CN109821062B - Preparation method of medical antibacterial gel - Google Patents
Preparation method of medical antibacterial gel Download PDFInfo
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Abstract
The invention discloses a preparation method of medical antibacterial gel, which comprises the following operation steps: (1) carrying out addition reaction on polyethylene glycol and thioglycollic acid according to the mass ratio of 25-30:2 to obtain sulfhydryl modified polyethylene glycol, PEG-4-SH; (2) dissolving PEG-4-SH and cecropin antibacterial peptide in PBS solution according to the mass ratio of 10-15:1, and dialyzing to obtain cecropin antibacterial peptide modified polyethylene glycol, PEG-4-SH-AMP; (3) sequentially adding glycerol, polyethylene glycol, PEG-4-SH-AMP, carbomer, methyl paraben and propyl paraben into distilled water, stirring, adding sodium hydroxide solid, continuously stirring, performing ultrasonic defoaming treatment, and performing freezing-thawing cycle treatment to obtain the medical gel. The medical gel prepared by the preparation method has the advantages of obvious antibacterial effect and strong chemical stability, and the antibacterial agent cannot be separated out in the storage process, so that the service life of the medical gel is effectively prolonged, and the medical gel cannot cause damage to human bodies.
Description
Technical Field
The invention belongs to the technical field of new medical materials, and particularly relates to a preparation method of medical antibacterial gel.
Background
A hydrogel is a hydrophilic, water-insoluble polymer macromolecule in the form of a semi-open network system cross-linked by entangled chains or short chains of varying lengths. Upon contact with water or any biological fluid, large amounts of solvent can be trapped within the pores or interstitial spaces, expanding to several times their volume, which results in a drastic change in its rheological properties and a final phase change. The stiffness and water absorption capacity of hydrogels are caused by the presence of hydrophilic functional groups (such as alcohols, fusidic acids, phthalamides, and the like) attached to the polymer backbone, while the presence of cross-linking makes them resistant to dissolution in aqueous media. Hydrogels have been widely used to date in various biomedical fields including tissue engineering, drug delivery, gene delivery, 3D bioprinting, artificial skin, biosensors, wound healing, cancer research and antibacterial research, contact lenses, and the like. The hydrogel material is contacted with body fluid, and in a complex body fluid environment, protein accumulation and microorganism propagation are easily caused, and the high water content of the hydrogel material provides a good living environment for the microorganism propagation, so that an inflammatory reaction at the hydrogel implantation or contact part can be caused. Therefore, in the prior art, some antibacterial drugs are often added in the preparation process of the hydrogel, and the antibacterial drugs and the hydrogel are combined by a physical or chemical method (the antibacterial hydrogel), so that the local antibacterial efficacy of the hydrogel can be enhanced, and the hydrogel is an effective method for overcoming infection caused by the hydrogel. In the prior art, the added antibacterial agent is not obvious in improvement of the antibacterial property of the hydrogel, so that the antibacterial property of the hydrogel needs to be improved by increasing the using amount of the antibacterial agent, and the excessive antibacterial agent not only increases the cost, but also can cause harm to a user. On the other hand, the stability of the existing antibacterial drugs in the hydrogel is poor, and the existing antibacterial drugs are easy to separate from large-structure molecules of the hydrogel for precipitation, so that the storage period of the existing antibacterial drugs is short.
Disclosure of Invention
According to the invention, the cecropin antibacterial peptide modified polyethylene glycol is prepared and added as a medical gel raw material, so that the dosage of the existing antibacterial drug is effectively reduced, and the storage time of the medical gel is prolonged.
The invention is realized by the following technical scheme.
