CN111803445B - A kind of preparation method of high stability nanoemulsion and nanoemulsion gel - Google Patents

Abstract

The invention provides a preparation method of high-stability nano emulsion and nano emulsion gel, wherein the preparation method of the nano emulsion adjusts the pH value of a water phase to 7.2-7.5 by using an alkaline solution, so that a system keeps alkalescence, and OH in the nano emulsion is increased^‑Content of (1), OH in the nanoemulsion^‑Can be adsorbed on the surface of the nano emulsion film so as to increase the Zeta potential absolute value of the surface of the nano emulsion drop film and improve the stability of the nano emulsion. Then, the nano emulsion obtained by the method is used as a water phase, a thickening agent is added into the water phase to prepare nano emulsion crude gel, triethanolamine is added to enable the nano emulsion crude gel to be fully crosslinked, so that nano emulsion droplets are promoted to be uniformly dispersed in a nano emulsion gel matrix, the stability of the obtained nano emulsion gel is improved, the nano emulsion gel can be uniformly distributed in the transverse direction and the longitudinal direction of the skin in the drug delivery process, and the slow release effect of the drug is improved.

Description

A kind of high stability nanoemulsion and preparation method of nanoemulsion gel

technical field

The invention belongs to the technical field of skin drug delivery preparations, and in particular relates to a preparation method of a high-stability nano-emulsion and a nano-emulsion gel.

Background technique

Nanoemulsion gel refers to a special gel formulation formed by mixing nanoemulsion and gel matrix in a certain proportion. This formulation reduces the fluidity of nanoemulsion and improves the applicability of nanoemulsion. However, the nanoemulsion gel in the prior art has the following technical problems: (1) the influence of pH on the zeta potential of the nanoemulsion droplets is not considered in the preparation process of this type of dosage form at present; (2) the existing nanoemulsion gel preparation method has defects, namely The preparation of nanoemulsion and subsequent mixing of the nanoemulsion with a fully cross-linked equal-quality gel matrix cannot guarantee the uniform distribution of the nanoemulsion droplets in the nanoemulsion gel and the uniform delivery of the drug longitudinally and transversely in the skin.

At present, a prior art has prepared citral-terbinafine compound nanoemulsion gel, which is found by adjusting the content of thickener, with the increase of the content of thickener (1%, 2% and 3%), the nanoemulsion gel The transdermal drug delivery system gradually transitioned from the transdermal drug delivery system to the local drug delivery system, and the cumulative transdermal drug volume decreased significantly (P<0.01) in 24 hours, among which citral decreased from 1021μg/cm ² to 353μg/cm ² , terbinafine from 213μg /cm ² decreased to 74.3μg/cm ² ; Nanoemulsion was labeled with BBOT, and the results of drug distribution traced by laser confocal microscopy showed that with the increase of thickener content, although the drug tended to be deposited in the epidermis and superficial dermis, This distribution is not uniform, i.e., the drug is delivered in different depths, and a considerable amount of the drug still enters the dermis.

At present, another prior art uses carbomer 940 gel matrix to prepare terbinafine nanoemulsion gel (1% carbomer 940, w/w). The transdermal test found that the nanoemulsion gel prepared within 24h The penetration rate of terbinafine was extremely significant (P<0.01) higher than that of the commercially available terbinafine gel preparation (Lamisil). Significantly higher than that in the lamishil group (P<0.01).

However, on the one hand, the nanoemulsion gel prepared by the prior art has poor kinetic stability; , it is impossible to ensure that the nanoemulsion droplets are evenly dispersed in the gel matrix, resulting in uneven distribution of the delivered drug in the skin longitudinally and laterally.

SUMMARY OF THE INVENTION

In order to solve the above technical problems, the present invention provides a preparation method of nanoemulsion gel which improves the dynamic stability of nanoemulsion gel and improves the dispersion uniformity of nanoemulsion droplets.

The purpose of this invention is to provide a kind of preparation method of high stability nanoemulsion.

Another object of the present invention is to utilize the above-mentioned high stability nanoemulsion to prepare the method of nanoemulsion gel.

