CN108997354B

CN108997354B - Dihydropyrimidinoisoindolinone compounds, cream thereof and application thereof in treating hyperuricemia

Info

Publication number: CN108997354B
Application number: CN201810898543.8A
Authority: CN
Inventors: 贺玉伟; 李鑫德; 李长贵; 吕烨
Original assignee: Affiliated Hospital of University of Qingdao
Current assignee: Affiliated Hospital of University of Qingdao
Priority date: 2018-08-08
Filing date: 2018-08-08
Publication date: 2021-12-31
Anticipated expiration: 2038-08-08
Also published as: CN108997354A

Abstract

The invention discloses a dihydropyrimidoisoindolone compound or a pharmaceutically acceptable salt thereof,

. Through the in-vitro inhibition effect on xanthine oxidase, the influence on the serum uric acid level of a hyperuricemia mouse, an in-vivo anti-acute gout arthritis test and the influence on a pain model caused by thermal stimulation, the compound disclosed by the invention is found to have good effects of reducing the serum uric acid level and relieving pain, and especially has an obvious effect on gout acute attack stage.

Description

Dihydropyrimidinoisoindolinone compounds, cream thereof and application thereof in treating hyperuricemia

Technical Field

The invention relates to the field of medicines, in particular to a dihydropyrimido isoindolone compound, a cream thereof and application thereof in treating hyperuricemia.

Background

Hyperuricemia, also called Gout (Gout), is a systemic metabolic disease in which urate crystals can be deposited in joints and soft tissues due to excessive uric acid production or reduced uric acid discharge caused by purine metabolic disorders in the human body. In normal humans, about 1200 mg of uric acid is normally accumulated, about 600 mg is eliminated daily, and about 600 mg is regenerated. Under normal conditions, the body works orderly according to the rhythm and the law in cycles, but once the balance is broken, the uric acid is increased due to excessive uric acid generation or reduced uric acid excretion, hyperuricemia is caused, and finally gout is formed.

According to the Chinese guidelines for diagnosis and treatment of renal hyperuricemia (2017 edition), uric acid-lowering drug therapy includes (1) drugs that inhibit uric acid production, such as allopurinol that competitively binds with Xanthine Oxidase (XO) to inhibit uric acid production; febuxostat inhibits XO activity and reduces uric acid production by noncompetitive binding to XO. (2) Drugs that promote uric acid excretion, such as benzbromarone and probenecid, increase urate excretion by inhibiting active reabsorption of urate in renal tubules, thereby reducing blood uric acid levels. (3) Drugs promoting uric acid decomposition, such as labyrinase.

The natural course and clinical manifestations of gout patients can be roughly divided into the following four stages: firstly, in an asymptomatic hyperuricemia period; ② acute gouty arthritis attack period; ③ interval period of gout attack (inter-critical gout); chronic gouty arthritis (chronic tophaceous). Acute gouty arthritis is caused to be acute and often suddenly attacks at night, firstly occurs in the first metatarsophalangeal joint, is severe in pain, reaches the peak within hours, obviously swells and turns red, obviously relieves pain and causes dysfunction. Associated with fever, up to 38-39 ℃. It has symptoms of debilitation, anorexia, headache, etc. At present, nonsteroidal anti-inflammatory drugs, colchicine and glucocorticoid exist as drugs aiming at the acute attack stage of gout, but the use of the drugs has obvious limitation conditions. For example, gout patients with digestive tract risk factors need to select non-steroidal anti-inflammatory drugs of COX-2; gout patients with cardiovascular risk factors need to select non-steroidal anti-inflammatory drugs of COX-1; the effective dose of colchicine is close to the toxic dose (adverse reactions such as vomit, diarrhea and the like appear); the symptoms easily recur after glucocorticoid withdrawal, and repeated use increases the chance of gout attack. Therefore, the search for new anti-hyperuricemia drugs, especially drugs aiming at acute gout attack, is of great significance, and the research on the dihydro-pyrimido-isoindolone compounds in the aspect of anti-hyperuricemia has not been reported so far.

Disclosure of Invention

The invention provides a dihydropyrimido isoindolone compound, which has a structure shown in a formula I:

wherein R is selected from 4-methoxyphenyl, 2-thienyl or isopropyl.

Further, the dihydropyrimidino isoindolones compound is a pharmaceutically acceptable salt of the formula I.