A preparation method of medical antibacterial gel comprises the following operation steps:
(1) completely dissolving polyethylene glycol and thioglycolic acid in toluene according to the mass ratio of 25-30:2, dripping concentrated sulfuric acid with the volume of 0.1% of the volume of the mixed solution into the toluene, performing reflux reaction for 30-40 hours to obtain a reaction solution, adding the reaction solution into cold ether, standing for precipitation, filtering, and drying a filter cake in vacuum to obtain sulfhydryl modified polyethylene glycol, PEG-4-SH;
(2) dissolving PEG-4-SH and cecropin antibacterial peptide in PBS solution according to the mass ratio of 10-15:1, dialyzing in distilled water for 4-5 days, and freeze-drying to obtain cecropin antibacterial peptide modified polyethylene glycol, PEG-4-SH-AMP;
(3) according to the weight portion, 8-13 portions of glycerol, 77-84 portions of polyethylene glycol, 40-50 portions of PEG-4-SH-AMP, 8-12 portions of Carm's glue, 0.2-0.5 portion of methyl paraben and 0.2-0.5 portion of propyl paraben are sequentially added into 840-860 portions of distilled water, after stirring treatment, 3-6 portions of sodium hydroxide solid are added into the distilled water, after continuing stirring treatment, ultrasonic defoaming treatment is carried out for 40-50min, and then freezing-unfreezing circulation treatment is carried out for 5-7 times, thus obtaining the medical gel.
Specifically, in the step (1), the average molecular weight of polyethylene glycol is 10500-.
Specifically, in the step (1), the cold diethyl ether is diethyl ether, and the cold diethyl ether is prepared after being placed in a refrigerator at the temperature of minus 20 ℃ for 1 hour.
Specifically, in the step (1), the filter cake is washed before vacuum drying, and the washing operation is as follows: dissolving the filter cake with dichloromethane, washing the obtained solution with saturated sodium bicarbonate solution, drying the organic phase with anhydrous sodium sulfate after liquid separation, performing rotary evaporation and concentration on the organic phase after filtration to obtain viscous liquid, dropwise adding the obtained viscous liquid into excessive cold ether, precipitating, filtering, and performing vacuum drying.
Specifically, in the step (2), the molecular cut-off amount of the dialysis bag during dialysis was 10000.
Specifically, in the step (3), the frequency of the ultrasonic wave during the ultrasonic defoaming is 28-32 kHz.
Specifically, in the step (3), the operation of the freeze-thaw cycle process is: freezing at-20 deg.C for 12 hr, and thawing at room temperature for 6 hr.
According to the technical scheme, the beneficial effects of the invention are as follows:
the medical gel prepared by the preparation method has the advantages of obvious antibacterial effect and strong chemical stability, and the antibacterial agent cannot be separated out in the storage process, so that the service life of the medical gel is effectively prolonged, and the medical gel cannot cause damage to human bodies. The antibacterial agent has low content of methyl paraben and propyl paraben, so that the medical gel has excellent antibacterial effect and cannot cause damage to human bodies; PEG-4-SH generated after the addition reaction of polyethylene glycol and thioglycolic acid can be effectively combined with antibacterial peptide, so that the phenomenon that the antibacterial peptide is easy to lose efficacy due to the independent addition of the antibacterial peptide is avoided, the antibacterial peptide cannot cause harm to human bodies, the antibacterial effect is obvious, and the relative content of methyl paraben and propyl paraben is effectively reduced; the PEG-4-SH-AMP prepared by the invention can exist stably in medical gel, and meanwhile, the existence of the antibacterial peptide can also improve the liquid absorption capacity of the gel, maintain the moist environment of the wound surface of a patient and prevent a large amount of loss of tissue fluid.
Detailed Description
The following examples are intended to illustrate the invention but are not intended to limit the scope of the invention. The conditions used in the examples may be further adjusted according to the manufacturer's conditions, and the unexplained conditions are generally conventional experimental conditions.
