CN115444815A - PH response type bacteriostatic slow-release gel and preparation method thereof - Google Patents
PH response type bacteriostatic slow-release gel and preparation method thereof Download PDFInfo
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- CN115444815A CN115444815A CN202211312340.9A CN202211312340A CN115444815A CN 115444815 A CN115444815 A CN 115444815A CN 202211312340 A CN202211312340 A CN 202211312340A CN 115444815 A CN115444815 A CN 115444815A
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- paclitaxel
- slow
- release
- gel
- mesoporous silica
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Abstract
The invention particularly relates to a pH response type bacteriostatic slow-release gel and a preparation method thereof, wherein the bacteriostatic slow-release gel comprises the following components in parts by weight: 1-5 parts of octoxynol, 1-5 parts of benzalkonium chloride, 1-5 parts of melatonin, 1-10 parts of paclitaxel slow release microcapsules, 5-15 parts of a humectant, 10-20 parts of a thickening agent and 40-80 parts of a solvent, wherein the core material of the paclitaxel slow release microcapsules is modified mesoporous silica loaded paclitaxel, and the wall material is a cross-linked chitosan-gelatin composite wall material; the modified mesoporous silica is nano-scale hollow mesoporous silica which is subjected to amination modification and polyacrylic acid grafting modification in sequence. The gel has extremely strong antibacterial and antiviral effects, has a good inhibiting and killing effect on HPV (human papillomavirus), improves the slow release effect of the gel by adding the paclitaxel slow release microcapsules, enables the gel to have pH responsiveness, has an effect of preventing cervical cancer by combining melatonin, and has balanced osmotic pressure and no discomfort.
Description
Technical Field
The invention belongs to the technical field of bacteriostatic gels, and particularly relates to a pH response type bacteriostatic slow-release gel, a preparation method and application thereof.
Background
HPV virus, named human papilloma virus in Chinese, is a generic name of viruses, and can infect skin and mucosa of different parts of human body to cause different lesions. HPV viral infection is very common, and most people, both men and women, infect HPV at some stage in human life. The HPV virus is latent and may carry HPV for many years after infection, and during the period, 80% of infected people carry the virus which is eliminated by the body immune system, especially in young women, and the risk of disease is mainly dependent on the special subtype of HPV. HPV strains of certain high-risk subtypes remain latent in the body for a long time, may induce cervical cellular abnormalities, and may develop precancerous lesions. Although these precancerous lesions do not necessarily mean cancer, a part of abnormal cells may become cancer cells with the lapse of time. Once the tumor appears, it spreads around the cervix, resulting in cervical cancer.
Cervical cancer is the most common gynecological malignant tumor, wherein the high-incidence age of carcinoma in situ is 30-35 years old, and the invasive cancer is 45-55 years old, and the incidence of the carcinoma tends to be younger in recent years. The current five-year survival rate after world cervical cancer treatment is 55.5%, wherein stage I80.04%. 58.9% in stage II, 32.8% in stage III and 7.1% in stage IV. About half of patients relapse within one year of treatment, 25% in the second year and 5% in the fifth year, and therefore cervical cancer threatens the health of many women as a malignancy.
The condom and HPV vaccine are not 100% reliable for preventing HPV virus, but no specific medicine for treating HPV infection exists at present, the active prevention idea is mainly adopted, the existing treatment method has many defects, and no product in the market can fully and effectively meet the prevention and treatment requirement of cervical cancer. In view of this, it is imperative to develop more reliable products for preventing HPV infection and safe and reliable cervical cancer prevention and treatment products.
Patent CN105168676A discloses a female safety bacteriostatic gel, which comprises the following raw materials in parts by weight: a material: 0.1-1.5 parts of carbomer, 1-15 parts of polyethylene glycol and 68-96 parts of pure water; b, material B: tween 80 to 6 parts, aloe extract 0.05 to 1 part, benzalkonium chloride 0.05 to 0.2 part, sodium hyaluronate 0.05 to 2 parts and triethanolamine 0.1 to 1.5 parts; c, material C: 0.1 to 0.5 portion of Germa and 1 to 3.5 portions of octoxynol. The invention also discloses a preparation method of the lady safe antibacterial gel. The invention can kill sperm, resist pregnancy, sterilize, prevent genital tract infection, has small irritation to vagina and has bidirectional protection effect. However, the invention has limited bactericidal and anti-inflammatory effects, has weak inhibition and killing effects on HPV virus, and cannot play a role in preventing and treating cervical cancer.
Therefore, the prior art develops the antibacterial and antiviral gel and simultaneously increases the efficacy of preventing other gynecological diseases and tumors such as cervical cancer and the like, and the patent CN114129688A discloses a gel for preventing cervical cancer and condyloma acuminatum and treating papilloma virus infection, relating to the technical field of medicines. The gel for preventing cervical cancer and condyloma acuminatum and treating papillomavirus infection comprises the following raw materials in parts by weight: 0.1-5% of tea tree oil, 1-6% of carbomer, 1-10% of zedoary turmeric oil, 0.1-5% of matrine, 0.001-5% of carrot extract, 0.1-5% of polyhexamethylene biguanide, 97.697-100% of pure water and 0.002-0.1% of nocardia rubra cell wall skeleton. On the basis of bacteriostasis and inflammation diminishing, the immunity of the human body is improved through the zedoary turmeric oil, and the matrine, the nocardia rubra cell wall skeleton and the polyhexamethylene biguanide HPV virus are removed to the outside of the human body. However, the invention has weak bacteriostatic effect, cannot meet the use requirement, and has more complex preparation method and shorter effective time of gel.