Further, the dihydropyrimidino isoindolinone compound shown in the formula I is selected from a compound 1, a compound 2 and a compound 3, and the structure is shown as follows:

；

；

。

see the examples section for structural data and methods of synthesis for compounds 1, 2 and 3.

The invention also provides an in-vitro inhibition effect experiment of the compound on xanthine oxidase, an influence on the serum uric acid level of a hyperuricemia mouse, an in-vivo anti-acute gout arthritis experiment and an influence on a thermal stimulation pain model.

The dihydropyrimidino isoindolone compound formula I cream formula provided by the invention comprises the following components: 0.01-2 parts of dihydropyrimidino isoindolinone compound or pharmaceutically acceptable salt thereof, 3-10 parts of humectant, 1-15 parts of solid in oil phase component, 5-20 parts of consistency regulator, 0.5-5 parts of emulsifier and 0.01-0.25 part of preservative. Wherein the adjuvants with moisture keeping effect are one or more of glycerol, propylene glycol, and sorbitol. Wherein the solid in the oil phase is one or more of stearic acid, paraffin, beeswax, cetyl alcohol, and stearyl alcohol. Wherein the adjuvant used as consistency regulator is one or more of vaseline, liquid paraffin, and oleum ricini. Wherein the adjuvant acting as emulsifier is one or more of gelatin, acacia, tragacanth, apricot gum, pectin, peregal A-20, and sodium dodecyl sulfate. Wherein the adjuvants used as antiseptic are one or more of sodium benzoate, butylated hydroxytoluene, butylated hydroxyanisole, ethylenediamine tetraacetic acid, phenylmercuric nitrate, methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, potassium sorbate, and benzalkonium bromide. Other moisturizing agents with moisturizing effect, other solids in the oil phase components, other consistency regulators with consistency regulating effect, other emulsifying agents with emulsifying effect and other preservatives with preservative effect can also be selected for application in the present invention.

The preparation method comprises the following steps in sequence:

(1) heating the solid and the consistency regulator in the oil phase components according to the prescription amount in a water bath to be completely melted, uniformly mixing, and keeping the temperature at 80 ℃;

(2) dissolving a prescription amount of dihydropyrimido isoindolone compound in ethyl acetate;

(3) mixing emulsifier, antiseptic, humectant and distilled water according to the prescription amount, heating to about 80 deg.C for completely dissolving, slowly adding into the mixture obtained in step (1), rapidly stirring, adding into the ethyl acetate solution of dihydropyrimido isoindolinone compound in step (2), mixing, and condensing to obtain ointment.

Drawings

FIG. 1 is a graph showing the effect of compounds of the present invention on rat serum nitric oxide levels.

FIG. 2 is a graph showing the effect of the compounds of the present invention on the IL-8 level in rat serum.

FIG. 3 is a graph showing the effect of compounds of the present invention on rat prostaglandin-2 levels.

Detailed Description

Example 1: synthesis of Compound 1

To a dry reaction flask were added (E) -2 (propyl-1-enyl) -1H-isoindole-1, 3 (2H) -dione (0.25 mmoL), N- (methoxy- (4-methoxyphenyl) methyl) benzamide (0.28 mmoL)And dichloromethane (2.5 mL). Under the protection of argon, a solution of tin tetrachloride in methylene chloride (1M, 0.5 mL) was added dropwise at-30 ℃. After the dropwise addition, the reaction solution was slowly heated to 0 ℃ over 3 hours. After completion of the reaction was monitored by TLC, aqueous trifluoroacetic acid (1M, 0.25 mL), tetrabutylammonium iodide (0.25 mmoL) and water (0.75 mL) were added to the reaction mixture. The mixture was stirred at 0 ℃ overnight, and saturated aqueous ammonium chloride (10 mL) was added. Separating, extracting the water phase with dichloromethane, combining the organic phases, drying, concentrating, and purifying the crude product by column chromatography to obtain the compound 1. By structure confirmation, of the synthesized compound¹H-NMR and¹³C-NMR data and literature (Stereoselective One-Point Synthesis of Dipyrimid [2,1-a ]]isoindole-6(2H)-ones（Org. Lett. 2018, 20: 178-.

