CN108158975B - Graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel and preparation method and application thereof - Google Patents
Graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel and preparation method and application thereof Download PDFInfo
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- CN108158975B CN108158975B CN201810030085.6A CN201810030085A CN108158975B CN 108158975 B CN108158975 B CN 108158975B CN 201810030085 A CN201810030085 A CN 201810030085A CN 108158975 B CN108158975 B CN 108158975B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/24—Heavy metals; Compounds thereof
- A61K33/38—Silver; Compounds thereof
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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Abstract
The invention provides graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel and a preparation method and application thereof. In the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel, graphene oxide is used as a drug slow-release carrier, so that the drug release and action time is prolonged; meanwhile, the loaded nano silver can continuously release silver ions to assist in enhancing the antifungal effect, and due to the special sterilization mechanism of the silver ions, the problem of drug resistance is avoided, and the recurrence probability is low; similarly, poloxamer is used as an adjuvant, so that the medicine is in a liquid state at normal temperature, and becomes gel due to temperature rise when being applied to an affected part, so that the medicine is convenient to administer, and the contact time of the medicine and the affected part can be prolonged.
Description
Technical Field
The invention relates to the field of antifungal preparations, in particular to graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel and a preparation method and application thereof.
Background
Dermatophytes are fungi that cause skin infections that colonize keratin tissues and cause fungal infections, such as symptoms of dermatophyte infections of the foot moss characterized by inter-toe lesions that may also spread to the outside of the epidermis and sole of the foot. The most common signs and symptoms of an infected site are redness, itching, and peeling, and the infection is transmissible by contact and may recur.
At present, the conventional treatment method for skin infection is to treat skin infection by topical application or cleaning of common dosage form drugs such as antifungal cream, ointment, powder, solution or spray, such as terbinafine, ketoconazole, miconazole, itraconazole and the like.
However, the existing therapeutic means still have more disadvantages, mainly including: 1. because the drug resistance of antifungal drugs is common, fungal infection is difficult to radically cure and easy to relapse; 2. the duration of the drug effect is short; 3. common dosage forms are inconvenient to use: the cream is inconvenient to apply; the spray has high fluidity and is not easy to remain in the affected part for a long time.
In view of the above, the present invention is particularly proposed.
Disclosure of Invention
The first purpose of the invention is to provide a preparation method of the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel, the preparation method has the advantages of simple and convenient process, excellent antibacterial performance of the prepared graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel, convenience in administration and the like.
The second purpose of the invention is to provide the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel obtained by the preparation method, and the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel has the advantages of long drug effect time, convenience in administration and no drug resistance.
The third purpose of the invention is to provide an application of the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel.
In order to achieve the above purpose of the present invention, the following technical solutions are adopted:
a preparation method of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel comprises the following steps:
(a) carrying out ultrasonic cracking on the single-layer graphene oxide to obtain nano single-layer graphene oxide, mixing the nano single-layer graphene oxide with a silver-ammonia solution, and reducing to obtain nano silver graphene oxide;
(b) mixing the obtained nano-silver graphene oxide with antifungal drug terbinafine to obtain a nano-silver graphene oxide drug mixture;
(c) adding water to the poloxamer for swelling to obtain a swollen matter solution;
mixing the nano-silver graphene oxide medicine mixture with a surfactant, adding a preservative and glycerol, and mixing the obtained mixed system with the swelling solution to obtain the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel.
Preferably, in the step (a) of the preparation method, micron-sized single-layer graphene oxide is used as a raw material, and the nano-sized single-layer graphene oxide is obtained by ultrasonic cracking;
more preferably, the ultrasonic cracking is carried out under the ice-bath condition for 45-90 min.
Preferably, in the step (b) of the preparation method of the present invention, the nano-silver graphene oxide and the antifungal drug terbinafine are stirred and mixed under the solution condition, and then the solvent is removed to obtain the nano-silver graphene oxide drug mixture.
Preferably, in step (c) of the preparation method of the present invention, the poloxamer includes poloxamer 188 and poloxamer 407.
Preferably, in the step (c) of the preparation method, after adding water to the poloxamer, swelling the poloxamer for 6-18 hours at the temperature of 1-10 ℃;
more preferably, in the step (c), the poloxamer is added with water and then is swelled at 4-8 ℃ for 10-12 h.