Paclitaxel (Taxol, paclitaxel): the alias taxol is the best natural anticancer drug found at present, and is widely used for treating various solid tumors clinically. Paclitaxel shows good anticancer effect on various solid tumor cells, wherein, the paclitaxel has good treatment effect on cervical carcinoma in situ and 1 to 4 cervical carcinoma, and has already begun to be used for preventing and treating cervical carcinoma, wherein, a proper amount of paclitaxel is not added in bacteriostatic antiviral gel to improve the efficacy of the gel. Patent CN108324682A discloses a multivalent bond nanogel, which is compounded by polyacrylic acid grafted cyclodextrin polymer and polyacrylic acid grafted paclitaxel polymer through non-covalent bonds. CN114209847A discloses a secondary nanocrystallized albumin paclitaxel preparation and application thereof. Specifically, the nano-drugs with anticancer activity of the invention, including but not limited to albumin-bound paclitaxel and liposome daunorubicin, can be prepared into a gel dosage form, and albumin-bound paclitaxel is used, although some aspects are superior to the paclitaxel in a common dosage form, side effects are brought, although the invention provides a preparation method of the drug for reducing toxic and side effects, the side effects of the albumin-bound paclitaxel are different from those of the common paclitaxel, and the incidence rate of peripheral neurotoxicity is still high. In addition, although the paclitaxel gel plays a certain role in preventing cervical cancer, the hydrophobicity of paclitaxel is very high, which greatly affects the effect of the drug, so it is very important to improve the hydrophobicity of paclitaxel. In addition, the gel has limited time for taking effect in the vagina, and can not realize the slow release effect, in addition, the pH value of the healthy vagina is about 3.8-4.4, and the pH value of the vagina is increased under the condition of inflammation or other diseases, so the antibacterial, antiviral and disease prevention capability of the gel can be further improved if the controlled release effect of the gel is realized according to the characteristics.
Therefore, how to obtain a pH response type, which has a slow release function and a long effective time, and has the effects of inhibiting bacteria and viruses and preventing cervical cancer becomes a technical problem to be solved in the field.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the pH response type antibacterial slow-release gel which has long effective time and has the effects of inhibiting bacteria and viruses and preventing cervical cancer.
Specifically, the invention provides a pH response type bacteriostatic slow-release gel which comprises the following components in parts:
the core material of the paclitaxel slow release microcapsule is modified mesoporous silica loaded paclitaxel, and the wall material is a cross-linked chitosan-gelatin composite wall material;
the mass percentage ratio of the core material to the wall material is 1: (2-4);
the modified mesoporous silica is nano-scale hollow mesoporous silica which is subjected to amination modification and polyacrylic acid grafting modification in sequence.
Octylphenol glycan is a main active ingredient for killing HPV, and comprises at least one of octaphenyl polyether-9, octaphenyl polyether-10, octaphenyl polyether-11, octaphenyl polyether-12, octaphenyl polyether-13, octaphenyl polyether-16, octaphenyl polyether-20, octaphenyl polyether-25, octaphenyl polyether-30, octaphenyl polyether-33, octaphenyl polyether-40 and octaphenyl polyether-70. The octoxynol is a natural active microecological preparation, can cause the cell contents to leak out by destroying cell membranes of bacteria and envelope substances of viruses, provides other components to enter cells to further exert killing effect, kills 20 pathogens of 6 types and male sperms, protects reproductive organs from being invaded by various bacteria, viruses, fungi, chlamydia, mycoplasma and trichomonas, is safe and nontoxic, can be used for a long time, and has better inhibiting and killing effect on HPV viruses. Meanwhile, by means of the holes formed by membrane rupture of the octoxynol, the benzalkonium chloride can quickly enter pathogenic microorganism plasma, and genetic substances of the benzalkonium chloride are further destroyed to play a killing role.
Benzalkonium Chloride (Benzalkonium Chloride) is a cationic surfactant, belongs to a non-oxidative bactericide, has broad-spectrum and high-efficiency bactericidal capability, can kill any contacted pathogenic microorganism within 1 minute, can play a role in bacteriostasis and antivirus, and comprises HPV (human papilloma virus), HSV-2 and the like capable of inducing cervical cancer.
Melatonin is used as a strong antioxidant and scavenger in a gel product with prevention as a main effect, can remove free radicals such as oxygen, nitrogen and the like and oxidants, can timely remove metabolites or foreign substances of body cells, stabilize and clean the internal environment of the vagina, can avoid new canceration induced by persistent adverse stimulation, also has an anticancer effect, has the effects of strongly inhibiting tumorigenesis, development, transformation and metastasis, and is another important reason for cervical cancer except HPV infection, instability and persistent vaginal internal environment with pollutants such as metabolic waste, foreign matters caused by sexual life and the like. In the invention, melatonin is used as a strong antioxidant and scavenger, and can immediately remove free radicals such as oxygen, nitrogen and the like, oxidants, metabolites of body cells and foreign substances, so as to stabilize and clean the internal environment of vagina and avoid the possibility of inducing precancerous lesions due to persistent adverse stimulation.
Paclitaxel: stabilize microtubule, and block division, differentiation, metastasis, and infiltration of cancer cells. The paclitaxel slow release microcapsule of the invention is a slow release microcapsule with pH value response function, which takes nano-modified mesoporous silica negative paclitaxel as a core material and cross-linked chitosan-gelatin as a composite wall material. The modified mesoporous silica has improved paclitaxel loading capacity, remarkably improved paclitaxel water solubility, and pH responsiveness.
The carbomer sodium and the hydroxypropyl methyl cellulose can form a cross-linked skeleton, so that active ingredients in the gel can stay in a body for a long time, a drug slow-release medium is provided, the exerting time of the drug is prolonged, and the local drug concentration is prevented from being too high.
Further, the thickener is hydroxypropyl methylcellulose, the humectant is carbomer sodium, the solvent comprises an aqueous solvent and an oily solvent, the aqueous solvent is double distilled water, and the oily solvent is glycerol.
The double distilled water is obtained by utilizing the difference of volatility of each component in a liquid mixture to vaporize the mixture, condensing steam again to obtain distilled water, vaporizing the obtained distilled water, and condensing again to obtain the double distilled water, thereby removing most pollutants. In the preparation process of the double distilled water, although volatile impurities such as carbon dioxide, ammonia and some organic matters cannot be removed, after twice distillation, the content of inorganic salts, organic matters, microorganisms, soluble gases and volatile impurities in the water is extremely low, and particularly, the double distilled water is sterile, removes pyrogen and is suitable for preparing final gel.