Example 2: synthesis of Compound 2

To the dried reaction flask were added (E) -2 (propyl-1-alkenyl) -1H-isoindole-1, 3 (2H) -dione (0.25 mmoL), N- (methoxy (thiophen-2-yl) methyl) benzamide (0.28 mmoL), and dichloromethane (2.5 mL). Under the protection of argon, a solution of tin tetrachloride in methylene chloride (1M, 0.5 mL) was added dropwise at-30 ℃. After the dropwise addition, the reaction solution was slowly heated to 0 ℃ over 3 hours. After completion of the reaction was monitored by TLC, aqueous trifluoroacetic acid (1M, 0.25 mL), tetrabutylammonium iodide (0.25 mmoL) and water (0.75 mL) were added to the reaction mixture. The mixture was stirred at 0 ℃ overnight, and saturated aqueous ammonium chloride (10 mL) was added. Separating, extracting the water phase with dichloromethane, combining the organic phases, drying, concentrating, and purifying the crude product by column chromatography to obtain the compound 2. By structure confirmation, of the synthesized compound¹H-NMR and¹³C-NMR data and literature (Stereoselective One-Point Synthesis of Dipyrimid [2,1-a ]]isoindole-6(2H)-ones（Org. Lett. 2018, 20: 178-.

Example 3: synthesis of Compound 3

To a dry reaction flask were added (E) -2 (propyl-1-alkenyl) -1H-isoindole-1, 3 (2H) -dione (0.25 mmoL), N- (1-methoxy-2-methylpropyl) benzamide (0.28 mmoL), and dichloroMethane (2.5 mL). Under the protection of argon, a solution of tin tetrachloride in methylene chloride (1M, 0.5 mL) was added dropwise at-30 ℃. After the dropwise addition, the reaction solution was slowly heated to 0 ℃ over 3 hours. After completion of the reaction was monitored by TLC, aqueous trifluoroacetic acid (1M, 0.25 mL), tetrabutylammonium iodide (0.25 mmoL) and water (0.75 mL) were added to the reaction mixture. The mixture was stirred at 0 ℃ overnight, and saturated aqueous ammonium chloride (10 mL) was added. Separating, extracting the water phase with dichloromethane, combining the organic phases, drying, concentrating, and purifying the crude product by column chromatography to obtain the compound 3. By structure confirmation, of the synthesized compound¹H-NMR and¹³C-NMR data and literature (Stereoselective One-Point Synthesis of Dipyrimid [2,1-a ]]isoindole-6(2H)-ones（Org. Lett. 2018, 20: 178-.

Example 4:

first, prescription

12 g of compound, 10 g of glycerol, 10 g of stearic acid, 15 g of vaseline, 2.8 g of gelatin, 0.2 g of sodium benzoate and 2 g of ethyl acetate.

Secondly, the process steps

1. Preparing various raw materials according to the raw material composition of the compound 1 emulsifiable paste, firstly heating stearic acid and vaseline in a water bath to completely melt, then uniformly mixing, and keeping the temperature at 80 ℃;

2. dissolving compound 1 in ethyl acetate;

3. mixing gelatin, sodium benzoate, glycerol and distilled water, heating to about 80 deg.C for completely dissolving, slowly adding into the mixture obtained in step 1, rapidly stirring, adding the ethyl acetate solution of compound 1 in step 2, mixing, and condensing to obtain paste.

Example 5:

first, prescription

22 g of compound, 10 g of glycerol, 10 g of stearic acid, 15 g of vaseline, 2.8 g of gelatin, 0.2 g of sodium benzoate and 2 g of ethyl acetate.

Secondly, the process steps

1. Preparing various raw materials according to the raw material composition of the compound 2 emulsifiable paste, firstly heating stearic acid and vaseline in a water bath to completely melt, then uniformly mixing, and keeping the temperature at 80 ℃;

2. dissolving compound 2 in ethyl acetate;

3. mixing gelatin, sodium benzoate, glycerol and distilled water, heating to about 80 deg.C for completely dissolving, slowly adding into the mixture obtained in step 1, rapidly stirring, adding the ethyl acetate solution of compound 2 in step 2, mixing, and condensing to obtain paste.

Example 6:

first, prescription

12 g of compound, 8 g of propylene glycol, 6.8 g of paraffin, 18 g of castor oil, 5 g of Arabic gum, 0.2 g of methyl p-hydroxybenzoate and 2 g of ethyl acetate.

