Long-acting bactericidal ichthrite preparation and preparation method thereof

Abstract

The invention relates to the technical field of disinfection and anticorrosion preparations, in particular to a long-acting sterilization ichthin preparation and a preparation method thereof. The invention discloses a long-acting bactericidal ichthrite preparation which is prepared from the following raw materials in parts by mass: 15-26 parts of ichthrite, 5-12 parts of graphene oxide, 1-5 parts of butyl titanate, 6-12 parts of an emulsifier, 8-16 parts of sophocarpidine, 15-30 parts of water, 10-20 parts of liquid paraffin and 100-150 parts of vaseline. According to the invention, the local pain symptom can be quickly relieved, the anti-inflammatory effect is obvious, the slow-release effect is good, the drug effect time is greatly prolonged, the pain of a patient is relieved, and the obtained ointment preparation is high in sensory evaluation and free from the use defects of allergy and irritation in the use process. The preparation method is simple, the obtained product has good antibacterial, anti-inflammatory, detumescent, analgesic and hemostatic effects, and the curative effect of the product is guaranteed.

Description

Technical Field

[0001] The present invention relates to the technical field of disinfection and antiseptic preparations, and particularly relates to an ichthammol preparation with long-acting bactericidal effect and a preparation method thereof. Background Art

[0002] As the first physiological defense line and the largest organ of the human body, the skin maintains the unity of opposites between the body and the natural environment and participates in the body's functional activities at all times. The skin has many physiological protection functions: such as barrier function, sensory function, body temperature regulation, absorption function, secretion and excretion function, etc., and plays a very important role in maintaining the health of the body. When the physiological functions of the skin are damaged, skin diseases will occur.

[0003] Skin and soft tissue infections are common surgical diseases, usually acute suppurative inflammatory reactions caused by the invasion of local tissues by common pathogenic bacteria, etc., showing characteristic symptoms such as redness, swelling, heat, and pain. However, antibiotics will bring many adverse reactions and also cause corresponding drug resistance.

[0004] While ichthammol ointment has a certain curative effect in the external application treatment of acute cellulitis, improper use of existing ichthammol may aggravate the original infection. Preparing an ointment that is safe, stable, mild and non-irritating to the skin, and has a significant curative effect has excellent application prospects. Summary of the Invention

[0005] The purpose of the present invention is to solve the disadvantages existing in the prior art, and to propose an ichthammol preparation with long-acting bactericidal effect and a preparation method thereof.

[0006] An ichthammol preparation with long-acting bactericidal effect, the raw materials of which include, by mass: 15-26 parts of ichthammol, 5-12 parts of graphene oxide, 1-5 parts of tetrabutyl titanate, 6-12 parts of emulsifier, 8-16 parts of matrine, 15-30 parts of water, 10-20 parts of liquid paraffin, and 100-150 parts of vaseline.

[0007] Preferably, the vaseline is yellow vaseline with a melting point of 45-60°C.

[0008] Preferably, the HLB value of the emulsifier is less than or equal to 6.0.

[0009] Preferably, the emulsifier is at least one of sorbitan fatty acid ester, glycerol monostearate, and propylene glycol fatty acid ester.

[0010] The preparation method of the above-mentioned ichthammol preparation with long-acting bactericidal effect includes the following steps:

[0011] S1. Heat the vaseline until it melts, slowly add the liquid paraffin under stirring, stir for 10-20 min, add the ichthammol and the emulsifier and stir evenly to obtain a premix;

[0012] S2. Add graphene oxide to acetic acid aqueous solution and ultrasonically disperse for 10-20 minutes, adjust the pH value of the system to 4-6, add butyl titanate, stir at 60-70°C for 1-2 hours, let stand for 5-10 hours, filter, wash, dry and crush; then mix with matrine, then add to water and ultrasonically disperse for 10-20 minutes, then add dropwise to the premix which is continuously stirred, continue stirring for 10-20 minutes after the addition is complete, and cool to 20-23°C during the stirring process.

[0013] Preferably, in S2, the mass fraction of the acetic acid aqueous solution is 1-2%.

[0014] Preferably, in S2, the graphene oxide is added to the acetic acid aqueous solution and the ultrasonic dispersion frequency is 5-12 kHz.