The preparation method of the high stability nanoemulsion according to the specific embodiment of the present invention comprises the following steps:

(1) get medicine, dissolve in solvent, obtain medicine dissolving solution;

(2) get emulsifier and 1,2-propylene glycol and mix, obtain mixed surfactant, and the weight ratio of described emulsifier and 1,2-propylene glycol is 5-9:1;

(3) uniformly mix the mixed surfactant obtained in step (2) and the drug dissolving solution obtained in step (1) according to a mass ratio of 5-9:1 to obtain a mixed solution, then at a high speed of 8000-20000r/min Under homogenization conditions, add water to the mixed solution, the weight ratio of the mixed solution to water is 6-9:14-11, and adjust the pH to 7.2-7.5, and homogenize at a high speed for 10-60min to form the high stability. Nanoemulsion.

In the preparation method of the high-stability nanoemulsion provided by the present invention, in the preparation process, the drug is first dissolved in an organic solvent to form an oil phase; then the emulsifier is mixed with 1,2-propanediol in a specific ratio to obtain a mixed Surfactant; mix the mixed surfactant with the drug dissolving liquid in the oil phase, and use an alkaline solution to adjust the pH of the system to 7.2-7.5, which greatly increases the OH ^- content of the water phase and makes the surface of the nanoemulsion droplets adsorb more The OH ^- increases the absolute value of the Zeta potential of the nanoemulsion, and the nanoemulsion is more stable and does not polymerize for a long time.

Preferably, in step (1), the solvent is one of ethyl acetate, isopropyl myristate, cinnamaldehyde, citral, eugenol, and carvacrol. The organic solvents provided by the present invention are all non-toxic or low-toxic organic solvents as carriers of medicines.

Preferably, in step (1), the weight ratio of the drug to the solvent is 1:8-12. When the weight ratio of the drug to the solvent provided by the present invention is within the above range, the drug can be better dissolved in the solvent to form a uniform and stable drug solution.

Preferably, in step (2), the emulsifier is polyoxyethylene hydrogenated castor oil RH40, polyoxyethylene hydrogenated castor oil RH60, Tween-80, Tween-60, Tween-20, castor oil polyoxyethylene A kind of ether EL-40 and Span-80. The emulsifier in the present invention has the functions of emulsifying and solubilizing, significantly reduces the interfacial tension between the drug and the water phase, and utilizes the emulsification to increase the solubility of the drug in water, thereby effectively improving the curative effect of the drug.

Preferably, in step (3), one of 0.5-2 mol/L sodium hydroxide solution, 0.5-2 mol/L potassium hydroxide solution, and 0.8-1.2 mol/L sodium carbonate solution is used to adjust the pH. Further preferably, the pH is adjusted to 7.2-7.4.

In the present invention, a specific concentration of sodium hydroxide, potassium hydroxide or sodium carbonate solution is used as a pH regulator to adjust the pH of the system to between 7.2 and 7.5, preferably between 7.2 and 7.4, so as to increase the OH ^- content of the water phase, so that the The surface of nanoemulsion droplets adsorb more OH ^- , which increases the absolute value of Zeta potential of nanoemulsion droplets.

The present invention provides a method for preparing nanoemulsion gel by utilizing the above nanoemulsion, comprising the following steps:

(1) get the high-stability nanoemulsion that above-mentioned method obtains, add thickening agent, stir, obtain nanoemulsion thick gel;

(2) adding triethanolamine to the crude nanoemulsion gel obtained in step (1), stirring at a rate of 60-120 r/min at 20-25° C. for 6-12 h, to obtain the nanoemulsion gel.

In the preparation method of nanoemulsion gel provided by the present invention, a nanoemulsion is prepared by the above method, then the nanoemulsion is used as a water phase, a thickening agent is added to prepare a nanoemulsion coarse gel, and finally triethanolamine is used to adjust the cross-linking to prepare nanoemulsion gels. The method provided by the present invention overcomes the problem of preparing nanoemulsion and gel matrix separately in the preparation method of nanoemulsion gel in the prior art, and then mixing the fully cross-linked gel matrix with the nanoemulsion of equal quality, which cannot guarantee the drop of nanoemulsion. The technical problem of uniform dispersion ensures that the nanoemulsion droplets are uniformly dispersed in the nanoemulsion gel matrix, ensures that the drug in the nanoemulsion gel is uniformly delivered in the skin horizontally and vertically, and improves the sustained release effect of the drug.