Example 1
A preparation method of medical antibacterial gel comprises the following operation steps:
(1) completely dissolving 25g of polyethylene glycol and 2g of thioglycolic acid in 100ml of toluene, dripping concentrated sulfuric acid with the volume of 0.1% of the volume of the mixed solution into the toluene, performing reflux reaction for 30 hours to obtain a reaction solution, adding the reaction solution into cold diethyl ether, standing and precipitating, filtering, dissolving a filter cake with dichloromethane, washing the obtained solution with a saturated sodium bicarbonate solution, drying an organic phase after liquid separation with anhydrous sodium sulfate, performing rotary evaporation and concentration on the filtered organic phase to obtain a viscous liquid, dripping the obtained viscous liquid into excessive cold diethyl ether, performing vacuum drying after precipitation and filtration to obtain a filter cake, and performing vacuum drying to obtain sulfhydryl-modified polyethylene glycol, PEG-4-SH, wherein the cold diethyl ether is prepared by placing diethyl ether in a refrigerator at the temperature of 20 ℃ below zero for 1 hour;
(2) dissolving 10g of PEG-4-SH and 1g of cecropin antibacterial peptide in 100ml of PBS solution, dialyzing for 4 days in distilled water by using a dialysis bag with the molecular interception amount of 10000, and freeze-drying to obtain cecropin antibacterial peptide modified polyethylene glycol, PEG-4-SH-AMP;
(3) according to the weight portion, 8 portions of glycerol, 77 portions of polyethylene glycol, 40 portions of PEG-4-SH-AMP, 8 portions of Carm's glue, 0.2 portion of methyl hydroxybenzoate and 0.2 portion of propyl hydroxybenzoate are sequentially added into 840 portions of distilled water, 3 portions of sodium hydroxide solid are added into the distilled water after stirring treatment, ultrasonic defoaming treatment is carried out for 40min at the ultrasonic frequency of 28kHz after continuous stirring treatment, then the mixture is added into a tetrafluoroethylene mold, freezing is carried out for 12h at the temperature of-20 ℃, unfreezing is carried out for 6h at the room temperature, and freezing-unfreezing circulation treatment is carried out for 5 times, so that the medical gel is obtained.
Wherein the polyethylene glycol used in the step (1) has an average molecular weight of 10500, and the polyethylene glycol used in the step (3) has an average molecular weight of 400.
Example 2
A preparation method of medical antibacterial gel comprises the following operation steps:
(1) completely dissolving 28g of polyethylene glycol and 2g of thioglycolic acid in 100ml of toluene, dripping concentrated sulfuric acid with the volume of 0.1% of the volume of the mixed solution into the toluene, performing reflux reaction for 35 hours to obtain a reaction solution, adding the reaction solution into cold diethyl ether, standing and precipitating, filtering, dissolving a filter cake with dichloromethane, washing the obtained solution with a saturated sodium bicarbonate solution, drying an organic phase after liquid separation with anhydrous sodium sulfate, performing rotary evaporation and concentration on the filtered organic phase to obtain a viscous liquid, dripping the obtained viscous liquid into excessive cold diethyl ether, performing vacuum drying after precipitation and filtration to obtain a filter cake, and performing vacuum drying to obtain sulfhydryl-modified polyethylene glycol, PEG-4-SH, wherein the cold diethyl ether is prepared by placing diethyl ether in a refrigerator at the temperature of 20 ℃ below zero for 1 hour;
(2) dissolving 13g of PEG-4-SH and 1g of cecropin antibacterial peptide in 100ml of PBS solution, dialyzing for 4 days in distilled water by using a dialysis bag with the molecular interception amount of 10000, and freeze-drying to obtain cecropin antibacterial peptide modified polyethylene glycol, PEG-4-SH-AMP;
(3) according to the weight portion, 10 portions of glycerol, 80 portions of polyethylene glycol, 45 portions of PEG-4-SH-AMP, 10 portions of Carm glue, 0.4 portion of methyl hydroxybenzoate and 0.4 portion of propyl hydroxybenzoate are sequentially added into 850 portions of distilled water, 5 portions of sodium hydroxide solid is added after stirring treatment, ultrasonic defoaming treatment is carried out for 45min at the frequency of ultrasonic wave of 30kHz after continuous stirring treatment, then the mixture is added into a tetrafluoroethylene mold, freezing is carried out for 12h at the temperature of-20 ℃, unfreezing is carried out for 6h at the room temperature, and freezing-unfreezing circulation treatment is carried out for 6 times, so that the medical gel is obtained.