Further, the bacteriostatic slow-release gel also comprises an osmotic pressure regulator, wherein the osmotic pressure regulator is selected from at least one of sodium chloride salt and potassium chloride salt, and the osmotic pressure of the bacteriostatic slow-release gel is 250-340 mOsm/kg-H 2 O。
While normal oncotic pressure is beneficial for the comfort of longer in vivo retention of the gel, too low oncotic pressure has its negative aspects. The osmotic pressure regulator provides the gel of the present invention with a crystal osmotic pressure in equilibrium with body fluid. On one hand, under the condition of no damage, ulcer or erosion, the gel of the invention is injected into the vagina immediately to about two minutes, the local epithelial cells of the vagina wall and the cervix capable of contacting the gel can generate stress reaction, and a user can feel short discomfort; on the other hand, in the presence of injury, breakage, ulcer or erosion, the gel of the present invention is injected into the vagina immediately to about 10 minutes, the vaginal wall and the cervix can contact local epithelial cells of the gel, other tissue cells in gap and communication connection with the epithelial cells, exposed smooth muscle cells which are not completely covered by the epithelium, somatic and visceral sensory neurons distributed in the vaginal wall, the uterine orifice and the peripheral processes of the cervix, visceral motor neurons dominate the vaginal wall, the uterine orifice and the motor branches of the cervix, etc., water fluctuation and electrolyte surge are generated due to the rapid change of the crystal osmotic pressure inside and outside the cell membrane, the outflow of potassium ions and/or the inflow of sodium ions are excited, the membrane potential is depolarized, and the stress reaction is generated. Therefore, the gel of the invention is added with NaCl or KCl salt with physiological concentration, so that the crystal osmotic pressure is in the level of ions required for maintaining the cell resting potential, when the gel of the invention is injected into the vagina, the gel has no stimulation to the vagina, no damage, ulcer or erosion exists, the vaginal wall, cervical epithelium, smooth muscle, nerve endings and the like can maintain the due resting potential, and the stress reaction is avoided.
Further, the preparation method of the paclitaxel sustained-release microcapsule comprises the following steps:
(1) Preparing a core material: adding the modified mesoporous silica into an organic solvent for ultrasonic dispersion, adding paclitaxel, magnetically stirring, centrifuging, repeatedly washing the centrifuged precipitate, and freeze-drying to obtain the core material;
(2) Heating gelatin solution to 50-60 deg.C, adding glycerol, dispersing and emulsifying for 20-30s;
(3) Adding the cross-linked chitosan solution and stirring;
(4) Adding the core material, adding water while stirring, adding a sodium hydroxide solution after dilution is finished, adjusting the pH to 5.9-6.20, and reacting for 20-30min;
(5) After cooling, adding glutaraldehyde solution, standing and curing;
(6) Repeatedly cleaning and drying to obtain the taxol slow-release microcapsule.
The organic solvent is any one of dimethyl sulfoxide, dichloromethane and acetone, and the mass percentage ratio of the modified mesoporous silica to the paclitaxel is 1: (0.6-1.2).
Further, the preparation method of the modified mesoporous silica comprises the following steps:
step 1: amination modification of nano-scale hollow mesoporous silicon dioxide
1.1, adding the nano-scale hollow mesoporous silicon dioxide into absolute ethyl alcohol for ultrasonic dispersion;
1.2 heating to 80-95 ℃, continuously introducing argon, adding gamma-aminopropyltriethoxysilane, and magnetically stirring;
1.3 after centrifugation, repeatedly cleaning the precipitate by using anhydrous ethyl alcohol, and freeze-drying to obtain the aminated modified nano-scale hollow mesoporous silica;
step 2: polyacrylic acid graft modification
2.1 adding the aminated and modified nano-scale hollow mesoporous silicon dioxide and polyacrylic acid into water, and magnetically stirring;
2.2 adding a composite initiator solution, reacting for 5-10min, adding an N, N-methylene bisacrylamide solution, and magnetically stirring under the protection of nitrogen;
2.3 centrifuging, repeatedly washing the centrifuged precipitate, and drying to obtain the modified mesoporous silica.
The mesoporous silica nanometer material has the advantages of controllable generation, large specific surface area, excellent biocompatibility, easy surface functionalization modification, targeted drug delivery and the like as a relatively mature nanometer material, and plays a huge role and a wide prospect in a drug delivery system.
First, the inventionThe mesoporous silica is subjected to amination modification, so that the drug loading capacity of the mesoporous silica is further improved, and the water solubility of paclitaxel is improved, so that the effect can be fully exerted. After polyacrylic acid grafting modification, the paclitaxel sustained-release microcapsule has pH responsiveness. The pH responsiveness mainly depends on the stimulation of the environmental pH to change the conformation of the material, thereby achieving the controlled release of the drug. Its interior is often carried with pair H + Or OH - Sensitive ionizable groups or chemical bonds which can be broken under specific conditions, so that the material per se is subjected to morphological change or chemical bond breakage under specific pH conditions or ionic strength, and the pH intelligent response release of the medicine is achieved. When infectious diseases and malignant tumors occur in a human body, the pH value of the microenvironment is changed, and the pH gradient difference of the microenvironment provides possibility for targeted drug delivery. The pH value of a healthy vagina is about 3.8-4.4, the pH value of the vagina is increased under the condition of inflammation or other diseases, and the pH value of an extracellular environment where inflammatory or cancer cells are located is 5.7-7.0, so that by utilizing the characteristic, the pH-responsive slow-release gel is prepared by utilizing the characteristic that polyacrylic acid receives protons at a low pH value and is deprotonated and swelled at a neutral pH value and a high pH value.
Further, the composite initiator solution is a mixed solution of ammonium persulfate and sodium bisulfite, and the mass percentage ratio of the ammonium persulfate to the sodium bisulfite in the mixed solution is (1.8-2.5): 1.
further, the mass percentage ratio of the cross-linked chitosan to the gelatin is 1: (0.8-1.2).
Further, the preparation method of the cross-linked chitosan comprises the following steps: dissolving chitosan in glacial acetic acid, magnetically stirring, adding a cross-linking agent solution, adjusting the pH of the solution to 4.8-5.2, reacting for 5-8h, centrifuging, repeatedly washing the centrifuged precipitate, and drying to obtain the cross-linked chitosan.
Further, a cross-linking agent is selected from at least one of phytic acid and sodium hexametaphosphate, and the mass percentage ratio of the cross-linking agent to the chitosan is 1: (1-3.5).
Among a plurality of natural materials, chitosan is polysaccharide with positive charge connected by beta- (1,4) glycosidic bond, and has wide application in the aspects of self-assembly composite materials, biopolymer membranes, drug delivery carriers and the like due to good biocompatibility and degradability and stability of physical and chemical properties. After the chitosan is crosslinked, the microstructure of the chitosan can be changed, so that the controlled release performance of the hydrogel is influenced. Therefore, the microcapsule prepared by the phytic acid and the sodium hexametaphosphate cross-linked chitosan has higher encapsulation efficiency and lower release rate, and the slow release performance of the microcapsule is optimized.