Preferably, in step (1), the thickener is Carbomer 934, Carbomer 940 or Carbomer 971.

Preferably, in step (1), the added amount of the thickener is 0.5-1.5 wt% of the nanoemulsion. When the content of the thickener in the present invention is 0.5-1.5 wt %, it is suitable for a transdermal drug delivery system.

Preferably, in step (1), the added amount of the thickener is 3-4 wt% of the nanoemulsion. When the content of the thickener in the present invention is 3-4 wt%, it is suitable for a local drug delivery system.

Preferably, in step (1), the stirring temperature is 20-25° C., the stirring speed is 60-120 r/min, and the stirring time is 6-12 h.

Preferably, in step (2), the amount of triethanolamine added is 0.02-0.08 g/L.

The present invention uses triethanolamine as the cross-linking agent, and under the condition of the above-mentioned addition amount, triethanolamine can fully cross-link with amino groups in the molecule and a large number of carboxyl groups in the carbomer to form a gel; the gel is uniformly cross-linked and is Uniform liquid crystal gel, the nanoemulsion droplets in the gel are evenly dispersed; triethanolamine is alkaline and can neutralize the acidity of the carbomer molecule, which helps to maintain the Zeta potential level of the nanoemulsion droplets in the nanoemulsion gel and enhance the nanoemulsion. Emulsion gel stability; triethanolamine is cheap, easy to obtain and easy to popularize and apply.

The beneficial effects of the present invention are:

The preparation method of the high-stability nanoemulsion provided by the present invention adjusts the pH of the water phase to 7.2-7.5 with an alkaline solution, so that the system remains weakly alkaline, and the content of OH ^- in the nanoemulsion is increased, and the OH ^- in the nanoemulsion can It is adsorbed on the surface of the nanoemulsion film to increase the absolute value of the Zeta potential on the surface of the nanoemulsion droplet film and improve the stability of the nanoemulsion. Then the nanoemulsion is obtained by the above method as the water phase, a thickening agent is added to the water phase to prepare a nanoemulsion coarse gel, and triethanolamine is added to make the nanoemulsion coarse gel fully cross-linked, on the one hand, to promote the uniform dispersion of the nanoemulsion droplets in the In the nanoemulsion gel matrix, on the other hand, the stability of the obtained nanoemulsion gel is improved to ensure that the nanoemulsion gel can be uniformly distributed in the transverse and longitudinal directions of the skin during the drug delivery process, and the sustained release effect of the drug is improved.

Description of drawings

In order to illustrate the embodiments of the present invention or the technical solutions in the prior art more clearly, the following briefly introduces the accompanying drawings that are used in the description of the embodiments or the prior art. Obviously, the drawings in the following description are only These are some embodiments of the present invention. For those of ordinary skill in the art, other drawings can also be obtained according to these drawings without creative efforts.

Fig. 1 is the Zeta potential value of the nanoemulsion obtained in Comparative Example 1;

Fig. 2 is the Zeta potential value of the nanoemulsion obtained in Example 1;

Fig. 3 is the Zeta potential value of the nanoemulsion obtained in Example 2;

Fig. 4a is the particle size distribution before centrifugation of the nanoemulsion gel of Example 7;

Fig. 4b is the particle size distribution after the nanoemulsion gel of embodiment 7 is centrifuged;

Fig. 5a is the particle size distribution before centrifugation of the nanoemulsion gel of Example 8;

Fig. 5b is the particle size distribution after the nanoemulsion gel of embodiment 8 is centrifuged;

Figure 6a is the particle size distribution of the nanoemulsion gel of Comparative Example 2 before centrifugation;

Figure 6b is the particle size distribution of the nanoemulsion gel of Comparative Example 2 after centrifugation;

