CN108158975A - Antimycotic sustained release thermo-responsive hydro gel of stannic oxide/graphene nano silver Terbinafine and its preparation method and application - Google Patents

Abstract

The present invention provides antimycotic sustained release thermo-responsive hydro gels of stannic oxide/graphene nano silver Terbinafine and its preparation method and application.In the antimycotic sustained release thermo-responsive hydro gel of stannic oxide/graphene nano silver Terbinafine of the present invention, using graphene oxide as slow releasing carrier of medication, so as to extend drug release and action time；Meanwhile the sustainable release silver ion of nano silver loaded, auxiliary enhancing anti-mycotic efficiency, and due to the special bactericidal mechanism of silver ion, because without generating resistance problems, recurrence probability is low；Similarly, using poloxamer as adjuvant, may be implemented in drug under normal temperature state is liquid, become gel since temperature raises when smearing affected part, not only facilitate administration but also can extend drug and affected part time of contact, and since drug exists with nano components, some drugs can penetrate into skin pore in liquid form, then become gel after the effect of factor receptor temperature, the time of bactericidal effect can be further enhanced.

Description

Graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel and its preparation Methods and Applications

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 its preparation method and application.

Background technique

Dermatophytes are fungi that can cause skin infections. These organisms reside in keratinous tissue and cause fungal infections, such as athlete's foot. Symptoms of fungal skin infections are characterized by lesions between the toes, which may extend to the feet the outer surface of the epidermis and the sole of the foot. The most common signs and symptoms of the infected area are redness, itching, and peeling, and the infection is contagious and may recur.

At present, the conventional treatment method for skin infection is topical application of terbinafine, ketoconazole, miconazole, itraconazole and other antifungal creams, ointments, powders, solutions or sprays and other common dosage forms. Cover or wash for treatment.

However, there are still many shortcomings in the existing treatment methods, mainly in: 1. Due to the common drug resistance of antifungal drugs, fungal infections are difficult to cure and easy to relapse; 2. The duration of drug effect is short; 3. Common dosage forms Inconvenient to use: the cream is inconvenient to apply; the spray has high fluidity and is not easy to remain in the affected area for a long time.

In view of this, the present invention is proposed.

Contents of the invention

The first object of the present invention is to provide a preparation method of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel, the preparation method has the advantages of simple and convenient process, and the prepared graphene oxide nano-silver special Binafine antifungal sustained-release temperature-sensitive gel has excellent antibacterial performance and convenient administration.

The second object of the present invention is to provide a graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel obtained by the preparation method of the present invention. The temperature-sensitive release gel has a long drug effect time, is convenient to administer, and does not produce drug resistance.

The third object of the present invention is to provide an application of the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel.

In order to realize the above-mentioned purpose of the present invention, special adopt following technical scheme:

A preparation method of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel, the preparation method comprising the steps of:

(a) Ultrasonic cracking of single-layer graphene oxide to obtain nanometer single-layer graphene oxide, which is then mixed with silver ammonia solution and reduced to obtain nano-silver graphene oxide;

(b) Gained nano silver graphene oxide is mixed with antifungal drug terbinafine to obtain nano silver graphene oxide drug mixture;

(c) adding water to swell the poloxamer to obtain a swelling solution;

The nano-silver graphene oxide drug mixture is mixed with a surfactant, and then an antiseptic and glycerin are added, and the resulting mixed system is mixed with a swelling solution to obtain a graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel.

Preferably, in step (a) of the preparation method of the present invention, micron-scale single-layer graphene oxide is used as a raw material, and is subjected to ultrasonic cracking to obtain nanometer single-layer graphene oxide;

More preferably, the ultrasonic cracking is carried out under the condition of ice bath, and the time is 45-90 min.

Preferably, in 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 solution conditions, 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 of the present invention, the poloxamer is swelled at 1-10°C for 6-18 hours after adding water;

More preferably, in step (c), the poloxamer is swollen at 4-8°C for 10-12 hours after adding water.