Preferably, in the preparation method of the present invention, the preservative includes sodium benzoate; and/or, the surfactant comprises tween-80.
Preferably, in the step (c) of the preparation method, the raw materials are used in the following amounts by weight percent:
5-35% of poloxamer, 1-2% of a nano-silver graphene oxide medicine mixture, 2-10% of a surfactant, 0.01-1% of a preservative, 0.5-5% of glycerol and the balance of water;
more preferably, the amount of the raw materials in step (c) is as follows by weight percent: poloxamer 1882-10%, poloxamer 4075-25%, nano-silver graphene oxide medicine mixture 1-2%, surfactant 2-10%, preservative 0.01-1%, glycerol 0.5-5% and the balance of water;
further preferably, the amount of the raw materials in step (c) is as follows by weight percent: poloxamer 1885%, poloxamer 40715%, nano-silver graphene oxide medicine mixture 1.6%, surfactant 5%, preservative 0.1%, glycerol 2%, and the balance of water.
Meanwhile, the invention also provides the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel obtained by the preparation method.
Similarly, the invention also provides application of the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel in preparation of fungal infection treatment medicines.
Furthermore, the invention also provides a medicament and/or a medicinal composition containing the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel.
Compared with the prior art, the invention has the beneficial effects that:
in the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel, graphene oxide is used as a drug slow-release carrier, so that the drug release and action time is prolonged; meanwhile, the loaded nano silver can continuously release silver ions to assist in enhancing the antifungal effect, and due to the special sterilization mechanism of the silver ions, the problem of drug resistance is avoided, and the recurrence probability is low; similarly, poloxamer is used as an adjuvant, so that the medicine is in a liquid state at normal temperature, and becomes gel due to temperature rise when being smeared on an affected part, thereby not only facilitating administration, but also prolonging the contact time of the medicine and the affected part.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a scanning electron microscope structure diagram of an antifungal slow-release temperature-sensitive gel of graphene oxide nano silver terbinafine according to an embodiment of the present invention;
fig. 2 is a cumulative release curve of terbinafine in the graphene oxide nano silver terbinafine antifungal sustained-release temperature-sensitive gel according to the embodiment of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products available commercially.
In view of the practical problems of inconvenient medication, difficult long-time maintenance of drug effect, easy generation of drug resistance and the like of the existing antifungal preparation, the invention particularly provides a novel sustained-release medicament to solve the defects of the existing antifungal preparation;
the sustained-release medicament provided by the invention is a load-type medicament taking graphene oxide as a carrier, has good biocompatibility due to the large amount of active functional groups on the surface of the graphene oxide, and can also have good adsorption effect on medicament components and medicament load and sustained-release effects due to the strong pi-pi bond conjugation effect; meanwhile, the nano silver load also enables the sustained-release medicament to be capable of sterilizing through the action of silver ions, and the problem of drug resistance is avoided; furthermore, the use of poloxamer serving as an auxiliary material also enables the sustained-release medicament to be coated on the skin surface in a liquid form, and the auxiliary material is changed into a gel form after the temperature of the body surface is sensed, so that the effective components can be contacted with the affected part for a long time, and the nano medicament can enter the inside of the skin surface of a human body through pores, thereby playing a role in killing fungi for a long time and effectively.