[0015] Preferably, in S2, 1-2 mol / L hydrochloric acid is used to adjust the pH value of the system to 4-6.

[0016] Beneficial effects:

[0017] Because graphene oxide has a large specific surface area, rich pore size, good chemical stability, the present invention is loaded with nano titanium dioxide on the surface of graphene oxide sheet structure, and the hydrophilicity of graphene oxide and titanium dioxide is excellent at the same time, and the graphene oxide loaded with titanium dioxide can be dispersed in water, and under the action of emulsifier, a water-in-oil structure is formed in premix, so that the graphene oxide loaded with titanium dioxide is uniformly dispersed in the premix, and as the temperature decreases, vaseline solidifies in an ointment state. The above-mentioned structures are coordinated, so that the drug effect of the present invention continues to play a role in 24h after dressing change, and the redness, swelling, heat and pain of local tissues disappear quickly, and the inflammatory reaction of local tissues is suppressed to a certain extent at the same time, and leukocytes, neutrophils and proinflammatory cytokines are significantly reduced, and anti-inflammatory factors are significantly increased, which effectively suppresses original infection, and can quickly and effectively play the effect of promoting blood circulation and removing blood stasis of fish stone fat ointment, suppressing inflammatory reaction.

[0018] The invention can quickly relieve local pain symptoms, has significant anti-inflammatory effects, has good sustained-release effects, greatly increases the duration of drug efficacy, and relieves the pain of patients. The obtained ointment preparation has high sensory evaluation during use and has no allergic or irritating use defects. The preparation method of the invention is simple, and the obtained product has good antibacterial, anti-inflammatory, detumescent, analgesic, and hemostatic effects, and the efficacy of the product is guaranteed. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] Figure 1 It is a comparison chart of the white blood cell content and neutrophil ratio in the blood of rats in the blank group, model group, positive control group, Example 5 group, Comparative Example 1 group, and Comparative Example 2 group.

[0020] Figure 2Comparison chart of the contents of TNF-α and IFN-α in the sera of rats in the blank group, model group, positive control group, Example 5 group, Comparative Example 1 group, and Comparative Example 2 group.

[0021] Figure 3 For the contents of IL-1α and IL-6 in the sera of mice in the blank group, model group, Example 5 group, Comparative Example 1 group, and Comparative Example 2 group

[0022] Figure 4 Comparison chart of the contents of IL-1β and IL-10 in the sera of mice in the blank group, model group, Example 5 group, Comparative Example 1 group, and Comparative Example 2 group. Detailed implementation manners

[0023] The present invention will be further illustrated below in conjunction with specific embodiments.

[0024] Example 1

[0025] A long-acting bactericidal ichthammol preparation, the raw materials of which include: 150 g of ichthammol, 50 g of graphene oxide, 10 g of tetrabutyl titanate, 60 g of glyceryl monostearate, 80 g of matrine, 150 g of water, 100 g of liquid paraffin, and 1000 g of vaseline.

[0026] The preparation method of the above long-acting bactericidal ichthammol preparation includes the following steps:

[0027] S1. Add vaseline to an emulsifying tank and heat it to 60°C. Slowly add liquid paraffin under stirring, stir for 10 min, add ichthammol and glyceryl monostearate, and stir evenly to obtain a premix.

[0028] S2. Add graphene oxide to 500 g of an aqueous acetic acid solution with a mass fraction of 1% and ultrasonically disperse it for 10 min. The ultrasonic frequency is 5 kHz. Adjust the pH value of the system to 4 with hydrochloric acid with a concentration of 1 mol / L. Add tetrabutyl titanate, stir at a temperature of 60°C for 1 h, the stirring speed is 100 r / min, let it stand for 5 h, filter by suction, wash successively with deionized water and absolute ethanol, dry in vacuum, and pulverize; then mix with matrine, then add it to deionized water and ultrasonically disperse it for 10 min, and then drop it into the continuously stirred premix. After complete dropping, continue to stir for 10 min, and cool down to 20°C during the continuous stirring process.

[0029] Example 2

[0030] A long-acting bactericidal ichthammol preparation, the raw materials of which include: 260 g of ichthammol, 120 g of graphene oxide, 50 g of tetrabutyl titanate, 120 g of propylene glycol monostearate, 160 g of matrine, 300 g of water, 200 g of liquid paraffin, and 1500 g of vaseline.