Preferably, in the preparation method of the present invention, the preservative includes sodium benzoate; and/or, the surfactant includes Tween-80.

Preferably, according to weight percentage, in the preparation method step (c) of the present invention, the amount of each raw material is as follows:

5-35% poloxamer, 1-2% nano-silver graphene oxide drug mixture, 2-10% surfactant, 0.01-1% preservative, 0.5-5% glycerin, and the rest water;

More preferably, in terms of weight percentage, the amount of each raw material in step (c) is as follows: Poloxamer 188 2-10%, Poloxamer 407 5-25%, nano-silver graphene oxide drug mixture 1-2% , 2-10% surfactant, 0.01-1% preservative, 0.5-5% glycerin, and the rest water;

Further preferably, according to percentage by weight, the amount of each raw material in step (c) is as follows: poloxamer 1885%, poloxamer 407 15%, nano-silver graphene oxide drug mixture 1.6%, surfactant 5%, Preservative 0.1%, glycerin 2%, and the balance water.

At the same time, the present invention also provides the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel obtained by the preparation method.

Similarly, the present invention also provides the application of the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel described in the present invention in the preparation of drugs for the treatment of fungal infections.

Further, the present invention also provides a medicine and/or a pharmaceutical composition comprising the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel described in the present invention.

Compared with prior art, the beneficial effect of the present invention is:

In the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel of the present invention, graphene oxide is used as a drug sustained-release carrier, thereby prolonging drug release and action time; at the same time, the loaded nano-silver can be continuously released Silver ions can assist in enhancing the antifungal effect, and due to the special bactericidal mechanism of silver ions, there will be no drug resistance and a low recurrence rate; similarly, using poloxamer as an adjuvant can realize the drug as an antifungal agent at room temperature. Liquid state, when applied to the affected area, it will become gel due to the temperature rise, which is convenient for administration and can prolong the contact time between the drug and the affected area, and because the drug carrier exists in nano-components, part of the drug can penetrate into the skin pores in liquid form, and then After body temperature, it becomes gel, which can further enhance the time of bactericidal effect.

Description of drawings

In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following will briefly introduce the drawings that need to be used in the description of the embodiments or the prior art.

1 is a scanning electron microscope structure diagram of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel gel according to an embodiment of the present invention;

Fig. 2 is the cumulative release curve of terbinafine in graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel according to an example of the present invention.

Detailed ways

Embodiments of the present invention will be described in detail below in conjunction with examples, but those skilled in the art will understand that the following examples are only for illustrating the present invention, and should not be considered as limiting the scope of the present invention. Those who do not indicate the specific conditions in the examples are carried out according to the conventional conditions or the conditions suggested by the manufacturer. The reagents or instruments used were not indicated by the manufacturer, and they were all conventional products that could be purchased from the market.

In view of the practical problems of existing antifungal preparations such as inconvenient medication, difficulty in maintaining drug efficacy for a long time, and easy drug resistance, the present invention provides a new type of slow-release agent to solve the problems existing in the existing antifungal preparations. Defects;

The sustained release medicament provided by the present invention is a loaded medicament with graphene oxide as a carrier, and has good biocompatibility due to the large number of active functional groups on the surface of graphene oxide, and at the same time due to its strong π-π bond conjugation, so it can also play a good role in the adsorption of drug ingredients, and can play the role of drug loading and sustained release; at the same time, the loading of nano-silver also enables the slow-release drug of the present invention to pass through The role of silver ions to sterilize, and will not produce drug resistance problems; further, the use of the auxiliary material poloxamer also enables the sustained release agent of the present invention to be coated on the skin surface in the form of liquid, while sensing temperature on the body surface Finally, the excipients become gel-like, so that the active ingredients can be in contact with the affected area for a long time, and the nano-medicine can also enter the interior of the human skin surface through the pores, thereby playing a long-term and effective role in killing fungi.