Figure 7a is the particle size distribution of the nanoemulsion gel of Comparative Example 3 before centrifugation;

Figure 7b is the particle size distribution of the nanoemulsion gel of Comparative Example 3 after centrifugation;

8 is a schematic diagram of the drug distribution in the nanoemulsion gel 2h skin of Example 9;

Fig. 9 is the schematic diagram of drug distribution in the nanoemulsion gel 2h skin of Comparative Example 4;

Figure 10 is a schematic diagram of the drug distribution in the nanoemulsion gel 2h skin of Example 10;

Figure 11 is a schematic diagram of the drug distribution in the skin of the nanoemulsion gel of Comparative Example 5 for 2 hours.

Detailed ways

In order to make the objectives, technical solutions and advantages of the present invention clearer, the technical solutions of the present invention will be described in detail below. Obviously, the described embodiments are only some, but not all, embodiments of the present invention. Based on the embodiments of the present invention, all other implementations obtained by those of ordinary skill in the art without creative work fall within the protection scope of the present invention.

Example 1

A kind of high stability nano-emulsion, its preparation method comprises the following steps:

(1) get terbinafine, be dissolved in the citral of 10 times of weight, obtain medicine dissolving solution;

(2) getting castor oil polyoxyethylene ether EL-40 and 1,2-propylene glycol is 5:1 mixing according to weight ratio, obtains mixed surfactant;

(3) uniformly mix the mixed surfactant obtained in step (2) and the drug dissolving solution obtained in step (1) according to a mass ratio of 5:1 to obtain a mixed solution, take 6 parts of the mixed solution and then add 6 parts of the mixed solution at 8000r/ Under the condition of high-speed homogenization for 1 min, water was added to the mixed solution to 20 parts by weight, 1 mol/L sodium hydroxide solution was added to adjust the pH to 7.2, and the high-speed homogenization was performed for 10 min to form the high-stability nanoemulsion.

Example 2

A high-stability nanoemulsion, the preparation method of which is the same as that of Example 1, except that the pH is adjusted to 7.5 in step (3).

Example 3

A kind of high stability nano-emulsion, its preparation method comprises the following steps:

(1) get artemisinin, be dissolved in the carvacrol of 10 times of weight, obtain medicine dissolving solution;

(2) get emulsifier Tween-80 and 1,2-propanediol and mix according to weight ratio and be 9:1 to mix, obtain mixed surfactant;

(3) uniformly mix the mixed surfactant obtained in step (2) and the drug dissolving solution obtained in step (1) with a mass ratio of 9:1 to obtain a mixed solution, take 9 parts of the mixed solution and then add 9 parts of the mixed solution at 10000r/ Under the condition of high-speed homogenization of min, water was added to the mixed solution to 20 parts by weight, 2 mol/L potassium hydroxide solution was added to adjust the pH to 7.3, and the high-speed homogenization was carried out for 10 min to form the high-stability nanoemulsion.

Example 4

A kind of high stability nano-emulsion, its preparation method comprises the following steps:

(1) get naftifine, be dissolved in the ethyl acetate of 12 times of weight, obtain medicine dissolving solution;

(2) get emulsifier Tween 60 and 1,2-propanediol and mix according to weight ratio and be 8:1 to mix, obtain mixed surfactant;

(3) uniformly mix the mixed surfactant obtained in step (2) and the drug dissolving solution obtained in step (1) according to a mass ratio of 8:1 to obtain a mixed solution, take 9 parts of the mixed solution and then add 9 parts of the mixed solution at 11000r/ Under the conditions of high-speed homogenization for min, water was added to the mixed solution to 20 parts by weight, 0.5 mol/L potassium hydroxide solution was added to adjust the pH to 7.4, and the high-speed homogenization was carried out for 30 min to form the high-stability nanoemulsion.