Specifically, the preparation method of the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel comprises the following steps:
(a)
(i) performing ultrasonic cracking on the monolayer graphene oxide, preferably, in the step, using micron-sized monolayer graphene oxide as a raw material, and performing ultrasonic cracking to obtain nano monolayer graphene oxide, wherein the size of the obtained nano monolayer graphene oxide is about 200 nm;
specifically, the raw material micron-sized graphene oxide can be added into deionized water, and the mass ratio of the micron-sized graphene oxide to the deionized water is controlled to be 0.2-0.5: 100;
then, adding the mixture into an ultrasonic crusher under an ice bath condition for ultrasonic cracking, wherein the ultrasonic cracking time is 45-90 min, more preferably 45-60 min, and obtaining a nano monolayer graphene oxide solution with the mass concentration of 0.2-0.5 mg/ml;
(ii) mixing the obtained nano single-layer graphene oxide solution with a silver ammonia solution;
among them, the preparation of silver ammonia solution is preferably referred to as follows: dissolving silver nitrate in deionized water, and then dropwise adding ammonia water to obtain a silver-ammonia solution;
further preferably, the ratio of the volume milliliter number of the nano monolayer graphene oxide solution used as the raw material for further reaction to the mass milligram number of silver nitrate used for preparing the silver ammonia solution is 100: 105;
stirring and mixing the graphene oxide solution and the silver ammonia solution for 30min at 50 ℃, adding a reducing agent glucose, reacting for 1h at 95 ℃, centrifuging the obtained product system, removing supernatant, and recovering the obtained precipitate, namely the nano-silver graphene oxide, which is marked as Ag-nGO;
(b) mixing the obtained nano-silver graphene oxide with terbinafine to obtain a nano-silver graphene oxide medicine mixture;
in this step, preferably under solution conditions, the solvent used is preferably ethanol;
specifically, in the step, the nano-silver graphene oxide and terbinafine can be stirred and mixed in an ethanol solution, and the stirring and mixing time is preferably 24 hours; then, performing rotary evaporation to remove the solvent to obtain a nano-silver graphene oxide medicine mixture;
meanwhile, terbinafine can be preferably replaced by ketoconazole, miconazole or itraconazole with the same bactericidal effect;
the mass ratio of the nano-silver graphene oxide as the raw material to the terbinafine is preferably 0.6: 1;
(c)
(i) adding water to the poloxamer for swelling to obtain a swollen matter solution;
in this step, a small amount of water is used as a solvent (i.e., a partial amount of water is used as a solvent) to swell the poloxamer;
meanwhile, preferably, the poloxamer used as the raw material is poloxamer 188 and poloxamer 407;
therefore, the invention more preferably adds poloxamer 188 and poloxamer 407 into a small amount of water, and swells for 6-18 h at the temperature of 1-10 ℃; more preferably, poloxamer 188 and poloxamer 407 are added into a small amount of water, and then the mixture is swelled at 4-8 ℃ for 10-12 h;
(ii) mixing the nano-silver graphene oxide medicine mixture with a surfactant, preferably, the surfactant is tween-80; then, adding a preservative and glycerol, wherein the preferred preservative is sodium benzoate;
(iii)
mixing the mixed system obtained in the step (ii) with the swelling solution obtained in the step (i), then adding the residual amount of water, and uniformly mixing to obtain the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel;
further preferably, in the step (c), the following raw materials are used in percentage by weight: poloxamer 5-35%, for example but not limited to 7, 10, 12, 15, 17, 20, 22, 25, 27, or 30%; 1-2% of the nano-silver graphene oxide drug mixture can be, but is not limited to, 1.1, 1.3, 1.5, 1.6, or 1.8%, and the like; 2-10% of surfactant, for example, but not limited to, 3, 5, 7, or 9%; 0.01 to 1% of a preservative, for example, but not limited to, 0.05, 0.1, 0.3, 0.5, 0.7, or 0.9%; 0.5 to 5% of glycerin, for example, but not limited to, 1, 2, or 4%; and the balance of water, wherein,
the condition is that the sum of the using amount of all the raw materials is 100 percent;
more preferably, the amount of the raw materials in step (c) is as follows by weight percent:
poloxamer 1882-10%, for example, but not limited to, 3, 5, 7, or 9%; poloxamer 4075-25%, for example but not limited to 10, 15, or 20%; 1-2% of the nano-silver graphene oxide drug mixture can be, but is not limited to, 1.1, 1.3, 1.5, 1.6, or 1.8%, and the like; tween-802-10%, for example, but not limited to, 3, 5, 7, or 9% and the like; sodium benzoate 0.01 to 1%, for example, but not limited to, 0.05, 0.1, 0.3, 0.5, 0.7, or 0.9%; 0.5 to 5% of glycerin, for example, but not limited to, 1, 2, or 4%; and the balance of water, wherein,
the condition is that the sum of the using amount of all the raw materials is 100 percent;
more preferably, the amount of the raw materials in step (c) is as follows by weight percent:
poloxamer 1885%, poloxamer 40715%, nano-silver graphene oxide medicine mixture 1.6%, surfactant 5%, antiseptic 0.1%, glycerol 2%, and water in balance,
provided that the sum of the use amount of the raw materials is 100 percent.
The graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel prepared by the method not only has good drug slow release and treatment effects on skin diseases caused by fungi, but also can play excellent effects of long-acting treatment and no drug resistance; furthermore, the use of the adjuvant poloxamer enables the graphene nano silver terbinafine antifungal slow-release temperature-sensitive gel to be in a liquid state before being coated at normal temperature, and to be more easily smeared and uniformly distributed on the surface of the skin, and to be changed into a gel state after being dared and asked on the surface of the skin, so that the nano single-layer graphene oxide loaded with antifungal drugs terbinafine and silver can be fully contacted with an affected part, and long-acting and effective treatment can be realized.
Furthermore, the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel can be used for preparing corresponding therapeutic drugs for diseases caused by fungi, in particular various skin diseases caused by fungi;
in the actual treatment process, the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel can be used as a treatment agent alone, or can be used together with other oral/external application/injection preparations to achieve a comprehensive treatment effect.
Example 1
(1) Dispersing 0.2g of micron-sized single-layer graphene oxide in 100ml of deionized water, then placing the mixture in an ultrasonic crusher under the ice bath condition, and carrying out ultrasonic cracking for 1 hour to obtain a nano single-layer graphene oxide aqueous solution with the mass concentration of 0.2 mg/ml;
adding 105mg of silver nitrate into 5ml of deionized water, and then dropwise adding ammonia water with the concentration of 3% until the precipitate disappears to obtain a silver-ammonia solution;
mixing 100ml of nano monolayer graphene oxide aqueous solution with the silver ammonia solution prepared above at 50 ℃ for 30min, adding 1g of glucose aqueous solution, and reacting at 90 ℃ for 1 h;
placing the reaction product system in a centrifuge, centrifuging for 20min at the rotating speed of 12000r/min, discarding the supernatant, and recovering the obtained precipitate, namely the nano silver oxide graphene oxide, which is recorded as Ag-nGO;
(2) stirring and mixing 0.6g of Ag-nGO and 1g of terbinafine in 100ml of ethanol for 24 hours, and then removing the ethanol by rotary evaporation to obtain 1.6g of Ag-nGO terbinafine mixture;
(3) adding 5g of poloxamer 188 and 15g of poloxamer 407 into 20g of deionized water, and swelling at 4 ℃ for 12 hours to obtain a swollen matter solution;
mixing 1.6g of Ag-nGO terbinafine mixture with 5g of Tween-80, adding 0.1g of sodium benzoate and 2g of glycerol, mixing the obtained mixed system with the swelling substance, adding 51.3g of water, and continuously mixing uniformly to obtain the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel of the embodiment 1.
The product of example 1 was examined by electron microscopy and the structure is shown in FIG. 1.
Example 2
(1) Dispersing 0.4g of micron-sized single-layer graphene oxide in 100ml of deionized water, then placing the mixture in an ultrasonic crusher under the ice bath condition, and carrying out ultrasonic cracking for 1 hour to obtain a nano single-layer graphene oxide aqueous solution with the mass concentration of 0.4 mg/ml;
adding 200mg of silver nitrate into 5ml of deionized water, and then dropwise adding ammonia water with the concentration of 3% until the precipitate disappears to obtain a silver-ammonia solution;
mixing 100ml of nano monolayer graphene oxide aqueous solution with the silver ammonia solution prepared above at 50 ℃ for 30min, adding 3g of glucose aqueous solution, and reacting at 90 ℃ for 1 h;
placing the reaction product system in a centrifuge, centrifuging for 20min at the rotating speed of 12000r/min, discarding the supernatant, and recovering the obtained precipitate, namely the nano silver oxide graphene oxide, which is recorded as Ag-nGO;
(2) stirring and mixing 0.8g of Ag-nGO and 1.2g of terbinafine in 100ml of ethanol for 24 hours, and then removing the ethanol by rotary evaporation to obtain 2g of Ag-nGO terbinafine mixture;
(3) adding 2g of poloxamer 188 and 25g of poloxamer 407 into 25g of deionized water, and swelling at 5 ℃ for 12 hours to obtain a swollen matter solution;
mixing 2g of Ag-nGO terbinafine mixture with 10g of Tween-80, adding 0.1g of sodium benzoate and 5g of glycerol, mixing the obtained mixed system with the swelling substance, adding 31.1g of water, and continuously mixing uniformly to obtain the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel of the embodiment 2.