Specifically, the preparation of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel of the present invention comprises the following steps:

(a)

(i) Ultrasonic cracking of single-layer graphene oxide, preferably, in this step, use micron-scale single-layer graphene oxide as raw material, and obtain nanometer single-layer graphene oxide through ultrasonic cracking, gained nanometer single-layer graphene oxide The size is about 200nm;

Specifically, the raw material micron-scale graphene oxide can be added to deionized water, and the mass ratio of micron-scale graphene oxide to deionized water is controlled at 0.2-0.5:100;

Then, add it into an ultrasonic pulverizer under ice bath conditions for ultrasonic cracking, the time for ultrasonic cracking is 45-90 min, more preferably 45-60 min, and obtain nano single-layer graphite oxide with a mass concentration of 0.2-0.5 mg/ml Alkene solution;

(ii) gained nano single-layer graphene oxide solution mixes with silver ammonia solution;

Wherein, the preferred reference for the preparation of the silver-ammonia solution is as follows: silver nitrate is dissolved in deionized water, and then ammonia water is added dropwise to obtain the silver-ammonia solution;

Further preferably, the ratio of the volume milliliters of the nanometer monolayer graphene oxide solution as further reaction raw material to the mass milligrams of silver nitrate used to prepare the silver ammonia solution is 100:105;

Mix the graphene oxide solution and silver ammonia solution preferably at 50°C for 30 minutes, then add the reducing agent glucose, and preferably react at 95°C for 1 hour, centrifuge the obtained product system, remove the supernatant, and recover The resulting precipitate is nano-silver graphene oxide, which is denoted as Ag-nGO;

(b) Gained nano silver graphene oxide is mixed with terbinafine to obtain nano silver graphene oxide drug mixture;

In this step, it is preferably carried out under solution conditions, and the solvent used is preferably ethanol;

Specifically, in this step, nano-silver graphene oxide and terbinafine can be stirred and mixed in an ethanol solution, and the time of stirring and mixing is preferably 24h; then rotary evaporation is used to remove the solvent to obtain a nano-silver graphene oxide drug mixture ;

At the same time, it is also preferable to replace terbinafine with ketoconazole, miconazole, or itraconazole, which also have bactericidal effects;

The mass ratio of nano-silver graphene oxide and terbinafine as raw material is preferably 0.6:1;

(c)

(i) adding water to swell the poloxamer to obtain a swelling solution;

In this step, the poloxamer is swollen with a small amount of water as the solvent (that is, part of the dose of water is used as the solvent);

Meanwhile, preferably, the poloxamer used as raw material is poloxamer 188 and poloxamer 407;

Therefore, it is more preferred in the present invention to add Poloxamer 188 and Poloxamer 407 to a small amount of water, and to swell for 6-18 hours at 1-10°C; more preferably, Poloxamer Add 188 and poloxamer 407 to a small amount of water, and then swell at 4-8°C for 10-12 hours;

(ii) nano-silver graphene oxide drug mixture is mixed with a surfactant, preferably, the surfactant used is Tween-80; then, preservative and glycerin are added, and the preferred preservative used is sodium benzoate;

(iii)

Mix the mixed system obtained in step (ii) with the swell solution obtained in step (i), then add the remaining dose of water, and mix evenly to obtain graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel;

Further preferably, in step (c), in terms of weight percentage, the amount of each raw material is as follows: Poloxamer 5-35%, for example, but not limited to 7, 10, 12, 15, 17, 20, 22, 25, 27, or 30%, etc.; nano-silver graphene oxide drug mixture 1-2%, for example, can be, but not limited to, 1.1, 1.3, 1.5, 1.6, or 1.8%, etc.; surfactant 2-10%, for example Can be, but not limited to, 3, 5, 7, or 9%, etc.; preservatives 0.01-1%, for example, can be, but not limited to, 0.05, 0.1, 0.3, 0.5, 0.7, or 0.9%; glycerin 0.5-5% %, for example, can be, but not limited to, 1, 2, or 4%; and the remaining water,