On the other hand, the preparation method of the pH response type bacteriostatic slow-release gel comprises the following steps:
s1: preparing paclitaxel sustained-release microcapsules;
s2: mixing octoxynol, benzalkonium chloride and an aqueous solvent to obtain a mixture A;
s3: mixing melatonin and paclitaxel sustained-release microcapsules with an aqueous solvent to obtain a mixture B;
s4: mixing the humectant with an osmotic pressure regulator to obtain a mixture C;
s5: and adding the mixture A, the mixture B, the mixture C and a thickening agent into an oily solvent, and stirring to obtain the antibacterial slow-release gel.
The invention has the advantages that:
1) According to the invention, the combination of octoxynol and benzalkonium bromide is used as the main active ingredient for killing HPV, and the membrane breaking function of octoxynol is that after pathogenic microorganisms indicate that holes are formed, benzalkonium chloride can rapidly enter pathogenic microorganism plasma wrapping to further destroy genetic substances of the pathogenic microorganism plasma wrapping to exert a killing effect, so that the vaginal suppository has strong bacteriostatic and antiviral effects and keeps vagina clean.
2) The invention has the effect of preventing cervix uteri by adding a proper amount of paclitaxel and combining melatonin. The paclitaxel is added into the gel in a mode of loading paclitaxel on modified mesoporous silica and coating a cross-linked chitosan-gelatin composite layer, the hollow mesoporous silica is subjected to amination modification, the drug loading capacity is improved, the water solubility of the paclitaxel is improved, and the paclitaxel sustained-release microcapsule has pH responsiveness after polyacrylic acid grafting modification, is released in a sustained-release manner when the pH value of the vagina is increased under the condition of inflammation or other diseases, and is embedded in the medicament by using the cross-linked chitosan, so that the sustained-release performance of the microcapsule is enhanced.
3) The invention uses carbomer sodium and hydroxypropyl methylcellulose to ensure that active ingredients in the gel can stay in vivo for a long time, and provides a medium for slow release of the drug, thereby prolonging the exerting time of the drug and avoiding overhigh local drug concentration.
4) The osmotic pressure of the bacteriostatic sustained-release gel is 250-340 mOsm/kg. H 2 O, which facilitates the colloid osmotic pressure to be beneficial to the long-time in-vivo retention of the gel, avoids the discomfort and the stress reaction from affecting the gel effect.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention will be further described in detail with reference to the following examples.
The pH response type antibacterial slow-release gel comprises the following components in parts by weight:
the octaphenesan comprises at least one of octaphenenol-9, octaphenenol-10, octaphenenol-11, octaphenenol-12, octaphenenol-13, octaphenenol-16, octaphenenol-20, octaphenenol-25, octaphenenol-30, octaphenenol-33, octaphenenol-40 and octaphenenol-70. The humectant is carbomer sodium, the thickener is hydroxypropyl methylcellulose, the solvent comprises an aqueous solvent and an oily solvent, the aqueous solvent is double distilled water, and the oily solvent is glycerol.
The core material of the paclitaxel slow release microcapsule is modified mesoporous silica loaded paclitaxel, and the wall material is a cross-linked chitosan-gelatin composite wall material; wherein, the modified mesoporous silica is nano-scale hollow mesoporous silica which is sequentially subjected to amination modification and polyacrylic acid grafting modification, and the cross-linked chitosan is chitosan of cross-linked phytic acid or sodium hexametaphosphate. The mass percentage ratio of the core material to the wall material is 1: (2-4); the mass percentage ratio of the mesoporous silicon dioxide to the paclitaxel is 1: (0.6-1.2), the mass percentage ratio of the cross-linked chitosan to the gelatin is 1: (0.8-1.2).
The bacteriostatic slow-release gel also comprises an osmotic pressure regulator, wherein the osmotic pressure regulator is selected from at least one of sodium chloride salt and potassium chloride salt, and is added to ensure that the osmotic pressure of the bacteriostatic slow-release gel is 250-340 mOsm/kg.H 2 O。
A preparation method of pH response type bacteriostatic slow-release gel comprises the following steps:
s1: preparing the paclitaxel sustained-release microcapsule:
s1.1 preparation of core Material
(1) Preparation of modified mesoporous silica
1. Amination modification
1.1, adding the nano-scale hollow mesoporous silicon dioxide into absolute ethyl alcohol for ultrasonic dispersion for 20-30min;
1.2 heating to 80-95 ℃, continuously introducing argon, adding gamma-aminopropyl triethoxysilane, and magnetically stirring for 5-7h;
1.3 centrifuging at 11000-13000rpm for 25-35min, repeatedly cleaning with anhydrous ethyl, and freeze drying to obtain aminated modified nanometer hollow mesoporous silica;
2. polyacrylic acid graft modification
2.1, adding the aminated and modified nano-scale hollow mesoporous silicon dioxide and polyacrylic acid into water, and magnetically stirring for 2-4 hours at the temperature of 40-50 ℃;
2.2 adding the following components in percentage by mass (1.8-2.5): 1, reacting for 5-10min, adding 6-8% by mass of N, N-methylene bisacrylamide solution, and magnetically stirring for 6-8h under the protection of nitrogen;
2.3 centrifuging at 9000-11000rpm for 20-30min, repeatedly washing and drying the centrifuged precipitate to obtain modified mesoporous silica;
(2) Adding the modified mesoporous silica into an organic solvent, performing ultrasonic dispersion for 5-10min, adding paclitaxel, and performing magnetic stirring for 10-12h, wherein the organic solvent is any one of dimethyl sulfoxide, dichloromethane and acetone;
(3) Centrifuging at 10000-12000rpm for 15-25min, repeatedly washing the centrifuged precipitate, and freeze-drying to obtain core material;
s1.2, heating a gelatin solution with the mass fraction of 20-25% and full swelling to 50-60 ℃, adding glycerol, and shearing for 20-30S by a high-shear dispersion emulsifier at 10000-12000 rpm;
s1.3 preparation of cross-linked chitosan: dissolving chitosan in glacial acetic acid with the mass fraction of 1-1.5%, magnetically stirring for 0.5-1h at 20-30 ℃, adding a cross-linking agent solution with the concentration of 0.8-1.5%, adjusting the pH of the solution to 4.8-5.2, reacting for 5-8h, centrifuging at the speed of 8000-10000r/min for 10-15min, repeatedly washing the centrifuged precipitate, and drying to obtain the cross-linked chitosan;
s1.4, adding a cross-linked chitosan solution with the mass fraction of 2-2.5% preheated at the temperature of 50-60 ℃, and stirring at 400-500rpm for 10-15min;
s1.5, adding a core material, adding distilled water at the temperature of 50-60 ℃ while stirring, adding a sodium hydroxide solution with the mass fraction of 1.5-2%, adjusting the pH to 5.9-6.2, and continuously reacting for 20-30min at the temperature of 50-60 ℃;
s1.6, reducing the temperature to 15-25 ℃, adding 4.5-5.5 mass percent of glutaraldehyde solution, standing and curing at 30-35 ℃ for 25-30min after 5-10 min;
s1.7, repeatedly cleaning, and drying to obtain the paclitaxel sustained-release microcapsule;
s2: mixing and stirring octoxynol, benzalkonium chloride and an aqueous solvent to obtain a mixture A, wherein the stirring speed is 200-300r/min, and the stirring time is 30-40min;
s3: mixing melatonin and paclitaxel sustained-release microcapsule with aqueous solvent, stirring at 500-600r/min for 30-40min to obtain mixture B;
s4: mixing the humectant with the osmotic pressure regulator, stirring at 400-500r/min for 30-40min to obtain a mixture C;
s5: and adding the mixture A, the mixture B, the mixture C and the thickening agent into an oily solvent, and stirring to obtain the antibacterial slow-release gel, wherein the stirring speed is 400-500r/min, and the stirring time is 30-40min.
