranunculaceae family, and the dried root or whole herb of Pycnostelma Paniculatum (Bunge) K. Schu, a plant of the Asclepiadaceae family. It is used in traditional Chinese medicine to clear heat and cool blood, promote blood circulation and remove blood stasis. It has multiple pharmacological activities such as antipyretic and analgesic, anti-inflammatory, anti-allergic and antibacterial, and overcomes the disadvantages of traditional hormone drugs such as easy recurrence after discontinuation of medication and large side effects. It is widely used in the treatment of skin diseases such as psoriasis and allergic dermatitis in clinical practice. However, paeonol has low water solubility and poor stability. The existing transdermal delivery technology is relatively simple, and there are common problems such as complex preparation process and poor medication compliance, which limits its use and efficacy in AD.

[0004] Thermosensitive gel is a temperature-responsive in-situ gel. After being administered in a solution state, a phase transition from a liquid state to a non-chemically cross-linked semisolid gel can occur immediately and adhere to the administration site. The viscosity is suitable and the skin feel is good. It has been widely used in the local medication treatment of various skin diseases in recent years. By adjusting the matrix and the prescription ratio, the thermosensitive gel can effectively encapsulate drugs of different polarities, and has high stability and a long retention time of the drug on the skin surface. Once adverse drug reactions are found, the administration can be interrupted at any time. Based on this, the present invention combines traditional Chinese medicine theory and modern pharmaceutical preparation technology, prepares paeonol into a spray thermosensitive gel, and combines wormwood oil, menthol, clove oil, three kinds of fragrant smells, and has anti-inflammatory and antibacterial, wind-dispelling and itching-relieving effects of Chinese medicine volatile oils, which are administered with specific spray equipment and directly act on the affected part. The preparation has good stability, high bioavailability, and lasting drug effect time, and good patient compliance, providing a new pharmaceutical preparation for the treatment of allergic dermatitis with the Chinese medicine paeonol. Summary of the invention

[0005] The purpose of the present invention is to provide a compound paeonol thermosensitive gel preparation. Another purpose of the present invention is to provide a method for preparing the above-mentioned compound paeonol thermosensitive gel preparation. The third purpose of the present invention is to provide the use of the above-mentioned compound paeonol thermosensitive gel preparation in the preparation of a drug for treating allergic dermatitis,

[0006] The key problem to be solved by the present invention is to ensure the appropriate gelation temperature and system stability, and to investigate the effects of different ratios of gel matrix and oil-water phase ratio on the phase transition temperature and system stability of paeonol thermosensitive gel and its improvement effect on the symptoms of allergic dermatitis.

[0007] The first aspect of the present invention is to provide a compound paeonol thermosensitive gel.

[0008] A compound paeonol thermosensitive gel, the weight percentages of the main drug and auxiliary materials are:

[0009] Paeonol 1%~1.5%,

[0010] Menthol 1% to 2%,

[0011] Artemisia argyi oil 0.25%,

[0012] Clove oil 0.25%,

[0013] Propylene glycol 5%,

[0014] Gel matrix 15% to 25%,

[0015] The balance is water;

[0016] The gel matrix is ​​poloxamer 407 and poloxamer 188.

[0017] Furthermore, the compound paeonol thermosensitive gel is preferably:

[0018] Paeonol 1%~1.5%,

[0019] Menthol 1% to 2%,

[0020] Artemisia argyi oil 0.25%,

[0021] Clove oil 0.25%,

[0022] Propylene glycol 5%,

[0023] Poloxamer 407 6%~10%

[0024] Poloxamer 188 8%~12%

[0025] The balance is water, which is deionized water or water for injection.

[0026] Furthermore, the compound paeonol thermosensitive gel is preferably:

[0027] Paeonol 1%

[0028] Menthol 2%,

[0029] Artemisia argyi oil 0.25%,

[0030] Clove oil 0.25%,

[0031] Propylene glycol 5%,

[0032] Poloxamer 407 8%

[0033] Poloxamer 188 10%

[0034] The balance is water.

[0035] The second aspect of the present invention is to provide a method for preparing the above-mentioned compound paeonol thermosensitive gel. The method for preparing the compound paeonol thermosensitive gel is as follows:

[0036] A. Add the prescribed amount of poloxamer 407 and poloxamer 188 into deionized water and place in a 4°C refrigerator to swell overnight.

[0037] B. Add the prescribed amount of menthol, wormwood oil and clove oil into propylene glycol and mix well for later use.