[0031] The preparation method of the above-mentioned ichthammol preparation with long-acting bactericidal effect comprises the following steps:

[0032] S1. Add vaseline into an emulsifying tank, heat it to 70 °C, slowly add liquid paraffin under stirring, stir for 20 min, add ichthammol and propylene glycol monostearate, and stir evenly to obtain a premix.

[0033] S2. Add graphene oxide into 1000 g of acetic acid aqueous solution with a mass fraction of 2%, ultrasonically disperse for 20 min, the ultrasonic frequency is 12 kHz, adjust the pH value of the system to 6 with 2 mol / L hydrochloric acid, add tetrabutyl titanate, stir at 70 °C for 2 h, the stirring speed is 300 r / min, stand for 10 h, filter by suction, wash successively with deionized water and absolute ethanol, dry in vacuum, and pulverize; then mix with matrine, then add it into deionized water and ultrasonically disperse for 20 min, and then dropwise add it into the continuously stirred premix. After complete dropping, continue to stir for 20 min, and cool down to 23 °C during the continuous stirring process.

[0034] Example 3

[0035] An ichthammol preparation with long-acting bactericidal effect, whose raw materials include: 220 g of ichthammol, 100 g of graphene oxide, 20 g of tetrabutyl titanate, 100 g of span 80, 100 g of matrine, 240 g of water, 120 g of liquid paraffin, and 1300 g of vaseline.

[0036] The preparation method of the above-mentioned ichthammol preparation with long-acting bactericidal effect comprises the following steps:

[0037] S1. Add vaseline into an emulsifying tank, heat it to 62 °C, slowly add liquid paraffin under stirring, stir for 18 min, add ichthammol and span 80, and stir evenly to obtain a premix.

[0038] S2. Add graphene oxide into 700 g of acetic acid aqueous solution with a mass fraction of 1.5%, ultrasonically disperse for 18 min, the ultrasonic frequency is 6 kHz, adjust the pH value of the system to 4.5 with 1.7 mol / L hydrochloric acid, add tetrabutyl titanate, stir at 68 °C for 80 min, the stirring speed is 250 r / min, stand for 7 h, filter by suction, wash successively with deionized water and absolute ethanol, dry in vacuum, and pulverize; then mix with matrine, then add it into deionized water and ultrasonically disperse for 18 min, and then dropwise add it into the continuously stirred premix. After complete dropping, continue to stir for 13 min, and cool down to 22 °C during the continuous stirring process.

[0039] Example 4

[0040] A long-acting bactericidal ichthammol preparation, the raw materials of which include: 200 g of ichthammol, 60 g of graphene oxide, 40 g of tetrabutyl titanate, 80 g of span 65, 140 g of matrine, 200 g of water, 180 g of liquid paraffin, and 1100 g of vaseline.

[0041] The preparation method of the above-mentioned long-acting bactericidal ichthammol preparation includes the following steps:

[0042] S1. Add vaseline to an emulsifying tank, heat it to 68 °C, slowly add liquid paraffin under stirring, stir for 12 min, add ichthammol and span 65, and stir evenly to obtain a premix.

[0043] S2. Add graphene oxide to 900 g of an acetic acid aqueous solution with a mass fraction of 1.5%, ultrasonically disperse it for 12 min, the ultrasonic frequency is 9 kHz, adjust the pH value of the system to 5.5 with hydrochloric acid with a concentration of 1.3 mol / L, add tetrabutyl titanate, stir at a temperature of 62 °C for 100 min, the stirring speed is 150 r / min, let it stand for 9 h, filter by suction, wash with deionized water and absolute ethanol in sequence, dry in vacuum, and pulverize; then mix with matrine, then add it to deionized water and ultrasonically disperse it for 12 min, and then drop it into the continuously stirred premix. After complete dropping, continue to stir for 17 min, and cool down to 21 °C during the continuous stirring process.

[0044] Example 5

[0045] A long-acting bactericidal ichthammol preparation, the raw materials of which include: 210 g of ichthammol, 80 g of graphene oxide, 30 g of tetrabutyl titanate, 90 g of span 85, 120 g of matrine, 220 g of water, 150 g of liquid paraffin, and 1200 g of vaseline.