Standing for 10-12h after stirring in the steps S2, S3 and S4, wherein the volume ratio of the solvents in the steps S2, S3 and S4 is (2-3): (2-3): 1.
example 1
A pH response type bacteriostatic slow-release gel comprises the following components in parts:
the mass ratio of the octaphenyl glycan to the octaphenyl polyether-10, the octaphenyl polyether-30 and the octaphenyl polyether-33 is 1. The humectant is carbomer sodium, the thickener is hydroxypropyl methylcellulose, the solvent is aqueous solvent double distilled water and oily solvent glycerol.
The core material of the paclitaxel slow release microcapsule is modified mesoporous silica loaded paclitaxel, and the wall material is a cross-linked chitosan-gelatin composite wall material; wherein, the modified mesoporous silica is nano-scale hollow mesoporous silica which is sequentially subjected to amination modification and polyacrylic acid grafting modification, and the cross-linked chitosan is chitosan of cross-linked phytic acid or sodium hexametaphosphate. The mass percentage ratio of the core material to the wall material is 1:3; the mass percentage ratio of the mesoporous silicon dioxide to the paclitaxel is 1:1, the mass percentage ratio of the cross-linked chitosan to the gelatin is 1:1.
the bacteriostatic slow-release gel also comprises an osmotic pressure regulator, wherein the osmotic pressure regulator is sodium chloride salt, and the osmotic pressure of the bacteriostatic slow-release gel is 300 mOsm/kg. H 2 O。
A preparation method of pH response type bacteriostatic slow-release gel comprises the following steps:
s1: preparing the paclitaxel sustained-release microcapsule:
s1.1 preparation of core Material
(1) Preparation of modified mesoporous silica
1. Modification by amination
1.1, adding the nano-scale hollow mesoporous silicon dioxide into absolute ethyl alcohol for ultrasonic dispersion for 25min;
1.2 heating to 90 ℃, continuously introducing argon, adding gamma-aminopropyltriethoxysilane, and magnetically stirring for 6 hours;
1.3 centrifuging at 12000rpm for 30min, repeatedly cleaning with anhydrous ethyl, and freeze drying to obtain aminated modified nanometer hollow mesoporous silica;
2. polyacrylic acid graft modification
2.1 adding the aminated and modified nano-scale hollow mesoporous silica and polyacrylic acid into water, and magnetically stirring for 3 hours at 40 ℃;
2.2 adding the components in a mass percentage ratio of 2:1, reacting for 8min, adding 7.5 mass percent of N, N-methylene bisacrylamide solution, and magnetically stirring for 6h under the protection of nitrogen;
2.3 centrifuging for 25min at the speed of 10000rpm, repeatedly washing and drying the centrifuged precipitate to obtain modified mesoporous silicon dioxide;
(2) Adding the modified mesoporous silica into dimethyl sulfoxide, performing ultrasonic dispersion for 7min, adding paclitaxel, and performing magnetic stirring for 11h;
(3) Centrifuging at 11000rpm for 20min, repeatedly washing the centrifuged precipitate, and freeze-drying to obtain a core material;
s1.2, heating a gelatin solution with a mass fraction of 23% and sufficient swelling to 55 ℃, adding glycerol, and shearing for 25S by a high-shear dispersion emulsifier at 11000 rpm;
s1.3 preparation of cross-linked chitosan: dissolving chitosan in glacial acetic acid with the mass fraction of 1.5%, magnetically stirring for 1h at 25 ℃, adding a sodium hexametaphosphate solution with the concentration of 1.0%, adjusting the pH of the solution to 4.9, reacting for 6h, centrifuging at the speed of 10000r/min for 10min, repeatedly washing the centrifuged precipitate, and drying to obtain crosslinked chitosan;
s1.4, adding a cross-linked chitosan solution with the mass fraction of 2.5 percent preheated at the preheating temperature of 55 ℃, and stirring for 15min at 500 rpm;
s1.5, adding a core material, stirring while adding distilled water at the temperature of 55 ℃, adding a sodium hydroxide solution with the mass fraction of 2%, adjusting the pH to 5.9, and continuously reacting for 25min at the temperature of 55 ℃;
s1.6, reducing the temperature to 15 ℃, adding a glutaraldehyde solution with the mass fraction of 5.5%, standing and curing for 30min at 30 ℃ after 10 min;
s1.7, repeatedly cleaning and drying to obtain the taxol slow-release microcapsule;
s2: mixing and stirring octoxynol, benzalkonium chloride and an aqueous solvent to obtain a mixture A, wherein the stirring speed is 200r/min, and the stirring time is 30min;
s3: mixing melatonin and paclitaxel sustained release microcapsule with aqueous solvent, stirring at 600r/min for 30min to obtain mixture B;
s4: mixing and stirring the humectant and the osmotic pressure regulator to obtain a mixture C, wherein the stirring speed is 400r/min, and the stirring time is 30min;
s5: and adding the mixture A, the mixture B, the mixture C and the thickening agent into an oily solvent, and stirring to obtain the antibacterial slow-release gel, wherein the stirring speed is 500r/min, and the stirring time is 30min.