Example 5

A kind of high stability nano-emulsion, its preparation method comprises the following steps:

(1) get ivermectin, be dissolved in the ethyl acetate of 8 times of weight, obtain medicine dissolving solution;

(2) get emulsifier polyoxyethylene hydrogenated castor oil RH40 and 1,2-propylene glycol to mix according to weight ratio and be 7:1 to mix, obtain mixed surfactant;

(3) uniformly mix the mixed surfactant obtained in step (2) and the drug dissolving solution obtained in step (1) according to a mass ratio of 7:1 to obtain a mixed solution, take 8 parts of the mixed solution and then add 8 parts of the mixed solution at 12000r/ Under the condition of high-speed homogenization of min, water was added to the mixed solution to 20 parts by weight, 0.8 mol/L sodium carbonate solution was added to adjust the pH to 7.2, and the high-speed homogenization was carried out for 20 min to form the high-stability nanoemulsion.

Example 6

A kind of high stability nano-emulsion, its preparation method comprises the following steps:

(1) get terbinafine, be dissolved in the cinnamaldehyde of 12 times of weights to obtain drug dissolving solution;

(2) get emulsifier castor oil polyoxyethylene ether EL-40 and 1,2-propylene glycol to mix according to weight ratio and be 6:1 to mix, obtain mixed surfactant;

(3) uniformly mix the mixed surfactant obtained in step (2) and the drug dissolving solution obtained in step (1) according to a mass ratio of 6:1 to obtain a mixed solution, take 7 parts of the mixed solution and then add 7 parts of the mixed solution at 10000r/ Under the high-speed homogenization condition of min, water was added to the mixed solution to 20 parts by weight, 1.2 mol/L sodium carbonate solution was added to adjust the pH to 7.2, and the high-speed homogenization was carried out for 60 min to form the high-stability nanoemulsion.

Example 7

A kind of nano-emulsion gel, its preparation method comprises the following steps:

(1) Take the high stability nanoemulsion obtained in Example 1, add thickener carbomer 934, and stir at a rate of 120r/min for 6h at 20°C. The amount of carbomer 934 added is 1wt of the nanoemulsion % to obtain nanoemulsion coarse gel;

(2) adding triethanolamine to the nanoemulsion crude gel obtained in step (1), the amount of the triethanolamine added is 0.02g/L, and stirring at a rate of 120r/min for 6h at 20°C to obtain the Nanoemulsion gel.

Example 8

A nanoemulsion gel, the preparation method of which is the same as that in Example 7, the difference is that the amount of carbomer added in step (1) is 3wt% of the nanoemulsion.

Example 9

A kind of nano-emulsion gel, its preparation method comprises the following steps:

(1) Take the high stability nanoemulsion obtained in Example 1, add thickener carbomer 934, the addition of carbomer 934 is 4wt% of the nanoemulsion, stir at a rate of 120r/min under 20°C 6h, to obtain nanoemulsion coarse gel;

(2) adding triethanolamine to the nanoemulsion crude gel obtained in step (1), the amount of triethanolamine added is 0.08g/L, and stirring at a rate of 60r/min for 12h at 25°C to obtain the Nanoemulsion gel.

Example 10

A nanoemulsion gel, the preparation method of which is the same as that in Example 9, the difference is that the amount of carbomer added in step (1) is 1.5wt% of the nanoemulsion.

Comparative Example 1

A nanoemulsion, the preparation method of which is the same as that of Example 1, the difference is that in step (3), the pH is adjusted to 6.9.

Comparative Example 2

A nanoemulsion gel, the preparation method of which is the same as that of Example 7, the difference is that in step (1), the nanoemulsion obtained in Comparative Example 1 is used.

Comparative Example 3

A nanoemulsion gel, the preparation method of which is the same as that of Example 7, the difference is that in step (1), the nanoemulsion obtained in Comparative Example 1 is used.

Comparative Example 4

A kind of nano-emulsion gel, its preparation method comprises the following steps:

(1) Preparation of nanoemulsion: its preparation method is the same as in Example 1;

(2) Preparation of gel matrix: take carbomer 934, add water, the carbomer is 8wt% of the weight of water, and stir at a rate of 120r/min at 20°C for 6h to obtain a gel matrix;

(3) Take the nanoemulsion of step (1) and the gel matrix of step (2), mix evenly by equal weight, then add triethanolamine, the amount of triethanolamine added is 0.08g/L, under the condition of 25 ° C with 60 r The nanoemulsion gel was obtained by stirring at a rate of /min for 12 h.