[0046] The preparation method of the above-mentioned long-acting bactericidal ichthammol preparation includes the following steps:

[0047] S1. Add vaseline to an emulsifying tank, heat it to 65 °C, slowly add liquid paraffin under stirring, stir for 15 min, add ichthammol and span 85, and stir evenly to obtain a premix.

[0048] S2. Add graphene oxide to 800 g of an acetic acid aqueous solution with a mass fraction of 1.5%, ultrasonically disperse it for 15 min, the ultrasonic frequency is 7.5 kHz, adjust the pH value of the system to 5 with hydrochloric acid with a concentration of 1.5 mol / L, add tetrabutyl titanate, stir at a temperature of 65 °C for 90 min, the stirring speed is 200 r / min, let it stand for 8 h, filter by suction, wash with deionized water and absolute ethanol in sequence, dry in vacuum, and pulverize; then mix with matrine, then add it to deionized water and ultrasonically disperse it for 15 min, and then drop it into the continuously stirred premix. After complete dropping, continue to stir for 15 min, and cool down to 22 °C during the continuous stirring process.

[0049] Comparative Example 1

[0050] A ichthammol preparation, the raw materials of which include: 210 g of ichthammol, 80 g of graphene oxide, 30 g of tetrabutyl titanate, 90 g of Span 85, 120 g of matrine, 220 g of water, 150 g of liquid paraffin, and 1200 g of vaseline.

[0051] The preparation method of the above ichthammol preparation includes the following steps:

[0052] S1. Add vaseline to an emulsifying tank and heat it to 65 °C. Slowly add liquid paraffin under stirring, stir for 15 min, add ichthammol and Span 85 and stir evenly to obtain a premix.

[0053] S2. Mix graphene oxide and matrine, then add them to deionized water and ultrasonically disperse for 15 min, and then dropwise add them to the continuously stirred premix. After complete dropping, continue to stir for 15 min, and cool down to 22 °C during the continuous stirring process.

[0054] Comparative Example 2

[0055] A ichthammol preparation, the raw materials of which include: 210 g of ichthammol, 80 g of graphene oxide, 30 g of tetrabutyl titanate, 90 g of Span 85, 120 g of matrine, 220 g of water, 150 g of liquid paraffin, and 1200 g of vaseline.

[0056] The preparation method of the above ichthammol preparation includes the following steps:

[0057] S1. Add vaseline to an emulsifying tank and heat it to 65 °C. Slowly add liquid paraffin under stirring, stir for 15 min, add ichthammol and Span 85 and stir evenly to obtain a premix.

[0058] S2. Add tetrabutyl titanate to 800 g of an acetic acid aqueous solution with a mass fraction of 1.5% and ultrasonically disperse for 15 min. The ultrasonic frequency is 7.5 kHz. Adjust the pH value of the system to 5 with hydrochloric acid with a concentration of 1.5 mol / L, add tetrabutyl titanate, stir at 65 °C for 90 min, the stirring speed is 200 r / min, stand for 8 h, filter by suction, wash successively with deionized water and absolute ethanol, dry in vacuum, and pulverize; then mix with matrine and graphene oxide, then add them to deionized water and ultrasonically disperse for 15 min, and then dropwise add them to the continuously stirred premix. After complete dropping, continue to stir for 15 min, and cool down to 22 °C during the continuous stirring process.

[0059] Animal skin and soft tissue infection comparative experiments were carried out on the ichthammol preparations obtained in Example 5 and Comparative Examples 1-2, as follows:

[0060] Ninety 2-month-old Wistar rats (half male and half female, with a body weight of 240±20 g, feeding conditions: room temperature 23±2°C, humidity 40 - 50%, free access to food and water, natural circadian rhythm, and purified water as drinking water) were adaptively fed in an SPF-class laboratory for one week and then randomly divided into a blank group (CK), a model group (MC), a positive control group (PC), an Example 5 group (SS5), a Comparative Example 1 group (DB1), and a Comparative Example 2 group (DB2), with 15 rats in each group.