Standing for 12 hours after stirring in the steps S2, S3 and S4, wherein the volume ratio of the solvent in the steps S2, S3 and S4 is 2:2:1.
example 2
The difference between the present example and example 1 is that the gel has different parts of each component, and specifically includes:
example 3
The difference between the present example and example 1 is that the gel has different parts of each component, and specifically includes:
example 4
This example differs from example 1 in that the octaphenecan comprises octaphenyl polyether-11 and octaphenyl polyether-25 in a mass ratio of 7:1.
Example 5
This example differs from example 1 in that it is prepared by the following steps:
a preparation method of pH response type bacteriostatic slow-release gel comprises the following steps:
s1: preparing the paclitaxel sustained-release microcapsule:
s1.1 preparation of core Material
(1) Preparation of modified mesoporous silica
1. Amination modification
1.1, adding the nano-scale hollow mesoporous silicon dioxide into absolute ethyl alcohol for ultrasonic dispersion for 25min;
1.2 heating to 90 ℃, continuously introducing argon, adding gamma-aminopropyltriethoxysilane, and magnetically stirring for 6 hours;
1.3 centrifuging at 12000rpm for 30min, repeatedly cleaning with anhydrous ethyl, and freeze drying to obtain aminated modified nanometer hollow mesoporous silica;
2. polyacrylic acid graft modification
2.1 adding the aminated and modified nano-scale hollow mesoporous silica and polyacrylic acid into water, and magnetically stirring for 3 hours at 40 ℃;
2.2 adding the components in a mass percentage ratio of 2:1, reacting for 8min, adding 7.5 mass percent of N, N-methylene bisacrylamide solution, and magnetically stirring for 6h under the protection of nitrogen;
2.3 centrifuging for 25min at the speed of 10000rpm, repeatedly washing and drying the centrifuged precipitate to obtain modified mesoporous silica;
(2) Adding the modified mesoporous silica into dimethyl sulfoxide, performing ultrasonic dispersion for 7min, adding paclitaxel, and performing magnetic stirring for 11h;
(3) Centrifuging at 11000rpm for 20min, repeatedly washing the centrifuged precipitate, and freeze-drying to obtain a core material;
s1.2, heating a gelatin solution with a mass fraction of 23% and full swelling to 55 ℃, adding glycerol, and shearing for 25S by a high-shear dispersion emulsifier at 11000 rpm;
s1.3 preparation of cross-linked chitosan: dissolving chitosan in glacial acetic acid with the mass fraction of 1.5%, magnetically stirring for 1h at 25 ℃, adding a sodium hexametaphosphate solution with the concentration of 1.0%, adjusting the pH of the solution to 4.9, reacting for 6h, centrifuging at the speed of 10000r/min for 10min, repeatedly washing the centrifuged precipitate, and drying to obtain crosslinked chitosan;
s1.4, adding a cross-linked chitosan solution with the mass fraction of 2.5 percent preheated at the preheating temperature of 55 ℃, and stirring for 15min at 500 rpm;
s1.5, adding a core material, adding distilled water at the temperature of 55 ℃ while stirring, adding a sodium hydroxide solution with the mass fraction of 2%, adjusting the pH to 5.9, and continuously reacting for 25min at the temperature of 55 ℃;
s1.6, reducing the temperature to 15 ℃, adding a glutaraldehyde solution with the mass fraction of 5.5%, standing and curing for 30min at 30 ℃ after 10 min;
s1.7, repeatedly cleaning and drying to obtain the taxol slow-release microcapsule;
s2: mixing and stirring octoxynol, benzalkonium chloride and an aqueous solvent to obtain a mixture A, wherein the stirring speed is 300r/min, and the stirring time is 30min;
s3: mixing melatonin and paclitaxel sustained release microcapsule with aqueous solvent, stirring at 500r/min for 30min to obtain mixture B;
s4: mixing and stirring the humectant and the osmotic pressure regulator to obtain a mixture C, wherein the stirring speed is 500r/min, and the stirring time is 30min;
s5: and adding the mixture A, the mixture B, the mixture C and the thickening agent into an oily solvent, and stirring to obtain the antibacterial slow-release gel at the stirring speed of 400r/min for 30min.
Standing for 12 hours after stirring in the steps S2, S3 and S4, wherein the volume ratio of the solvent in the steps S2, S3 and S4 is 2:2:1.
example 6
The present example is different from example 1 in that the next step is performed without leaving the mixture after the stirring in steps S2, S3 and S4.
Comparative example 1
This comparative example differs from example 1 in that melatonin is not contained.
Comparative example 2
This comparative example differs from example 1 in that paclitaxel was added alone, not in the form of microcapsules.
Comparative example 3
This comparative example differs from example 1 in that it does not contain paclitaxel sustained release microcapsules.
Examples 1-6 and comparative examples 1-3 were subjected to the following experimental tests:
experiment 1 detection of arsenic, mercury and lead content
An instrument device: JA5003N type electronic balance; AFS-8220 atomic fluorescence photometer, beijing Jitian; shimadzu AA-6300C type atomic absorption photometer.
Reagent name, grade: nitric acid (GR), hydrochloric acid (GR), sodium hydroxide (GR), sodium borohydride (GR), thiourea (AR), ascorbic acid (GR) and pure water.
Standard solutions and concentrations: 100 mug/L arsenic, 20 mug/L mercury and 10mg/L lead.
The detection basis is as follows: chapter iv physical and chemical examination method of cosmetic safety specifications (2015 edition) 1.4 first method for arsenic, 1.2 first method for mercury, and 1.3 first method for lead.
Detection conditions are as follows: temperature 26 ℃, humidity 62% rh.