[0038] C. Add the prescribed amount of paeonol into the propylene glycol solution mixed in step B, stir and ultrasonicate to make it evenly dissolved and dispersed.

[0039] D. Add the drug solution prepared in step C to the thermosensitive gel matrix in step A and stir evenly to obtain the compound paeonol thermosensitive gel.

[0040] The stirring speed is 100-300 rpm / min, and the stirring time is 10-30 min.

[0041] The ultrasonic frequency is 50kHz, and the ultrasonic time is 10 to 15 minutes.

[0042] The third aspect of the present invention is to provide the use of the above-mentioned compound paeonol thermosensitive gel in the treatment of allergic dermatitis.

[0043] Gels have the advantages of smooth, transparent and delicate appearance, suitable consistency and viscosity. Thermosensitive gels are a type of preparation that can undergo a phase transition immediately at the medication site after administration in a solution state, transforming from a liquid state to form a non-chemically cross-linked semisolid gel. Gels have good tissue compatibility and can stay at the medication site for a long time, thereby storing drugs, achieving sustained release, and preventing drugs from being affected by the environment.

[0044] The present invention prepares the compound paeonol thermosensitive gel into a spray thermosensitive gel and combines it with a specific spray device for administration, which is applied to the treatment of AD, has high bioavailability, lasting efficacy, and good patient compliance, and provides a certain research basis for the development of clinical preparations for AD. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 The effect of the compound paeonol thermosensitive gel of the present invention on the ear swelling degree and spleen index of mice;

[0046] Figure 2 The effect of the compound paeonol thermosensitive gel of the present invention on Th2 cytokines in mouse ear homogenate;

[0047] Figure 3 The rheological curve of the compound paeonol thermosensitive gel of the present invention is shown in FIG. DETAILED DESCRIPTION

[0048] The specific implementation methods provided by the present invention are described in detail below in conjunction with examples.

[0049] Material:

[0050] Paeonol (Aladdin, batch number: E2223165)

[0051] Menthol (Dipharma, batch number: K918471)

[0052] Artemisia argyi oil (medicinal, Adamas life, batch number: P2045121)

[0053] Clove oil (medicinal, Aladdin, batch number: 8000-34-8)

[0054] Propylene glycol (pharmaceutical, Adamas, batch number: 66889E)

[0055] Poloxamer 407 (P407, Adamas life, batch number: 88982G)

[0056] Poloxamer 188 (P188, Adamas life, batch number: 88982M)

[0057] Example 1

[0058] Weigh 8 g of Poloxamer 407 and 10 g of Poloxamer 188, add deionized water and place in a 4° C. refrigerator to swell overnight.

[0059] Weigh 2g menthol, 0.25g wormwood oil, 0.25g clove oil, add 5g propylene glycol and mix well.

[0060] Add 1 g of paeonol into the mixed propylene glycol solution, stir and ultrasonicate to make the solution evenly dispersed.

[0061] The prepared drug solution is added into the swollen thermosensitive gel matrix and stirred evenly to obtain the compound paeonol thermosensitive gel.

[0062] Example 2

[0063] Weigh 9 g of Poloxamer 407 and 10 g of Poloxamer 188, add deionized water and place in a 4° C. refrigerator to swell overnight.

[0064] Weigh 2g menthol, 0.25g wormwood oil, 0.25g clove oil, add 5g propylene glycol and mix well.

[0065] Add 1 g of paeonol into the mixed propylene glycol solution, stir and ultrasonicate to make the solution evenly dispersed.

[0066] The prepared drug solution is added into the swollen thermosensitive gel matrix and stirred evenly to obtain the compound paeonol thermosensitive gel.

[0067] Example 3

[0068] Weigh 9 g of Poloxamer 407 and 12 g of Poloxamer 188, add deionized water and place in a 4° C. refrigerator to swell overnight.

[0069] Weigh 2g menthol, 0.25g wormwood oil, 0.25g clove oil, add 5g propylene glycol and mix well.

[0070] Add 1 g of paeonol into the mixed propylene glycol solution, stir and ultrasonicate to make the solution evenly dispersed.

[0071] The prepared drug solution is added into the swollen thermosensitive gel matrix and stirred evenly to obtain the compound paeonol thermosensitive gel.

[0072] Example 4

[0073] Weigh 8 g of Poloxamer 407 and 10 g of Poloxamer 188, add deionized water and place in a 4° C. refrigerator to swell overnight.

[0074] Weigh 2 g of menthol, 0.25 g of wormwood oil, and 0.25 g of clove oil, add them to 5 g of propylene glycol, mix well, and set aside.