[0061] For each rat in each group, a 2 cm×2 cm area was marked with a signature pen on the back near the neck side with the spine as the midline and then depilated; subsequently, the model group, the positive control group, the Example 5 group, the Comparative Example 1 group, and the Comparative Example 2 group were subcutaneously injected (0.5 mL of 1.68×10 10 / mL Escherichia coli solution) for modeling (fixed with oil sand, dressing, and tape, and raised individually in a single cage. If redness, swelling, heat, and pain were observed 8 hours later, the modeling was considered successful, and the covering was removed 8 hours later).

[0062] On the day after modeling, drugs were applied externally to the skin once a day for 15 consecutive days. After administration, the area was covered with a gauze and the rats were raised individually in a single cage. Among them, the blank group and the model group were smeared with 1.00 g of vaseline, the positive control group was smeared with 1.00 g of vaseline containing mupirocin (including 0.50 g of mupirocin), the Example 5 group was smeared with 1.00 g of the ichthammol preparation obtained in Example 5, the Comparative Example 1 group was smeared with 1.00 g of the ichthammol preparation obtained in Comparative Example 1, and the Comparative Example 2 group was smeared with 1.00 g of the ichthammol preparation obtained in Comparative Example 1.

[0063] 2 hours after the last administration, the rats were anesthetized and blood was collected from the abdominal aorta. 2 mL of the blood was taken out and put into a blood collection tube containing EDTA anticoagulant. The white blood cell count and neutrophil ratio in the whole blood were detected using a blood cell analyzer. The remaining blood was centrifuged (3500 r / min) to prepare serum, and the contents of TNF-α and IFN-α were detected using an ELISA kit.

[0064] It can be seen from Figure 1 and Figure 2 that:

[0065] (1) The white blood cell count, neutrophil ratio, TNF-α and IFN-α contents in the rats of the model group were all extremely significantly higher than those in the blank group (P < 0.01), confirming the success of modeling;

[0066] (2) The white blood cell count, neutrophil ratio, TNF-α and IFN-α contents in the rats of the positive control group, the Example 5 group, the Comparative Example 1 group, and the Comparative Example 2 group were all significantly lower than those in the model group (P < 0.05), confirming that mupirocin, the ichthammol preparation obtained in Example 5 and Comparative Examples 1 - 2 all had curative effects on skin and soft tissue infections and effectively inhibited the infections;

[0067] (3) The leukocyte count, neutrophil ratio, TNF-α and IFN-α contents in the positive control group and the rats in Example 5 group were significantly lower than those in Comparative Example 1 group and Comparative Example 2 group (P < 0.05), which confirmed that the efficacy of mupirocin and the ichthammol preparation obtained in Example 5 was better than that of the ichthammol preparation obtained in Comparative Examples 1-2;

[0068] (4) There was no significant difference in the leukocyte count, neutrophil ratio, TNF-α and IFN-α contents between the positive control group and the rats in Example 5 group (P > 0.05), which confirmed that the efficacy of mupirocin and the ichthammol preparation obtained in Example 5 was similar.

[0069] Animal anti-inflammatory comparative experiments were carried out using the ichthammol preparations obtained in Example 5 and Comparative Examples 1-2, as follows:

[0070] Sixty Balb / c mice (half male and half female, body weight 20 ± 2 g, breeding conditions: room temperature 23 ± 2 °C, humidity 40 - 50%, free access to food and water, natural circadian rhythm, drinking water was purified water) were taken. After being adaptively bred in an SPF-class laboratory for one week, they were randomly divided into a blank group (CK), a model group (MC), an Example 5 group (SS5), a Comparative Example 1 group (DB1), and a Comparative Example 2 group (DB2), with 12 mice in each group.

[0071] Among them, 1.00 g of vaseline was applied to the abdomen of the mice in the blank group and the model group, 1.00 g of the ichthammol preparation obtained in Example 5 was applied to the abdomen of the mice in the Example 5 group, 1.00 g of the ichthammol preparation obtained in Comparative Example 1 was applied to the abdomen of the mice in the Comparative Example 1 group, and 1.00 g of the ichthammol preparation obtained in Comparative Example 1 was applied to the abdomen of the mice in the Comparative Example 2 group. Administration was continued for 7 d. Except for the blank group, 0.2 mL of 0.67% glacial acetic acid solution was intraperitoneally injected into each mouse 40 min after administration to establish a peritonitis model group.