The condition is that the sum of the amounts of each raw material is 100%;

More preferably, according to weight percentage, each raw material consumption in step (c) is as follows:

Poloxamer 188 2-10%, for example, but not limited to 3, 5, 7, or 9%; Poloxamer 407 5-25%, for example, but not limited to 10, 15, or 20% etc.; Nano-silver graphene oxide drug mixture 1-2%, for example can be, but not limited to 1.1, 1.3, 1.5, 1.6, or 1.8% etc.; Tween-80 2-10%, for example can be, but Not limited to 3, 5, 7, or 9%; sodium benzoate 0.01-1%, for example, but not limited to 0.05, 0.1, 0.3, 0.5, 0.7, or 0.9%; glycerin 0.5-5%, for example For, but not limited to, 1, 2, or 4%; and the remainder of water,

The condition is that the sum of the amounts of each raw material is 100%;

More preferably, according to weight percentage, each raw material consumption in step (c) is as follows:

Poloxamer 188 5%, Poloxamer 407 15%, nano silver graphene oxide drug mixture 1.6%, surfactant 5%, preservative 0.1%, glycerin 2%, and the balance of water,

The condition is that the sum of the amounts of each raw material is 100%.

And the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel prepared by the above method not only has good drug sustained release and therapeutic effect on skin diseases caused by fungi, but also can play a long-term role. effective treatment and will not produce excellent effects of drug resistance; further, the use of the adjuvant poloxamer also makes graphene nano-silver terbinafine antifungal slow-release thermosensitive gel of the present invention coated at normal temperature It is in a liquid state before, which is easier to apply and evenly distribute on the skin surface, and it will become a gel after being exposed to the skin surface, so that the nano single-layer graphene oxide loaded with antifungal drugs terbinafine and silver can Fully contact with the affected area to achieve long-acting and effective treatment.

Further, the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel of the present invention can be used in the preparation of corresponding drugs for the treatment of diseases caused by fungi, especially various diseases caused by fungi. skin diseases;

In the actual treatment process, the graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel of the present invention can be used alone as a therapeutic agent, or it can be used together with other internal/external application/injection preparations to achieve Comprehensive treatment effect.

Example 1

(1) Take 0.2g of micron-sized single-layer graphene oxide and disperse it in 100ml of deionized water, then place it in an ultrasonic pulverizer under ice bath conditions, and ultrasonically crack it for 1h to obtain a nanometer monolayer with a mass concentration of 0.2mg/ml Graphene oxide aqueous solution;

Add 105 mg of silver nitrate to 5 ml of deionized water, and then dropwise add ammonia water with a concentration of 3% until the precipitate disappears to obtain a silver ammonia solution;

Take 100ml of nano single-layer graphene oxide aqueous solution and the above-prepared silver ammonia solution and stir and mix at 50°C for 30min, then add 1g of glucose aqueous solution, and react at 90°C for 1h;

The reaction product system was placed in a centrifuge, and centrifuged for 20 minutes at a speed of 12000r/min, the supernatant was discarded, and the resulting precipitate was recovered, which was nano-silver oxide graphene oxide, denoted as Ag-nGO;

(2) Stir and mix 0.6g Ag-nGO and 1g terbinafine in 100ml ethanol for 24h, then remove ethanol by rotary evaporation to obtain 1.6g of Ag-nGO terbinafine mixture;

(3) Add 5 g of Poloxamer 188 and 15 g of Poloxamer 407 into 20 g of deionized water, and swell at 4°C for 12 hours to obtain a swelling product solution;

After mixing 1.6g of Ag-nGO terbinafine mixture with 5g of Tween-80, add 0.1g of sodium benzoate and 2g of glycerin, then mix the resulting mixed system with the swollen product, then add 51.3g of water, and continue mixing to obtain The graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel of Example 1.