The preparation method provided in Comparative Example 4 is the traditional preparation method.

Comparative Example 5

A nanoemulsion gel, the preparation method of which is the same as that of Comparative Example 4, the difference is that in step (2), the carbomer is 3wt% of the weight of water.

Test example

1. The effect of pH on the Zeta potential of nanoemulsions

The absolute values of Zeta potential of the nanoemulsions obtained in Example 1, Example 2 and Comparative Example 1 were tested, and the results are shown in Figures 1-3.

In the preparation method of the nanoemulsion provided by Comparative Example 1, in step (3), the pH was adjusted to 6.9, the pH was adjusted to 7.2 in Example 1, and the pH was adjusted to 7.5 in Example 2, as can be seen from Figures 1-3 , the absolute value of the Zeta potential of the nanoemulsion in Comparative Example 1 is about 0.83mv, the absolute value of the Zeta potential of the nanoemulsion obtained in Example 1 is about 8.26mv, and the absolute value of the Zeta potential of the nanoemulsion obtained in Example 2 is about 21.13mv , the absolute value of Zeta potential of the nanoemulsion obtained by the method provided by the present invention is obviously greater than the absolute value of Zeta potential of the nanoemulsion of Comparative Example 1. This shows that the preparation method of the nanoemulsion provided by the present invention can greatly increase the OH ^- content of the water phase by using an alkaline solution to adjust the pH of the system to 7.2-7.5, so that more OH ^- can be adsorbed on the surface of the nanoemulsion droplets, and the nanoemulsion can be increased. The absolute value of the Zeta potential of the emulsion droplet, the nanoemulsion droplet is more stable and does not polymerize for a long time.

2. Dynamic stability of nanoemulsion gels obtained by different preparation methods

The particle size distribution before and after centrifugation of the nanoemulsion gel obtained in Example 7, Example 8, Comparative Example 2 and Comparative Example 3 at a centrifugal speed of 12000 r/min was tested, and the results are shown in Figures 4a-7b.

The particle size distribution of the nanoemulsion gel in Figure 4a is 17.67 ± 1.84 nm,

The particle size distribution of the nanoemulsion gel in Figure 4b is 35.37±1.67nm;

The particle size distribution of the nanoemulsion gel in Fig. 6a is 28.35±1.62 nm,

The particle size distribution of the nanoemulsion gel in Figure 6b is 97.03±1.91nm;

The particle size distribution of the nanoemulsion gel in Fig. 5a is 18.24±1.36nm,

The particle size distribution of the nanoemulsion gel in Figure 5b is 25.71±1.49nm;

The particle size distribution of the nanoemulsion gel in Figure 7a is 27.52 ± 1.91 nm,

The particle size distribution of the nanoemulsion gel in Figure 7b is 66.82±0.98nm;

From the comparison of Figures 4a, 4b and Figures 6a, 6b and Figures 5a, 5b and Figures 7a, 7b, it can be seen that under the premise of the same thickener content, the nanoemulsion obtained by adjusting the pH to 7.2 and 7.5 The particle size of the nanoemulsion gel obtained by the method provided by the present invention does not increase significantly before and after centrifugation, and the kinetic stability is good; and the nanoemulsion obtained by adjusting the pH to 6.9 is prepared in the water phase. The particle size of the nanoemulsion gel before and after centrifugation increased significantly, and the kinetic stability was poor. This also shows that in the process of preparing the nanoemulsion, the kinetic stability of the obtained nanoemulsion gel can be significantly improved by adjusting the pH to 7.2-7.5.

3. Drug sustained-release effect of nanoemulsion gels obtained by different preparation methods

The nanoemulsion gels obtained in Example 9, Example 10, Comparative Example 4 and Comparative Example 5 were subjected to intradermal drug delivery fluorescent tracing for 2 hours, and the results are shown in Figures 8-11.