The results are shown in the following table:
| group of | Arsenic (As) | Mercury | Lead (II) |
| Example 1 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Example 2 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Example 3 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Example 4 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Example 5 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Example 6 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Comparative example 1 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Comparative example 2 | ＜0.010 | ＜0.0020 | ＜1.5 |
| Comparative example 3 | ＜0.010 | ＜0.0020 | ＜1.5 |
Experiment 1 shows that the antibacterial sustained-release gel prepared by the preparation method has extremely low arsenic, mercury and lead contents, is safe to use and meets the requirements.
Experiment 2 stability assay
The instrument equipment comprises: JA5003N electronic balance, shimadzu LC-20AT liquid chromatograph, LHS-250HC-I constant temperature and humidity chamber.
Reagent name, grade: 0.1mol/L ammonium acetate buffer solution and acetonitrile.
Standard solution and concentration: 100 μ g/L benzalkonium chloride standard solution.
The detection basis is as follows: disinfecting technical Specification 2.2.3.2.1, 2002 edition, and cosmetic safety technical Specification (2015 edition) 4.4 benzalkonium chloride.
The instrument conditions were as follows: chromatography column, 250 x 4.6mm,5 μm CN column; column temperature, 25 ℃; sample injection volume, 20 μ L; flow rate, 1.0mL/min; detection wavelength, ultraviolet detector (260 nm); mobile phase, 0.1mol/L ammonium acetate buffer solution (pH = 5.0) + acetonitrile =50+50.
Sample preservation conditions: storing at 37 ℃ for 3 months.
Detection conditions are as follows: temperature 27 ℃, humidity 60% rh.
The results are shown in the following table:
the antibacterial sustained-release gel prepared by the invention is relatively stable, and the reduction rate of active ingredients in the gel is relatively low.
Experiment 3 bacteriostatic experiment
Test strains: escherichia coli (ATCC 25922), staphylococcus aureus (ATCC 6538) and Candida albicans (ATCC 10231), wherein the generation numbers of the above strains are 3-5, and bacterial suspension is prepared by using a solution containing 0.03 mol/LPBS.
Graduated pipettes (0.1 mL, 1.0mL, 5.0mL, 10.0 mL), and the like.
The detection method comprises the following steps: the test is carried out according to appendix C4 of GB15979-2002 hygienic Standard for Disposable sanitary articles, the sample 'gel' stock solution is used, the action time is 2min, 5min, 10min and 20min, and the test is repeated for 3 times. The test temperature was 24 ℃.
The results of the bacteriostatic rate are shown in the following table:
the slow-release antibacterial gel has good antibacterial effect and slow-release effect, and the antibacterial rate is still more than 99.0% after the gel is used for 10 minutes.
Experiment 4 inhibition of tumor cells
The concentration is 5X 10 4 Individual/mL human cervical carcinoma HeLa cell lines were inoculated into 6-well plates, respectively, cultured in DMEM (10% fetal bovine serum) medium for 24 hours to give 10 test groups, and the gels provided in examples 1 to 7 of the present invention and comparative examples 1 to 3 were added to the test groups to give a final concentration of 1.8X 10 -5 And M. After culturing for 24h, each experimental group was discarded, the culture solution was washed with PBS 3 times, each well was fixed with 4% paraformaldehyde for 20min, and then the solution was aspirated, washed with PBS, and mounted with glycerol to examine the survival rate of HeLa cells, with the results shown in the following table.
| Group of | Survival Rate (%) of HeLa cells |
| Example 1 | 21.73±1.15 |
| Example 2 | 23.48±1.14 |
| Example 3 | 24.45±0.92 |
| Example 4 | 22.47±0.87 |
| Example 5 | 21.43±1.14 |
| Example 6 | 25.08±0.74 |
| Comparative example 1 | 33.37±0.81 |
| Comparative example 2 | 37.04±0.91 |
| Comparative example 3 | 46.04±1.21 |
As can be seen from the results of the examples and the comparative examples, the invention has better inhibition effect on cancer cells, and as can be seen from the results of the examples and the comparative example 2, the inhibition effect of the paclitaxel sustained-release microcapsule adopted by the invention on cancer cells is greatly enhanced compared with the effect of adding paclitaxel alone.
Experiment 5 cumulative release rate of drug under different pH values of sustained-release antibacterial gel
3 parts of 15mg paclitaxel sustained-release microcapsules are weighed and respectively added into PBS buffer solution containing 5ml of pH 4, 5 and 6, and sustained release is carried out at 37 ℃. Taking 3ml of supernatant after 10h, measuring the absorbance of the solution, simultaneously adding 3ml of fresh PBS buffer solution with the corresponding pH value, keeping the total volume of the solution unchanged, and finally calculating the cumulative release rate of the drug, wherein the results are shown in the following table:
note: the drug release rate in this experiment was the maximum drug release rate.
As can be seen from the cumulative release rates of the drugs at different pH values, the drug release rate is lower when the pH value is lower, and the drug release rate is increased along with the gradual increase of the pH value, so that the paclitaxel sustained-release microcapsule of the invention has pH responsiveness.
In conclusion, the gel has strong bacteriostatic and antiviral effects and the effect of keeping vagina clean, has the effect of preventing cervix by adding a proper amount of paclitaxel slow-release microcapsules and combining melatonin, has an obvious slow-release effect, is lasting in effective time and excellent in stability, and ensures that active ingredients play a role continuously.
The foregoing describes preferred embodiments of the present invention, and is intended to provide a clear and concise description of the spirit and scope of the invention, and not to limit the same, but to include all modifications, substitutions, and alterations falling within the spirit and scope of the invention as defined by the appended claims.
Claims (10)
1. The pH-responsive bacteriostatic slow-release gel is characterized by comprising the following components in parts:
the core material of the paclitaxel slow release microcapsule is modified mesoporous silica loaded paclitaxel, and the wall material is a cross-linked chitosan-gelatin composite wall material;
the mass percentage ratio of the core material to the wall material is 1: (2-4);
the modified mesoporous silica is nano-scale hollow mesoporous silica sequentially subjected to amination modification and polyacrylic acid grafting modification.
2. The bacteriostatic sustained-release gel according to claim 1, wherein the thickener is hydroxypropyl methylcellulose, the humectant is carbomer sodium, the solvent comprises an aqueous solvent and an oily solvent, the aqueous solvent is double distilled water, and the oily solvent is glycerol.