[0075] Add 1.5 g of paeonol into the mixed propylene glycol solution, stir and ultrasonicate to make the solution evenly dispersed.

[0076] The prepared drug solution is added into the swollen thermosensitive gel matrix and stirred evenly to obtain the compound paeonol thermosensitive gel.

[0077] Example 5

[0078] Weigh 8 g of Poloxamer 407 and 10 g of Poloxamer 188, add deionized water and place in a 4° C. refrigerator to swell overnight.

[0079] Weigh 1g menthol, 0.25g wormwood oil, 0.25g clove oil, add 5g propylene glycol and mix well.

[0080] Add 1 g of paeonol into the mixed propylene glycol solution, stir and ultrasonicate to make the solution evenly dispersed.

[0081] The prepared drug solution is added into the swollen thermosensitive gel matrix and stirred evenly to obtain the compound paeonol thermosensitive gel.

[0082] Example 6 Pharmacodynamic Evaluation

[0083] Allergic dermatitis model mice were selected to carry out the pharmacodynamic evaluation of the drug of the present invention.

[0084] 1 Experimental animals and test drugs

[0085] Healthy male mice, SPF grade, male, were purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. (Production License No.: SCXK (Zhe) 2019-0001). All animal experiments were carried out in accordance with laboratory operation requirements and animal management regulations and approved by the Animal Theory Committee of the Affiliated Tumor Hospital of Fudan University. The compound paeonol thermosensitive gel in the present invention was prepared by Example 1;

[0086] 2. Detection and evaluation methods

[0087] 2.1 Establishment of mouse ACD model and drug administration regimen

[0088] After 2 days of adaptive feeding, BALB / c mice were shaved on the abdomen with a size of 3.5 cm × 3.5 cm on day 0 (d0). 80 μL of 1.5% FITC solution (solvent was acetone: butyl phthalate = 1:1) was applied to the hairless part of the abdomen on d1 and d2. 20 μL of 0.6% FITC solution was applied to the left and right ears of the mice on d6 (15 μL for the inner ear and 5 μL for the outer ear). The blank group was coated with an equal volume of solvent. After 24 hours, the thickness of the left and right ears of the mice was measured and the average value was calculated. (Ear swelling degree = ear thickness of the modeling group mice minus ear thickness of the blank group mice). After the mice were killed, an ear disc was knocked out at the same position of the right ear with an 8 mm diameter puncher, and the mass was immediately weighed. The ear mass difference between the right ear disc of the drug group mice and the right ear disc of the blank group mice was calculated. Part of the right ear tissue was soaked in 1 ml of 10% formalin for preservation, and the left ear was ground and slurried to test cytokines. The spleen of the mouse was weighed, the spleen index was calculated, and stored at -80°C.

[0089] The mice were randomly divided into blank control group, atopic dermatitis model group, compound paeonol thermosensitive gel group and dexamethasone group (0.67 mg / kg) according to body weight, with 6 mice in each group. The drug was administered once a day for 14 consecutive days starting from d1 (full course of administration).

[0090] 2.2SCORAD dermatitis scoring system

[0091] The back skin of mice was scored on the 8th, 10th and 14th days after modeling. The dermatitis scoring content and criteria include:

[0092] (1) Skin erythema / hemorrhage: 4 points if the area is larger than 75% of the exposed skin area; 3 points if the area is between 40% and 75%; 2 points if the area is between 10% and 40%; 1 point if the area is less than 10%; 0 points if there is no bleeding or erythema.

[0093] (2) Skin scratches / erosions: 4 points if the area is larger than 75% of the exposed skin area; 3 points if the area is between 40% and 75%; 2 points if the area is between 10% and 40%; 1 point if the area is less than 10%;

[0094] (3) Skin edema: 4 points if the skin is dark red, the surface is moist, the swelling is obvious, and there is no new hair; 3 points if the skin is light red, the surface is slightly dry, the edema is reduced, and there is no new hair; 2 points if the skin is pink, slightly darker than the normal mouse color, the surface is uneven, and there is new hair; 1 point if the skin color is close to the normal skin color of mice, there is a lot of new hair, and the skin is smooth; 0 points if there is no above manifestation. No bleeding or erythema is 0 points.

[0095] (4) Skin scaling or lichenification: 4 points if the area is larger than 75% of the exposed skin area; 3 points if the area is between 40% and 75%; 2 points if the area is between 10% and 40%; 1 point if the area is less than 10%; 0 points if there is no bleeding or erythema.