Electron microscopy was performed on the product of Example 1, and the structure was shown in Figure 1.

Example 2

(1) Take 0.4g micron-sized single-layer graphene oxide and disperse it in 100ml deionized water, then place it in an ultrasonic pulverizer under ice bath conditions, and ultrasonically crack it for 1h to obtain a nanometer monolayer with a mass concentration of 0.4mg/ml Graphene oxide aqueous solution;

Add 200 mg of silver nitrate to 5 ml of deionized water, and then dropwise add ammonia water with a concentration of 3% until the precipitate disappears to obtain a silver ammonia solution;

Take 100ml of nano single-layer graphene oxide aqueous solution and the above-prepared silver ammonia solution and stir and mix at 50°C for 30min, then add 3g of glucose aqueous solution, and react at 90°C for 1h;

The reaction product system was placed in a centrifuge, and centrifuged for 20 minutes at a speed of 12000r/min, the supernatant was discarded, and the resulting precipitate was recovered, which was nano-silver oxide graphene oxide, denoted as Ag-nGO;

(2) Stir and mix 0.8g Ag-nGO and 1.2g terbinafine in 100ml ethanol for 24h, then remove ethanol by rotary evaporation to obtain 2g of Ag-nGO terbinafine mixture;

(3) Add 2g of Poloxamer 188 and 25g of Poloxamer 407 into 25g of deionized water, and swell at 5°C for 12 hours to obtain a swelling product solution;

After mixing 2g of Ag-nGO terbinafine mixture with 10g of Tween-80, add 0.1g of sodium benzoate and 5g of glycerin, then mix the resulting mixed system with the swollen product, then add 31.1g of water, continue to mix well, and then implement The graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel of Example 2.

Example 3

(1) Take 0.5g of micron-sized single-layer graphene oxide and disperse it in 100ml of deionized water, then place it in an ultrasonic pulverizer under ice bath conditions, and ultrasonically crack it for 1h to obtain a nanometer monolayer with a mass concentration of 0.5mg/ml Graphene oxide aqueous solution;

Add 50 mg of silver nitrate to 5 ml of deionized water, and then dropwise add ammonia water with a concentration of 3% until the precipitate disappears to obtain a silver ammonia solution;

Take 30ml of nano single-layer graphene oxide aqueous solution and the above-prepared silver ammonia solution and stir and mix at 50°C for 30min, then add 0.8g of glucose aqueous solution, and react at 90°C for 1h;

The reaction product system was placed in a centrifuge, and centrifuged for 20 minutes at a speed of 12000r/min, the supernatant was discarded, and the resulting precipitate was recovered, which was nano-silver oxide graphene oxide, denoted as Ag-nGO;

(2) Stir and mix 0.4g Ag-nGO and 0.6g terbinafine in 100ml ethanol for 24h, then remove the ethanol by rotary evaporation to obtain 1g of Ag-nGO terbinafine mixture;

(3) Add 10 g of poloxamer 188 and 5 g of poloxamer 407 into 20 g of deionized water, and swell at 4°C for 10 h to obtain a swelling solution;

After mixing 1g of Ag-nGO terbinafine mixture with 3g of Tween-80, add 0.1g of sodium benzoate and 1g of glycerin, then mix the resulting mixed system with the swollen product, then add 51.3g of water, continue to mix well, and then implement The graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel of Example 3.