Example 3
(1) Dispersing 0.5g of micron-sized single-layer graphene oxide in 100ml of deionized water, then placing the mixture in an ultrasonic crusher under the ice bath condition, and carrying out ultrasonic cracking for 1 hour to obtain a nano single-layer graphene oxide aqueous solution with the mass concentration of 0.5 mg/ml;
adding 50mg of silver nitrate into 5ml of deionized water, and then dropwise adding ammonia water with the concentration of 3% until the precipitate disappears to obtain a silver-ammonia solution;
mixing 30ml of nano monolayer graphene oxide aqueous solution with the silver ammonia solution prepared above at 50 ℃ for 30min, adding 0.8g of glucose aqueous solution, and reacting at 90 ℃ for 1 h;
placing the reaction product system in a centrifuge, centrifuging for 20min at the rotating speed of 12000r/min, discarding the supernatant, and recovering the obtained precipitate, namely the nano silver oxide graphene oxide, which is recorded as Ag-nGO;
(2) stirring and mixing 0.4g of Ag-nGO and 0.6g of terbinafine in 100ml of ethanol for 24 hours, and then removing the ethanol by rotary evaporation to obtain 1g of Ag-nGO terbinafine mixture;
(3) adding 10g of poloxamer 188 and 5g of poloxamer 407 into 20g of deionized water, and swelling at 4 ℃ for 10 hours to obtain a swollen matter solution;
mixing 1g of Ag-nGO terbinafine mixture with 3g of Tween-80, adding 0.1g of sodium benzoate and 1g of glycerol, mixing the obtained mixed system with the swelling substance, adding 51.3g of water, and continuously mixing uniformly to obtain the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel of the embodiment 3.
Example 4
(1) Dispersing 0.3g of micron-sized single-layer graphene oxide in 100ml of deionized water, then placing the mixture in an ultrasonic crusher under the ice bath condition, and carrying out ultrasonic cracking for 1 hour to obtain a nano single-layer graphene oxide aqueous solution with the mass concentration of 0.3 mg/ml;
adding 120mg of silver nitrate into 5ml of deionized water, and then dropwise adding ammonia water with the concentration of 3% until the precipitate disappears to obtain a silver-ammonia solution;
mixing 100ml of nano monolayer graphene oxide aqueous solution with the silver ammonia solution prepared above at 50 ℃ for 30min, adding 1.5g of glucose aqueous solution, and reacting at 90 ℃ for 1 h;
placing the reaction product system in a centrifuge, centrifuging for 20min at the rotating speed of 12000r/min, discarding the supernatant, and recovering the obtained precipitate, namely the nano silver oxide graphene oxide, which is recorded as Ag-nGO;
(2) stirring and mixing 0.4g of Ag-nGO and 1.1g of terbinafine in 100ml of ethanol for 24 hours, and then removing the ethanol by rotary evaporation to obtain 1.5g of Ag-nGO terbinafine mixture;
(3) adding 13g of poloxamer 188 and 12g of poloxamer 407 into 15g of deionized water, and swelling at 4 ℃ for 12 hours to obtain a swollen matter solution;
mixing 1.6g of Ag-nGO terbinafine mixture with 7g of Tween-80, adding 0.1g of sodium benzoate and 5g of glycerol, mixing the obtained mixed system with the swelling substance, adding 46.6g of water, and continuously mixing uniformly to obtain the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel of the embodiment 4.
Experimental example 1
The graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel prepared in the example 1 is used as an experimental material to carry out a drug release test, and the experimental method is as follows:
(1) cumulative drug release test:
taking a certain mass of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel, adding 5ml of preheated PBS buffer solution into a dialysis bag with two ends sealed by clamps, then putting the dialysis bag into 95ml of PBS buffer solution to meet the leak tank condition, magnetically stirring at 37 ℃, absorbing 5ml of PBS buffer solution in a large system for measuring ultraviolet absorption in 0.5, 1, 2, 4, 6, 8, 16, 24, 36 and 48 hours respectively, and simultaneously supplementing 5ml of PBS buffer solution. An ultraviolet spectrophotometer measures an absorption peak at the wavelength of 289nm, and a cumulative release curve is drawn, wherein the experimental result is shown in figure 2.
The result of fig. 2 shows that the antifungal slow-release temperature-sensitive gel of the graphene oxide nano silver terbinafine is released to 28.3% cumulatively, and the release time is as long as 48 hours.
Therefore, the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel has higher terbinafine drug loading rate and can play an effective drug slow-release effect.