[0096] 2.3 Preparation of ear tissue homogenate

[0097] The mouse left ear tissue was weighed and cut into pieces, and ground in a glass homogenizer with pre-cooled PBS to prepare a 2.5% ear tissue slurry. The slurry was centrifuged at 12000 r / min at 4°C for 10 min, and the supernatant was collected and stored at -20°C for testing.

[0098] 2.4ELISA detection of cytokines IL-4, IL-5 and IL-13

[0099] Mouse ear homogenate and cell supernatant were operated according to the instructions of each cytokine ELISA kit, and the results of animal sample determination were corrected according to the total protein quantification of the sample.

[0100] 2.5 Statistical methods

[0101] One-way ANOVA analysis was performed in GraphPad Prism 9 software to compare the differences among the groups. Dunnett's test was used for comparison among the groups, and statistical significance was set at P < 0.05.

[0102] 3 Experimental results

[0103] 3.1 Construction of mouse AD model

[0104] After FITC sensitization and stimulation, the ears of mice were swollen, and the ear thickness difference and ear quality difference were significantly increased compared with the blank group (P<0.01). The levels of Th2 cytokines IL-4, IL-5 and IL-13 in ear homogenate increased by about 1.2 times (P>0.01), indicating that the mouse AD model was successfully established.

[0105] 3.2 SCORAD score of skin lesions in mouse model

[0106] The SCORAD scores of the skin lesions of the AD mouse model were performed before and after treatment, and the data are shown in Table 1. Compared with the blank control group, the SCORAD scores of the model group and the blank gel group were significantly increased (P<0.01), which once again verified the successful construction of the mouse AD model. After drug intervention, the scores of the compound paeonol thermosensitive gel group and the positive drug dexamethasone group were significantly reduced (P<0.01), and there was no statistical difference between the two groups (P>0.05).

[0107] Table 1 SCORAD scores of skin lesions in rat models of each group (x±s)

[0108]

[0109] 3.3 Effects of compound paeonol thermosensitive gel on ear swelling and spleen index in mice;

[0110] After administration of compound paeonol thermosensitive gel, the ear swelling of mice was significantly improved (P<0.01), and the spleen index was not affected. Figure 2 As shown, compared with the blank gel group, the level of Th2 cytokines in the ear homogenate of mice in the drug-treated group was significantly reduced, and the levels of IL-4 and IL-5 decreased by about 1 / 2.

[0111] The above results show that the compound paeonol thermosensitive gel prepared according to Example 1 of the present invention has a significant therapeutic effect on allergic dermatitis, and effectively inhibits the production of Th2 cytokines, and does not show an immunosuppressive effect similar to dexamethasone on the spleen of mice.

[0112] Example 7: Optimization of the formula of the compound paeonol thermosensitive gel

[0113] 1 Establishment of content determination method

[0114] 1.1 Chromatographic conditions

[0115] Column: Hypersil ODS2-C 18 (250mm×4.6mm, 5μm), methanol: water (70:30) as mobile phase; detection wavelength 273nm; column temperature: room temperature; flow rate: 1.0ml / min; injection volume: 20μL

[0116] 1.2 Solution preparation

[0117] (1) Preparation of the test solution: Accurately weigh 1 g of the compound paeonol thermosensitive gel prepared according to Example 1, dilute it with methanol into a 100 ml volumetric flask, centrifuge for 5 min (speed 10000 r / min), take 1 ml of the supernatant into a 10 ml volumetric flask, and dilute it to the mark with methanol to obtain the test solution.

[0118] (2) Preparation of reference solution: Accurately measure 1 mg of compound paeonol reference substance, dissolve it in methanol and dilute it into a 10 ml volumetric flask to obtain a 100 μg / ml reference solution.

[0119] 1.3 Investigation of linear relationship

[0120] Preparation of standard curve: Accurately measure 0.2ml, 0.4ml, 0.8ml, 1.0ml, 1.2ml, 1.6ml, 2.0ml of reference solution into 100ml volumetric flasks, dilute to scale with methanol, and obtain a series of reference solutions with concentrations of 0.2, 0.4, 0.8, 1.0, 1.2, 1.6, 2.0μg / ml. Inject according to the chromatographic conditions under 1.1 and measure the peak area (A). Linearly regress A against concentration c to obtain the standard curve equation A = 36712C-16281 (r 2 =0.999), indicating that paeonol has a good linear relationship in the range of 0.2-2.0 μg / ml.