Example 4

(1) Take 0.3g of micron-sized single-layer graphene oxide and disperse it in 100ml of deionized water, then place it in an ultrasonic pulverizer under ice bath conditions, and ultrasonically crack it for 1h to obtain a nanometer monolayer with a mass concentration of 0.3mg/ml Graphene oxide aqueous solution;

Add 120 mg of silver nitrate to 5 ml of deionized water, then dropwise add ammonia water with a concentration of 3% until the precipitate disappears to obtain a silver ammonia solution;

Take 100ml of nano single-layer graphene oxide aqueous solution and the above-prepared silver ammonia solution and stir and mix at 50°C for 30min, then add 1.5g of glucose aqueous solution, and react at 90°C for 1h;

The reaction product system was placed in a centrifuge, and centrifuged for 20 minutes at a speed of 12000r/min, the supernatant was discarded, and the resulting precipitate was recovered, which was nano-silver oxide graphene oxide, denoted as Ag-nGO;

(2) Stir and mix 0.4g Ag-nGO and 1.1g terbinafine in 100ml ethanol for 24h, then remove the ethanol by rotary evaporation to obtain 1.5g of Ag-nGO terbinafine mixture;

(3) Add 13g of Poloxamer 188 and 12g of Poloxamer 407 into 15g of deionized water, and swell at 4°C for 12 hours to obtain a swelling solution;

After mixing 1.6g of the Ag-nGO terbinafine mixture with 7g of Tween-80, add 0.1g of sodium benzoate and 5g of glycerin, then mix the resulting mixed system with the swollen product, then add 46.6g of water, and continue mixing to obtain The graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel of embodiment 4.

Experimental example 1

Taking the graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel prepared in Example 1 as the experimental material, a drug release test was carried out, and the experimental method was as follows:

(1) Cumulative drug release experiment:

Take a certain amount of graphene oxide nano-silver terbinafine antifungal slow-release temperature-sensitive gel, add 5ml of preheated PBS buffer solution to the dialysis bag closed with clips at both ends, and then put the dialysis bag into PBS In 95ml of buffer solution, meet the conditions of the sink, stir magnetically at 37°C, draw 5ml of PBS buffer solution in the large system at 0.5, 1, 2, 4, 6, 8, 16, 24, 36, and 48 hours to measure the UV absorption, and supplement at the same time 5ml PBS buffer. The ultraviolet spectrophotometer measures the absorption peak at a wavelength of 289nm, and draws the cumulative release curve. The experimental results are shown in Figure 2.

As can be seen from the results in Figure 2, the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel has a cumulative release of 28.3%, and the release time is as long as 48 hours.

It can be seen that the graphene oxide nano-silver terbinafine antifungal sustained-release temperature-sensitive gel of the present invention not only has a higher drug loading of terbinafine, but also has an effective drug slow-controlled release effect .

(2) Antibacterial test:

Candida albicans (the strain comes from the Dermatology Laboratory of the First Hospital of Jilin University), making bacterial suspension. The mass fraction of potato dextrose agar medium (PDA) is: potato 20%, glucose 2%, agar 1.8%. Add 5ml of medium to each test tube to prepare a slant medium; add 20ml of medium to a plate with a diameter of 90mm to prepare a plate medium.

Take 0.5ml of bacterial suspension and place it on the PDA plate culture medium, and use a sterilized coating stick to evenly distribute it on the surface of the culture medium. Use a hole puncher to punch a hole on the culture medium coated with bacteria, with a diameter of 6 mm, remove the agar in the hole, and apply graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel and 1% terbinafine cream (Qilu Pharmaceutical Co., Ltd.) were added to 1ml sterile syringes, and 0.1ml of medicine was added to each well, so that the ointment was fully in contact with the edge of the well, and the center was slightly higher than the agar plane of the culture medium. The drug susceptibility test plate was placed in a constant temperature incubator at 35°C, and at 24 hours, 48 hours, 72 hours, and 96 hours, the radius of the inhibition zone of each drug was measured with a vernier caliper, and the radius of the inhibition zone around each drug hole was recorded in mm. Make 3 plates for each strain at the same time. The results are shown in Table 1 below:

Table 1 Comparison of radius of inhibition zone between nGO-Ag-TBNF and TBNF against Candida albicans (mm)( n=3)

observation time Graphene oxide nano silver terbinafine thermosensitive gel Terbinafine Cream 24h 9.27±0.51 7.50±0.82 48 hours 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

It can be seen from the experimental control test results in Table 1 above that the bacteriostatic strength of graphene oxide nano-silver terbinafine antifungal slow-release thermosensitive gel is better than that of terbinafine cream, and the bacteriostatic effect time is also longer.