(2) Bacteriostatic experiments:
candida albicans (strain from dermatology laboratory, first hospital, Jilin university) was prepared as a bacterial suspension. The potato dextrose agar medium (PDA) comprises the following components in percentage by mass: 20% of potato, 2% of glucose and 1.8% of agar. Adding 5ml of culture medium into each test tube to prepare a slant culture medium; a plate medium was prepared by adding 20ml of the medium to a plate having a diameter of 90 mm.
0.5ml of the bacterial suspension is placed in a PDA plate culture medium and is uniformly distributed on the surface of the culture medium by a sterilized coating rod. Punching a hole on the bacterium-coated culture medium by using a puncher, wherein the diameter of the hole is 6mm, removing agar in the hole, respectively adding the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel and 1% terbinafine cream (Qilu pharmaceutical Co., Ltd.) into a 1ml sterile injector, and respectively adding 0.1ml of medicine into each hole to ensure that the cream is fully contacted with the edge of the hole, and the center of the cream is slightly higher than the agar plane of the culture medium. The drug sensitive experiment plate is placed in a constant temperature incubator at 35 ℃, the radius of the bacteriostatic ring of each drug is measured by using a vernier caliper after 24 hours, 48 hours, 72 hours and 96 hours respectively, and the radius mm value of the bacteriostatic ring around each drug hole is recorded. Each strain was plated on 3 plates simultaneously. The results are shown in table 1 below:
TABLE 1 nGO comparison of the radius of the inhibition ring of TBNF against Candida albicans (mm) with that of Ag-TBNF: (mm) (II)
n＝3)
| Observation time | Graphene oxide nano-silver terbinafine temperature-sensitive gel | Terbinafine cream |
| 24h | 9.27±0.51 | 7.50±0.82 |
| 48h | 9.78±0.63 | 7.61±0.43 |
| 72h | 9.81±0.48 | 6.31±0.30 |
| 96h | 9.20±0.17 | 5.48±0.54 |
As shown in the experiment control detection result in the table 1, the antibacterial strength of the graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel is superior to that of a terbinafine cream, and the antibacterial action time is longer.
While particular embodiments of the present invention have been illustrated and described, it will be appreciated that other changes and modifications may be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention.
Claims (4)
1. A preparation method of graphene oxide nano silver terbinafine antifungal slow-release temperature-sensitive gel is characterized by comprising the following steps:
(1) dispersing 0.2g of micron-sized single-layer graphene oxide in 100ml of deionized water, then placing the mixture in an ultrasonic crusher under the ice bath condition, and carrying out ultrasonic cracking for 1 hour to obtain a nano single-layer graphene oxide aqueous solution with the mass concentration of 0.2 mg/ml;
adding 105mg of silver nitrate into 5ml of deionized water, and then dropwise adding ammonia water with the concentration of 3% until the precipitate disappears to obtain a silver-ammonia solution;
mixing 100ml of nano monolayer graphene oxide aqueous solution with the silver ammonia solution prepared above at 50 ℃ for 30min, adding 1g of glucose aqueous solution, and reacting at 90 ℃ for 1 h;
placing the reaction product system in a centrifuge, centrifuging for 20min at the rotating speed of 12000r/min, discarding the supernatant, and recovering the obtained precipitate, namely the nano silver oxide graphene oxide, which is recorded as Ag-nGO;
(2) stirring and mixing 0.6g of Ag-nGO and 1g of terbinafine in 100ml of ethanol for 24 hours, and then removing the ethanol by rotary evaporation to obtain 1.6g of Ag-nGO terbinafine mixture;
(3) adding 5g of poloxamer 188 and 15g of poloxamer 407 into 20g of deionized water, and swelling at 4 ℃ for 12 hours to obtain a swollen matter solution;
mixing 1.6g of Ag-nGO terbinafine mixture with 5g of Tween-80, adding 0.1g of sodium benzoate and 2g of glycerol, mixing the obtained mixed system with the swelling substance, adding 51.3g of water, and continuously mixing uniformly to obtain the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel.
2. The graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel obtained by the preparation method according to claim 1, wherein the fungus is candida albicans.
3. The application of the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel in claim 2 in preparing a drug for treating fungal infection, wherein the fungus is candida albicans.
4. A medicament and/or pharmaceutical composition comprising the graphene oxide nanosilver terbinafine antifungal sustained-release temperature-sensitive gel of claim 2, wherein the fungus is Candida albicans.
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