[0121] The paeonol standard solution and the test solution were filtered through a 0.45 μm microporous filter membrane. The paeonol peak shapes in the standard and the gel were good, and other components in the gel had no interference with the absorption of the thermosensitive gel.

[0122] 1.4 Recovery rate experiment

[0123] Take appropriate amount of sample solution with known concentration and reference solution (0.4, 0.8, 1.0 μg / ml), mix and shake well, inject and measure the three groups of solutions respectively, record the peak area, substitute into the linear regression equation, calculate the content and the recovery rate, and the low, medium and high recovery rates are 97.12%, 98.11% and 96.68%, respectively.

[0124] Precision

[0125] 1.5 Precision experiment

[0126] (1) Intra-day precision experiment: Take 20 μl of each of the three concentrations of the reference solution, low, medium and high, and repeat the injection three times under the chromatographic conditions of 1.1, with an interval of 4 hours between each injection, record the peak area, and calculate the coefficient of variation of the peak area. The RSDs of the peak areas of the three concentrations of paeonol (0.4, 0.8, and 1.0 μg / ml) were 1.71%, 1.88%, and 1.72%, respectively.

[0127] (2) Inter-day precision test: Take 20 μl of each of the three concentrations of the reference solution, low, medium and high, and repeat the injection three times under the chromatographic conditions of 1.1, with an interval of 24 hours between each injection, record the peak area, and calculate the coefficient of variation of the peak area. The RSDs of the peak areas of low, medium and high concentrations (0.4, 0.8 and 1.0 μg / ml) of paeonol were 1.77%, 1.38% and 1.27%, respectively.

[0128] Take the standard solution in Item 1.2, repeat the injection 6 times according to the chromatographic conditions in Item 1.1, and record the peak area. The measurement results are shown in Table 1. The results show that the precision of the instrument test is good.

[0129] 1.6 Stability test

[0130] The sample solution was injected at 0, 2, 4, 6 and 8 hours respectively, and the peak area was recorded to investigate the stability of the sample solution. The results showed that the RSD of the sample solution within 8 hours was 1.68%, and the sample was basically stable.

[0131] 1.7 Content determination

[0132] Take three groups of compound paeonol thermosensitive gel respectively, prepare sample solutions according to the method in item 1.2, inject samples according to the chromatographic conditions in item 1.1, record the peak area, and calculate the content of paeonol in the gel according to linear regression. The average content of paeonol in the compound paeonol thermosensitive gel is shown in the table.

[0133] Table 2 Content determination results of 3 batches of compound paeonol thermosensitive gel samples

[0134]

[0135] 2 Preparation technology of compound paeonol thermosensitive gel

[0136] 2.1 Prescription composition of compound paeonol thermosensitive gel

[0137] Paeonol 1%, menthol 2%, wormwood oil 0.25%, clove oil 0.25%, a certain proportion of solvent, a certain proportion of poloxamer 407 and poloxamer 188, and the balance is deionized water.

[0138] 2.2 Preparation of compound paeonol thermosensitive gel

[0139] Aqueous matrix: Add appropriate amount of deionized water to poloxamer 407 and poloxamer 188 and completely swell in a refrigerator at 4°C.

[0140] Drug-containing oil phase: dissolve menthol, wormwood oil and clove oil in propylene glycol in turn and mix for later use, then add paeonol into the propylene glycol mixed solution, stir and ultrasonicate to make the solution disperse evenly.

[0141] The prepared drug solution is slowly added into the swollen thermosensitive gel matrix and stirred evenly to obtain the compound paeonol thermosensitive gel.

[0142] 2.3 Determination of gelation temperature

[0143] Weigh 2g of each gel sample into the same type of vial, place in a 15℃ water bath, and make the liquid level in the test tube below the water surface. Adjust the water bath temperature to 40℃ at a rate of 0.5℃~1℃ / min, tilt the test tube quickly every 30s, and observe the flow state of the liquid in the tube. The temperature at which the contents do not flow when the test tube is tilted 90 degrees is recorded as the gelation temperature of the gel.

[0144] 3. Prescription Optimization

[0145] 3.1 Effect of solvent

[0146] The remaining components and proportions in the fixed prescription remain unchanged, and solvents propylene glycol, Tween and glycerol are proposed to be selected as solvents to investigate the stability and gelation temperature of the preparation under different solvent systems.