Wherein the polyethylene glycol used in the step (1) has an average molecular weight of 13000, and the polyethylene glycol used in the step (3) has an average molecular weight of 500.
Example 3
A preparation method of medical antibacterial gel comprises the following operation steps:
(1) completely dissolving 30g of polyethylene glycol and 2g of thioglycolic acid in 100ml of toluene, dripping concentrated sulfuric acid with the volume of 0.1% of the volume of the mixed solution into the toluene, performing reflux reaction for 40 hours to obtain a reaction solution, adding the reaction solution into cold diethyl ether, standing and precipitating, filtering, dissolving a filter cake with dichloromethane, washing the obtained solution with a saturated sodium bicarbonate solution, drying an organic phase after liquid separation with anhydrous sodium sulfate, performing rotary evaporation and concentration on the filtered organic phase to obtain a viscous liquid, dripping the obtained viscous liquid into excessive cold diethyl ether, performing vacuum drying after precipitation and filtration to obtain a filter cake, and performing vacuum drying to obtain sulfhydryl-modified polyethylene glycol, PEG-4-SH, wherein the cold diethyl ether is prepared by placing diethyl ether in a refrigerator at the temperature of 20 ℃ below zero for 1 hour;
(2) dissolving 15g of PEG-4-SH and 1g of cecropin antibacterial peptide in 100ml of PBS solution, dialyzing for 5 days in distilled water by using a dialysis bag with the molecular interception amount of 10000, and freeze-drying to obtain cecropin antibacterial peptide modified polyethylene glycol, PEG-4-SH-AMP;
(3) according to the weight portion, 13 portions of glycerol, 84 portions of polyethylene glycol, 50 portions of PEG-4-SH-AMP, 12 portions of Carm glue, 0.5 portion of methyl hydroxybenzoate and 0.5 portion of propyl hydroxybenzoate are sequentially added into 840-860 portions of distilled water, after stirring treatment, 6 portions of sodium hydroxide solid are added, after continuing stirring treatment, ultrasonic defoaming treatment is carried out for 50min at the ultrasonic frequency of 32kHz, then the mixture is added into a tetrafluoroethylene mold, freezing is carried out for 12h at the temperature of-20 ℃, unfreezing is carried out for 6h at the room temperature, and freezing-unfreezing circulation treatment is carried out for 7 times, so that the medical gel is obtained.
Wherein the polyethylene glycol used in the step (1) has an average molecular weight of 15000, and the polyethylene glycol used in the step (3) has an average molecular weight of 600.
Comparative example 1
The procedure was exactly the same as in example 1 except that PEG-4-SH-AMP in step (3) was replaced with polyethylene glycol having an average molecular weight of 10500.
Comparative example 2
The PEG-4-SH-AMP in the step (3) is replaced by a mixture of PEG-4-SH and cecropin antibacterial peptide with equal weight (the PEG-4-SH and the cecropin antibacterial peptide are not dialyzed), wherein the mass ratio of the polyethylene glycol to the cecropin antibacterial peptide is 15:1, and the rest operation steps are completely the same as those in the example 3.
The test method comprises the following steps:
(1) determination of equilibrium swelling ratio: the prepared medical gel was dried in a vacuum oven at 60 ℃ for 24 hours and then weighed (Wa), and then the dried sample was soaked in 500mL of distilled water, and the sample was weighed (Wb) at intervals until the hydrogel reached an equilibrium swelling state, and the equilibrium Swelling Ratio (SR) was calculated by the following formula:
SR＝(Wb-Wa)/Wa；
(2) the antibacterial performance evaluation of the medical gel is carried out by adopting methods of GB 15979-2002 appendix C4 antibacterial performance test of sanitary Standard for Disposable sanitary articles and disinfection technical Specification (2002 edition 2.1.8.2 antibacterial Ring test).