Secondly, the process steps

1. Preparing various raw materials according to the raw material composition of the compound 1 emulsifiable paste, heating paraffin and castor oil in a water bath to completely melt, uniformly mixing, and keeping the temperature at 80 ℃;

2. dissolving compound 1 in ethyl acetate;

3. mixing Arabic gum, methyl p-hydroxybenzoate, propylene glycol and distilled water, heating to about 80 deg.C for completely dissolving, slowly adding into the mixture obtained in step 1, rapidly stirring, adding into the ethyl acetate solution of compound 1 in step 2, mixing, and condensing to obtain paste.

Example 7:

first, prescription

22 g of compound, 8 g of propylene glycol, 6.8 g of paraffin, 18 g of castor oil, 5 g of Arabic gum, 0.2 g of methyl p-hydroxybenzoate and 2 g of ethyl acetate.

Secondly, the process steps

1. Preparing various raw materials according to the raw material composition of the compound 2 emulsifiable paste, heating paraffin and castor oil in a water bath to completely melt, uniformly mixing, and keeping the temperature at 80 ℃;

2. dissolving compound 2 in ethyl acetate;

3. mixing Arabic gum, methyl p-hydroxybenzoate, propylene glycol and distilled water, heating to about 80 deg.C for completely dissolving, slowly adding into the mixture obtained in step 1, rapidly stirring, adding into the ethyl acetate solution of compound 2 in step 2, mixing, and condensing to obtain paste.

Example 8:

first, prescription

12 g of compound, 9 g of sorbitol, 7.9 g of octadecanol, 16 g of liquid paraffin, 5 g of sodium dodecyl sulfate, 0.1 g of sodium sorbate and 2 g of ethyl acetate.

Secondly, the process steps

1. Preparing various raw materials according to the raw material composition of the compound 1 emulsifiable paste, firstly heating octadecanol and liquid paraffin in a water bath to completely melt, then uniformly mixing, and keeping the temperature at 80 ℃;

2. dissolving compound 1 in ethyl acetate;

3. mixing sodium dodecyl sulfate, sodium sorbate, sorbitol and distilled water, heating to about 80 deg.C for complete dissolution, slowly adding into the mixture obtained in step 1, rapidly stirring, adding into the ethyl acetate solution of compound 1 in step 2, mixing, and condensing to obtain paste.

Example 9:

first, prescription

22 g of compound, 9 g of sorbitol, 7.9 g of octadecanol, 16 g of liquid paraffin, 5 g of sodium dodecyl sulfate, 0.1 g of sodium sorbate and 2 g of ethyl acetate.

Secondly, the process steps

1. Preparing various raw materials according to the raw material composition of the compound 2 emulsifiable paste, firstly heating octadecanol and liquid paraffin in a water bath to completely melt, then uniformly mixing, and keeping the temperature at 80 ℃;

2. dissolving compound 2 in ethyl acetate;

3. mixing sodium dodecyl sulfate, sodium sorbate, sorbitol and distilled water, heating to about 80 deg.C for complete dissolution, slowly adding into the mixture obtained in step 1, rapidly stirring, adding into the ethyl acetate solution of compound 2 in step 2, mixing, and condensing to obtain paste.

Test example 1: in vitro inhibition of xanthine oxidase by Compounds 1-3

Firstly, solution preparation:

1. preparing a phosphate buffer solution: 19.48 g of K are weighed out₂HPO₄.3H₂O and 1.99 g KH₂PO₄Dissolved in 500 mL of distilled water to prepare a phosphate buffer solution (pH = 7.5) having a concentration of 0.2 mmol/L.

2. Preparing a xanthine substrate solution: weighing 15.2 mg of xanthine, dissolving in 250 mL of distilled water to prepare a xanthine substrate solution with the concentration of 0.4 mmol/L.

3. Preparing a xanthine oxidase solution: taking 5U of xanthine oxidase, diluting to 160 mL with the above phosphate buffer solution to obtain xanthine oxidase solution with concentration of 80U/L, and storing at 4 deg.C.

4. Preparing a compound 1-3 and a positive control solution: precisely weighing 1-3 of the compound and Yangshenfebuxostat, dissolving with dimethyl sulfoxide and diluting with distilled water respectively to prepare the compound with the concentration of 0.01 mu mol/L^-2Mu mol/L of solutions of different concentrations were tested, with a final concentration of dimethyl sulfoxide of less than 1%.