[0147] According to the above prescription ratio, 9 parts of matrix solution and drug-containing oil phase with different solvents were prepared, and the solvents were propylene glycol (5%, 7.5%, 10%), Tween 80 (5%, 7.5%, 10%), and glycerol (5%, 7.5%, 10%). The results showed that after Tween 80 was added to the drug-containing oil phase, the stratification was obvious after centrifugation; when glycerol with three concentration ratios was used as the solvent, the gel quickly turned into a semi-solid jelly during the preparation process, and the gelation temperature was lower than room temperature. When 5% propylene glycol was used as the solvent, the oil phase was uniform, and the stability was good after being placed for two weeks, and the effect on the gelation temperature was small, which was the best ratio.

[0148] 3.2 Effect of gel matrix

[0149] Poloxamer 407 and Poloxamer 188 are commonly used thermosensitive polymers. The change in their ratio when used together as a gel matrix is ​​an important factor in the change of gelation temperature.

[0150] Compound paeonol gels with different ratios of P407 (6% to 12%) and P188 (8% to 14%) were prepared to investigate the effects of different conditions on rheological parameters. The experimental results are shown in the table

[0151] Table 3 Effect of different contents of P407 and P188 on rheological parameters

[0152]

[0153] According to the above results, P407:P188 (8:10) and P407:P188 (9:10) are more in line with the experimental design. However, P407:P188 (9:10) has a higher viscosity, which is not conducive to spraying from a spray bottle. Taking into account the system prescription P407:P188 (8:10) is the optimal ratio. The rheological curve shows that the compound paeonol thermosensitive gel under this prescription undergoes a phase transition at 32°C, and then the viscosity tends to be stable.

[0154] 4. Optimal prescription verification

[0155] Three batches of samples were prepared according to the optimal prescription (1% paeonol, 2% menthol, 0.25% wormwood oil, 0.25% clove oil, 5% propylene glycol, 8% poloxamer 407, 10% poloxamer 188, and the balance was deionized water). The average phase transition temperature was about 32.3°C and the viscosity was 3.22ηPas.

[0156] The preferred embodiments of the present invention have been specifically described above, but the present invention is not limited to the embodiments. Those skilled in the art may make various equivalent modifications or substitutions without violating the spirit of the present invention, all of which are within the scope defined by the claims of this application.

Claims

1. A compound paeonol thermosensitive gel, characterized in that: The temperature-sensitive gel is composed of the following components by weight percentage: Paeonol 1%~1.5%, Menthol 1% to 2%, Artemisia argyi oil 0.25%, Clove oil 0.25%, Propylene glycol 5%, Gel matrix 15% to 25%, The balance is water The gel matrix is ​​poloxamer 407 and poloxamer 188.

2. A compound paeonol thermosensitive gel according to claim 1, characterized in that It is composed of the following components by weight percentage: Paeonol 1%~1.5%, Menthol 1% to 2%, Artemisia argyi oil 0.25%, Clove oil 0.25%, Propylene glycol 5%, Poloxamer 407 6%~10% Poloxamer 188 8%~12% The balance is water.

3. The compound paeonol thermosensitive gel according to claim 1, characterized in that It is composed of the following components by weight percentage: Paeonol 1%, Menthol 2%, Artemisia argyi oil 0.25%, Clove oil 0.25%, Propylene glycol 5%, Poloxamer 407 6%~10% Poloxamer 188 8%~12% The balance is water.

4. The compound paeonol thermosensitive gel according to claim 1, characterized in that It is composed of the following components by weight percentage: Paeonol 1% Menthol 2%, Artemisia argyi oil 0.25%, Clove oil 0.25%, Propylene glycol 5%, Poloxamer 407 8%, Poloxamer 188 10% The balance is water.

5. A method for preparing the compound paeonol thermosensitive gel as claimed in claim 1, the method comprising the following steps: A. Add the prescribed amount of poloxamer 407 and poloxamer 188 into deionized water and place in a 4°C refrigerator to swell overnight. B. Add the prescribed amount of menthol, wormwood oil and clove oil into propylene glycol and mix well for later use. C. Add the prescribed amount of paeonol into the propylene glycol solution mixed in step B, stir and ultrasonicate to make it evenly dissolved and dispersed. D. Add the drug solution prepared in step C to the thermosensitive gel matrix prepared in step A and stir evenly to obtain the compound paeonol thermosensitive gel.

6. The method for preparing the compound paeonol thermosensitive gel according to claim 5, characterized in that: The stirring speed in steps B, C and D is 100-300 rpm / min, and the stirring time is 15-20 min.

7. Use of the compound paeonol thermosensitive gel according to any one of claims 1 to 7 in the preparation of a drug for treating allergic dermatitis.

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