3. The bacteriostatic slow-release gel according to claim 1, further comprising an osmotic pressure regulator, wherein the osmotic pressure regulator is at least one of sodium chloride salt and potassium chloride salt, and the osmotic pressure of the bacteriostatic slow-release gel is 250-340 mOsm/kg-H 2 O。
4. The method of claim 1, wherein the paclitaxel sustained-release microcapsule is prepared by the following steps:
(1) Preparing a core material: adding the modified mesoporous silica into an organic solvent for ultrasonic dispersion, adding paclitaxel, magnetically stirring, centrifuging, repeatedly washing the centrifuged precipitate, and freeze-drying to obtain the core material;
(2) Heating gelatin solution to 50-60 deg.C, adding glycerol, and dispersing and emulsifying for 20-30s;
(3) Adding the cross-linked chitosan solution and stirring;
(4) Adding core material, adding water while stirring, adding sodium hydroxide solution after dilution, adjusting pH to 5.9-6.2, and reacting for 20-30min;
(5) After cooling, adding glutaraldehyde solution, standing and curing;
(6) Repeatedly cleaning and drying to obtain the taxol slow-release microcapsule.
5. The preparation method according to claim 4, wherein the preparation method of the modified mesoporous silica comprises the following steps:
step 1: amination modification of nano-scale hollow mesoporous silica
1.1, adding the nano-scale hollow mesoporous silicon dioxide into absolute ethyl alcohol for ultrasonic dispersion;
1.2 heating to 80-95 ℃, continuously introducing argon, adding gamma-aminopropyltriethoxysilane, and magnetically stirring;
1.3 after centrifugation, repeatedly cleaning the precipitate with anhydrous B, and freeze-drying to obtain the aminated modified nano-scale hollow mesoporous silica;
and 2, step: polyacrylic acid graft modification
2.1 adding the aminated and modified nano-scale hollow mesoporous silicon dioxide and polyacrylic acid into water, and magnetically stirring;
2.2 adding a composite initiator solution, reacting for 5-10min, adding an N, N-methylene bisacrylamide solution, and magnetically stirring under the protection of nitrogen;
2.3 centrifuging, repeatedly washing the centrifuged precipitate, and drying to obtain the modified mesoporous silica.
6. The preparation method according to claim 5, wherein the composite initiator solution is a mixed solution of ammonium persulfate and sodium bisulfite, and the mass percentage ratio of ammonium persulfate to sodium bisulfite in the mixed solution is (1.8-2.5): 1.
7. the method according to claim 4, wherein the ratio of the cross-linked chitosan to the gelatin is 1: (0.8-1.2).
8. The method of claim 7, wherein the cross-linked chitosan is prepared by: dissolving chitosan in glacial acetic acid, magnetically stirring, adding a cross-linking agent solution, adjusting the pH of the solution to 4.8-5.2, reacting for 5-8h, centrifuging, repeatedly washing the centrifuged precipitate, and drying to obtain the cross-linked chitosan.
9. The preparation method according to claim 8, wherein the cross-linking agent is at least one selected from phytic acid and sodium hexametaphosphate, and the mass percentage ratio of the cross-linking agent to the chitosan is 1: (1-3.5).
10. A method for preparing a pH-responsive bacteriostatic slow-release gel according to any one of claims 1 to 9, characterized by comprising the following steps:
s1: preparing paclitaxel sustained-release microcapsules;
s2: mixing octoxynol, benzalkonium chloride and an aqueous solvent to obtain a mixture A;
s3: mixing melatonin and paclitaxel sustained-release microcapsules with an aqueous solvent to obtain a mixture B;
s4: mixing the humectant with an osmotic pressure regulator to obtain a mixture C;
s5: and adding the mixture A, the mixture B, the mixture C and a thickening agent into an oily solvent, and stirring to obtain the antibacterial slow-release gel.
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| CN116605884A (en) * | 2023-04-12 | 2023-08-18 | 天津市中西医结合医院（天津市南开医院） | A drug-loaded mesoporous silica sustained-release system and preparation method thereof |
| CN118666542A (en) * | 2024-08-26 | 2024-09-20 | 西南石油大学 | Enzymatic self-healing concrete and preparation method thereof |
| CN119349729A (en) * | 2024-10-21 | 2025-01-24 | 成都理工大学 | A pH-responsive slow-release antibacterial agent for in-situ inhibition of acid mine wastewater generation and a preparation method thereof |
| CN121183564A (en) * | 2025-11-25 | 2025-12-23 | 上海里奥纤维企业发展有限公司 | A method for preparing insect-repellent lyocell fiber |
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| US20080050413A1 (en) * | 2006-08-23 | 2008-02-28 | Ronald Adrianus Maria Horvers | Medical stent provided with a combination of melatonin and paclitaxel |
| CN103655484A (en) * | 2013-10-17 | 2014-03-26 | 南京林业大学 | Method for preparing paclitaxel sustained-release microspheres by use of self-assembly technology and product thereof |
| CN110693865A (en) * | 2019-10-24 | 2020-01-17 | 禾博药业有限公司 | Antibacterial gel and preparation process thereof |
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| US20080050413A1 (en) * | 2006-08-23 | 2008-02-28 | Ronald Adrianus Maria Horvers | Medical stent provided with a combination of melatonin and paclitaxel |
| CN103655484A (en) * | 2013-10-17 | 2014-03-26 | 南京林业大学 | Method for preparing paclitaxel sustained-release microspheres by use of self-assembly technology and product thereof |
| CN110693865A (en) * | 2019-10-24 | 2020-01-17 | 禾博药业有限公司 | Antibacterial gel and preparation process thereof |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116605884A (en) * | 2023-04-12 | 2023-08-18 | 天津市中西医结合医院（天津市南开医院） | A drug-loaded mesoporous silica sustained-release system and preparation method thereof |
| CN118666542A (en) * | 2024-08-26 | 2024-09-20 | 西南石油大学 | Enzymatic self-healing concrete and preparation method thereof |
| CN119349729A (en) * | 2024-10-21 | 2025-01-24 | 成都理工大学 | A pH-responsive slow-release antibacterial agent for in-situ inhibition of acid mine wastewater generation and a preparation method thereof |
| CN121183564A (en) * | 2025-11-25 | 2025-12-23 | 上海里奥纤维企业发展有限公司 | A method for preparing insect-repellent lyocell fiber |
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