Secondly, testing the inhibition effect:

1. sample group testing: sequentially adding 200 mu L of xanthine substrate solution, 100 mu L of sample solution and 200 mu L of xanthine oxidase solution into a 2 mL centrifuge tube, performing vortex oscillation for 5 s, placing the mixture into a water bath kettle at 25 ℃ for reaction for 5 min, adding 1.5 mL of absolute ethyl alcohol after the reaction is finished, and performing vortex oscillation for 5 s to terminate the reaction. The reaction solution is centrifuged for 5 min at 3500 rpm, 200 mu L to 1.5 mL centrifuge tubes are sucked, the Uric Acid (UA) value of each sample is respectively monitored by a biochemical analyzer, and the average value is obtained by parallelly operating each sample for three times.

2. Blank control group test: 200 mu L of xanthine substrate solution, 100 mu L of phosphate buffer solution and 200 mu L of xanthine oxidase solution are sequentially added into a 2 mL centrifuge tube, UA values of a blank control group are detected by the same method, and the average value is obtained by parallel operation for three times.

3. Positive control group test: 200 mu L of xanthine substrate solution, 100 mu L of positive control solution and 200 mu L of xanthine oxidase solution are sequentially added into a 2 mL centrifuge tube, UA values of a blank control group are detected by the same method, and the average value is obtained by parallel operation for three times.

Thirdly, a calculation method:

according to xanthine oxygenChemozyme inhibition rate = [ (blank control group UA value-sample group UA value)/blank group UA value]100, calculating inhibition rate; drug concentration in enzymatic reaction C = C₀*0.1/3.1（C₀As sample solution concentration); regressing the concentration of the medicine and the inhibition rate to obtain a regression equation; calculating the C value at 50% inhibition rate, i.e. half inhibition concentration IC, according to the regression equation₅₀The results are shown in table 1:

TABLE 1 test results of in vitro inhibition of xanthine oxidase by Compounds 1-3

Grouping	IC₅₀（μmol/L）
		Compound group 1	0.031
Compound 2 group	0.040
		Compound 3 group	0.132
Yangshen febuxostat group	0.058

The experimental result shows that the compound 1, the compound 2 and the compound 3 have certain xanthine oxidase inhibition effect. Wherein the xanthine oxidase inhibition effect of the compound 1 and the compound 2 is better than that of a positive control medicament febuxostat.

Test example 2: effect of Compounds 1-3 on lowering serum uric acid levels in hyperuricemic mice

1. Grouping experiments:

60 healthy male KM mice are averagely divided into 6 groups, and each group comprises 10 mice, namely a blank control group, a hyperuricemia model group, a positive control drug febuxostat group, a compound 1 group, a compound 2 group and a compound 3 group.

2. And (3) experimental operation:

mice were subjected to gavage administration after adaptive feeding, and were gavage 1 time a day in the morning. Suspending compound 1-3 with distilled water, and intragastrically administering at 2.0 mg/kg dose; suspending the positive control medicament febuxostat in distilled water, and performing intragastric administration according to the concentration of 2.0 mg/kg; the blank control group and the hyperuricemia model group are both subjected to intragastric gavage with distilled water for comparison, and the intragastric gavage is continuously carried out for 7 days.

Performing intraperitoneal injection molding on the mice after the gavage is performed for 0.5 h in the morning on the 7 th day, wherein a blank control group is subjected to intraperitoneal injection of 0.5% sodium carboxymethylcellulose solution; the hyperuricemia model group, the positive control febuxostat group, the compound 1 group, the compound 2 group, and the compound 3 group were injected with potassium oxonate in sodium carboxymethylcellulose solution (300 mg/kg body weight).

Removing eyeballs of the mice for blood collection after 1.5 h of intraperitoneal injection, placing the mice at room temperature for about 1h after the blood collection, centrifuging at 3500 rpm for 10 min after the blood is completely coagulated, taking serum to centrifuge again for 5 min under the same condition, and taking 0.2 mL of serum to detect UA value by using a biochemical analyzer.

TABLE 2 Effect of Compounds 1-3 on the serum uric acid level in hyperuricemia mice

Grouping	Serum uric acid (mu mol/L)
		Blank control group	100.9
Hyperuricemia positive model group	220.4
		Positive control febuxostat group	101.6
Compound group 1	90.7
		Compound 2 group	100.5
Compound 3 group	160.8

Test results show that the compound 1 and the compound 2 can obviously reduce the serum uric acid level of mice, and the compound 3 can reduce the uric acid level weakly. Under the same dosage, the uric acid reducing effect of the compound 1 and the compound 2 is the same as that of the positive control medicament febuxostat.