[0072] Blood was collected from the orbital venous plexus 20 min after injecting glacial acetic acid, serum was separated, and the contents of IL-1α, IL-1β, IL-6, and IL-10 in the serum were measured using an enzyme-linked immunosorbent assay (ELISA) as Figure 3 and Figure 4 shown.

[0073] It can be seen from Figure 3 and Figure 4 that:

[0074] (1) The contents of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6) in the rats in the model group were extremely significantly higher than those in the blank group (P < 0.01), while the content of the anti-inflammatory cytokine (IL-10) was significantly lower than that in the blank group (P < 0.05), which confirmed that the model was successfully established;

[0075] (2) The contents of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6) in the rats of the Example 5 group, the Comparative Example 1 group, and the Comparative Example 2 group were all significantly lower than those in the model group (P < 0.05), while the content of the anti-inflammatory cytokine (IL-10) was significantly higher than that in the model group, confirming that the ichthammol preparations obtained in Example 5 and Comparative Examples 1-2 have anti-inflammatory effects;

[0076] (3) The contents of pro-inflammatory cytokines (IL-1α, IL-1β, IL-6) in the rats of the Example 5 group were all significantly lower than those in the Comparative Examples 1-2 group (P < 0.05), while the content of the anti-inflammatory cytokine (IL-10) was significantly higher than that in the Comparative Examples 1-2 group, confirming that the anti-inflammatory effect of the ichthammol preparation obtained in Example 5 is better than that of Comparative Examples 1-2.

[0077] As described above, only the specific preferred embodiments of the present invention are provided, but the protection scope of the present invention is not limited thereto. Any person skilled in the art within the technical scope disclosed by the present invention, according to the technical solution and inventive concept of the present invention, makes equivalent substitutions or changes, and should be covered by the protection scope of the present invention.

Claims

1. A long-acting bactericidal ichthyol preparation, characterized in that: The raw materials include, by mass, 15-26 parts of ichthyol, 5-12 parts of graphene oxide, 1-5 parts of butyl titanate, 6-12 parts of emulsifier, 8-16 parts of matrine, 15-30 parts of water, 10-20 parts of liquid paraffin and 100-150 parts of vaseline.

2. The long-acting bactericidal ichthyol preparation according to claim 1, characterized in that: Vaseline is yellow vaseline with a melting point of 45-60°C.

3. The long-acting bactericidal ichthyol preparation according to claim 1, characterized in that: The HLB value of the emulsifier is less than or equal to 6.

0.

4. The long-acting bactericidal ichthyol preparation according to claim 1, characterized in that: The emulsifier is at least one of sorbitan fatty acid ester, glyceryl monostearate and propylene glycol fatty acid ester.

5. A method for preparing a long-acting bactericidal ichthyol preparation as claimed in any one of claims 1 to 4, characterized in that: The steps include: S1. Heat vaseline until it is melted, slowly add liquid paraffin while stirring, stir for 10-20 minutes, add ichthyol and emulsifier and stir evenly to obtain a premix; S2. Add graphene oxide to acetic acid aqueous solution and ultrasonically disperse for 10-20 minutes, adjust the pH value of the system to 4-6, add butyl titanate, stir at 60-70°C for 1-2 hours, let stand for 5-10 hours, filter, wash, dry and crush; then mix with matrine, then add to water and ultrasonically disperse for 10-20 minutes, then add dropwise to the premix which is continuously stirred, continue stirring for 10-20 minutes after the addition is complete, and cool to 20-23°C during the stirring process.

6. The method for preparing the long-acting bactericidal ichthyol preparation according to claim 1, characterized in that: In S2, the mass fraction of the acetic acid aqueous solution is 1-2%.

7. The method for preparing the long-acting bactericidal ichthyol preparation according to claim 1, characterized in that: In S2, graphene oxide is added to an acetic acid aqueous solution and the ultrasonic dispersion frequency is 5-12 kHz.

8. The method for preparing the long-acting bactericidal ichthyol preparation according to claim 1, characterized in that: In S2, 1-2 mol / L hydrochloric acid is used to adjust the pH value of the system to 4-6.

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