The results of the equilibrium swell ratio test are shown in table 1:
TABLE 1 equilibrium swelling ratio of medical gels
As shown in Table 1, the PEG-4-SH-AMP prepared by the method can effectively improve the swelling rate of medical gel, improve the liquid absorption capacity of the gel, maintain the moist environment of the wound surface of a patient and prevent a large amount of loss of tissue fluid.
The antimicrobial effect of the medical gel is shown in table 2:
TABLE 2 antibacterial Effect of medical gels
As can be seen from Table 2, the medical gel prepared by the invention has excellent antibacterial effect, wherein the antibacterial effect on staphylococcus aureus is most remarkable.
It is to be understood that the above description is not intended to limit the present invention, and the present invention is not limited to the above examples, and those skilled in the art should understand that they can make various changes, modifications, additions and substitutions within the spirit and scope of the present invention.
Claims (7)
1. The preparation method of the medical antibacterial gel is characterized by comprising the following operation steps:
(1) completely dissolving polyethylene glycol and thioglycolic acid in toluene according to the mass ratio of 25-30:2, dripping concentrated sulfuric acid with the volume of 0.1% of the volume of the mixed solution into the toluene, performing reflux reaction for 30-40 hours to obtain a reaction solution, adding the reaction solution into cold ether, standing for precipitation, filtering, and drying a filter cake in vacuum to obtain sulfhydryl modified polyethylene glycol, PEG-4-SH;
(2) dissolving PEG-4-SH and cecropin antibacterial peptide in PBS solution according to the mass ratio of 10-15:1, dialyzing in distilled water for 4-5 days, and freeze-drying to obtain cecropin antibacterial peptide modified polyethylene glycol, PEG-4-SH-AMP;
(3) according to the weight portion, 8-13 portions of glycerol, 77-84 portions of polyethylene glycol, 40-50 portions of PEG-4-SH-AMP, 8-12 portions of Carm's glue, 0.2-0.5 portion of methyl paraben and 0.2-0.5 portion of propyl paraben are sequentially added into 840-860 portions of distilled water, after stirring treatment, 3-6 portions of sodium hydroxide solid are added into the distilled water, after continuing stirring treatment, ultrasonic defoaming treatment is carried out for 40-50min, and then freezing-unfreezing circulation treatment is carried out for 5-7 times, thus obtaining the medical gel.
2. The method as claimed in claim 1, wherein the average molecular weight of the polyethylene glycol in the step (1) is 10500-15000, and the average molecular weight of the polyethylene glycol in the step (3) is 400-600.
3. The method for preparing a medical antibacterial gel according to claim 1, wherein in the step (1), the cold diethyl ether is diethyl ether, and the medical antibacterial gel is prepared after the cold diethyl ether is placed in a refrigerator at the temperature of 20 ℃ below zero for 1 hour.
4. The method for preparing medical antibacterial gel according to claim 1, wherein in the step (1), the filter cake is washed before vacuum drying, and the washing operation is as follows: dissolving the filter cake with dichloromethane, washing the obtained solution with saturated sodium bicarbonate solution, drying the organic phase with anhydrous sodium sulfate after liquid separation, performing rotary evaporation and concentration on the organic phase after filtration to obtain viscous liquid, dropwise adding the obtained viscous liquid into excessive cold ether, precipitating, filtering, and performing vacuum drying.
5. The method according to claim 1, wherein in the step (2), the molecular cut-off of the dialysis bag is 10000 during dialysis.
6. The method for preparing medical antibacterial gel according to claim 1, wherein in the step (3), the frequency of ultrasonic wave during ultrasonic defoaming is 28-32 kHz.
7. The method for preparing a medical antibacterial gel according to claim 1, wherein in the step (3), the freezing-thawing cycle is performed by: freezing at-20 deg.C for 12 hr, and thawing at room temperature for 6 hr.
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