Test example 3: in vivo anti-acute gouty arthritis assay of compound 1 and compound 2

1. Making a model:

a male healthy SD rat is fixed in a supine position, the hind limb, the lower leg and the ankle joint are disinfected by 75% alcohol, a No. 6 injection needle is inserted into the inner side of a tibial tendon at the back side of the hind limb and the ankle joint of the rat from the 45-degree direction, 100 mu L of 10% sodium urate solution is injected after the rat feels a falling sensation, and an acute gouty arthritis model is manufactured according to the bulging of the opposite side of a joint capsule. The hind limb ankle joint of the blank control group was injected with an equal volume of saline.

2. And (3) experimental operation:

SD rats were randomly divided into 5 groups: normal group, model group, yangsheng colchicine group, example 1 group, example 2 group, 8 per group. Except for normal group and model group, the same amount of physiological saline is used for intragastric administration, and the corresponding drugs are respectively intragastric administered for 1 time per day and 7 days continuously in the groups of the example 1 and the example 2 and the colchicine group, and the intragastric administration dosage is 0.315 mg/kg.

After the injection is carried out for 1 hour on the 7 th day, a model is prepared, each administration group is administered once again after 2 hours after the model is built, a 10% urethane solution is used for anaesthetizing the rat at the 5 th hour after the model is built, blood is taken from the abdominal aorta after the rat is anaesthetized, the blood is centrifuged at 4000 rpm, and serum is separated for later use and is used for measuring the levels of nitric oxide (shown in figure 1), interleukin-8 (shown in figure 2) and prostaglandin-2 (shown in figure 3).

Test results show that the compound 1 and the compound 2 can effectively reduce the levels of nitric oxide, interleukin-8 and prostaglandin-2 in the serum of animals of acute gouty arthritis models, and have good treatment effect on the acute gouty arthritis.

Test example 4: examples 4 and 5 Effect of the creams on the model of pain caused by thermal stimulation

The mice are placed on a thermal stimulation pain-causing instrument with the constant temperature of 55 ℃, the time from the time when the mice are put into a hot plate to the time when the mice lick the hind feet is recorded by a stopwatch, the time is taken as the pain threshold value, the total time is measured for 2 times, and the average value is qualified when the average value does not exceed 30 s. The screened qualified animals are randomly divided into 4 groups of 10 animals, and the drugs are continuously applied for 3 days twice a day. The test is carried out every 0.5 h after the last administration, and the pain threshold is measured in 60 s when the pain threshold exceeds 60 s.

TABLE 3 Effect of the creams of example 4 and example 5 on the pain response in mice to thermal stimulation

The test results show that the cream in example 4 and the cream in example 5 both have certain inhibition effect on animal nonspecific acute pain models. The example 4 cream had a better pain-suppressing effect than the yang ginseng sitagliptin cream, and the example 5 cream was slightly less effective.

Claims

1. The specific structure of the dihydropyrimidino isoindolone compound is as follows or the application of the pharmaceutically acceptable salt thereof in preparing the anti-hyperuricemia drug,

；

；

。

2. a cream comprising an active ingredient of a dihydropyrimidino isoindolone compound of claim 1 or a pharmaceutically acceptable salt thereof, a humectant, a solid in an oil phase component, a consistency regulator, an emulsifier, a preservative and water.

3. The cream as claimed in claim 2, wherein the dihydropyrimidino isoindolone compound or its pharmaceutically acceptable salt is formulated in an amount of 0.01-2 parts.

4. The cream as claimed in claim 2, wherein the humectant is selected from one or more of glycerin, propylene glycol and sorbitol, and the formula ratio of the humectant is 3-10 parts.

5. The cream as claimed in claim 2, wherein the solid in the oil phase component is selected from one or more of stearic acid, paraffin, beeswax, cetyl alcohol and stearyl alcohol, and the solid formula ratio in the oil phase component is 1-15 parts.

6. The cream as set forth in claim 2, wherein the consistency regulator is selected from one or more of vaseline, liquid paraffin and castor oil, and the prescription ratio of the consistency regulator is 5-20 parts.

7. The cream as claimed in claim 2, wherein the emulsifier is selected from one or more of gelatin, acacia, tragacanth, apricot, pectin, peregal A-20, and sodium lauryl sulfate, and the formula ratio of the emulsifier is 0.5-5 parts.