While particular embodiments of the invention have been illustrated and described, it should be appreciated that other changes and modifications can 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 (10)

1. a kind of preparation method of the antimycotic sustained release thermo-responsive hydro gel of stannic oxide/graphene nano silver Terbinafine, which is characterized in that The preparation method includes the following steps：

(a) single-layer graphene oxide ultrasound cracks, and obtains nanocrystal monolayer graphene oxide, after then being mixed with silver ammino solution also Original obtains nano silver graphene oxide；

(b) gained nano silver graphene oxide is mixed with antifungal drug Terbinafine, obtains nano silver graphene oxide drug Mixture；

(c) poloxamer adds water-swellable, obtains swelling object solution；

Nano silver graphene oxide medicinal mixture is mixed with surfactant, then adds in preservative and glycerine, gained mixing System is mixed with swelling object solution to get to the antimycotic sustained release thermo-responsive hydro gel of stannic oxide/graphene nano silver Terbinafine.

2. preparation method according to claim 1, which is characterized in that be with micron order mono-layer graphite oxide in step (a) Alkene is raw material, and cracks to obtain nanocrystal monolayer graphene oxide through ultrasonic；

Preferably, ultrasound cracking carries out under condition of ice bath, and the time is 45~90mi n.

3. preparation method according to claim 1, which is characterized in that be by nano silver under solution condition in step (b) Graphene oxide is stirred with antifungal drug Terbinafine, then removes solvent, obtains nano silver graphene oxide drug Mixture.

4. preparation method according to claim 1, which is characterized in that in step (c), it is husky that the poloxamer includes pool Lip river Nurse 188 and poloxamer188.

5. preparation method according to claim 1, which is characterized in that be after poloxamer is added water, 1 in step (c) 6~18h is swollen under the conditions of~10 DEG C；

Preferably, in step (c), it is after poloxamer is added water, 10~12h is swollen under the conditions of 4~8 DEG C.

6. preparation method according to claim 1, which is characterized in that the preservative includes sodium benzoate；

And/or the surfactant includes Tween-80.

7. preparation method according to claim 1, which is characterized in that according to percent by weight, each raw material in step (c) Dosage is as follows：

Poloxamer 5~35%, nano silver graphene oxide medicinal mixture 1~2%, surfactant 2~10%, preservative 0.01~1%, the water of glycerine 0.5~5% and surplus；

Preferably, according to percent by weight, each raw material dosage is as follows in step (c)：

PLURONICS F87 2~10%, poloxamer188 5~25%, nano silver graphene oxide medicinal mixture 1~2%, The water of surfactant 2~10%, preservative 0.01~1%, glycerine 0.5~5% and surplus；

It is further preferred that according to percent by weight, each raw material dosage is as follows in step (c)：

PLURONICS F87 5%, poloxamer188 15%, nano silver graphene oxide medicinal mixture 1.6%, surface-active The water of agent 5%, preservative 0.1%, glycerine 2% and surplus.

8. the obtained stannic oxide/graphene nano silver Terbinafine of preparation method according to any one of claim 1-7 resists Fungi is sustained thermo-responsive hydro gel.

9. the antimycotic sustained release thermo-responsive hydro gel of stannic oxide/graphene nano silver Terbinafine according to any one of claims 8 is preparing fungi sense Contaminate the application in medicine.

10. include the drug of the antimycotic sustained release thermo-responsive hydro gel of stannic oxide/graphene nano silver Terbinafine according to any one of claims 8 And/or pharmaceutical composition.