It can be seen from the results in Figures 8-11 that the thickener prepared by the method provided in Example 9 of the present invention is uniformly delivered in the skin within 2 hours of the 4wt% nanoemulsion gel, and most of the drugs are retained in the epidermis, In contrast, the nanoemulsion gel with the same content of thickener obtained in Comparative Example 4 delivered unevenly within 2 hours of the drug in the skin, and a large amount of the drug entered the dermis; the thickener prepared by the method provided in Example 10 of the present invention was 1.5 The wt% nanoemulsion gel was evenly delivered in the skin within 2h and most of the drug was evenly delivered to the dermis, while the nanoemulsion gel with the same content of thickener obtained in Comparative Example 5 did not deliver the drug in the skin within 2h. Uniform, local drug aggregation phenomenon is obvious. This shows that under the same conditions, the nanoemulsion gel prepared by the method provided by the present invention has uniform delivery in the skin and accurate drug delivery. However, the nanoemulsion gel obtained by the traditional method is unevenly delivered in the skin, and the local drug aggregation phenomenon will occur.

4. Dispersibility of nanoemulsions in nanoemulsion gels obtained by different preparation methods

The dispersibility of the nanoemulsion in the nanoemulsion gel was determined by high performance liquid chromatography. Under the chromatographic conditions, C18 reverse chromatographic column, mobile phase (methanol: water, 8:2, v/v), flow rate 1.1 mL/min and pH 3.5; establish a high performance liquid chromatography method for the determination of nanoemulsion gels Model drug (citral and terbinafine) content (citral standard curve y=3×10 ^-7 x-0.0122, r ² =0.9992; terbinafine content standard curve y=2×10 ^-7 x-0.0385 , r ² =0.9998). Subsequently, under the above-mentioned high performance liquid chromatography conditions, the drug content per gram of the nanoemulsion gel obtained by the preparation methods of Example 10 of the present invention and Comparative Example 5 was randomly analyzed for each gram of the gel. Example 10 should be citral 40mg/g, terbinafine 4mg/g; Comparative example 5 citral 20mg/mL, terbinafine 2mg/mL.

The test results are: the content of citral in the nanoemulsion gel obtained in Example 10 of the present invention is 40.18±0.36 mg/g; terbinafine is 4.12±0.23 mg/g; in the nanoemulsion gel obtained in Comparative Example 5 Citral was 25.12±12.22 mg/g; terbinafine was 2.32±3.44 mg/g. The test results show that the content of each gram of gel drug in the nanoemulsion gel obtained by the method of the present invention is uniform and stable, while the content of each gram of gel drug in the nanoemulsion gel prepared by the method of the comparative example and the traditional method is uniform and stable. The degree of dispersion is large and uneven.

The above are only specific embodiments of the present invention, but the protection scope of the present invention is not limited to this. Any person skilled in the art can easily think of changes or substitutions within the technical scope disclosed by the present invention. should be included within the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims (9)

1. A method of preparing a nanoemulsion gel, comprising the steps of:

(1) dissolving a drug in a solvent to obtain a drug solution;

(2) mixing an emulsifier and 1, 2-propylene glycol to obtain a mixed surfactant, wherein the weight ratio of the emulsifier to the 1, 2-propylene glycol is 5-9: 1;

(3) uniformly mixing the mixed surfactant obtained in the step (2) and the medicine dissolving solution obtained in the step (1) according to the mass ratio of 5-9:1 to obtain a mixed solution, then adding water into the mixed solution under the high-speed homogenization condition of 8000-20000r/min, wherein the weight ratio of the mixed solution to the water is 6-9:14-11, adjusting the pH value to 7.2-7.5, and homogenizing at a high speed for 10-60min to form the high-stability nano emulsion;

(4) adding a thickening agent into the obtained high-stability nano emulsion, and uniformly stirring to obtain a nano emulsion crude gel;

(5) and adding triethanolamine into the obtained crude nano-emulsion gel, and stirring at the temperature of 20-25 ℃ at the speed of 60-120r/min for 6-12h to obtain the nano-emulsion gel.

2. The method of claim 1, wherein in step (1), the solvent is one of ethyl acetate, isopropyl myristate, cinnamaldehyde, citral, eugenol, and carvacrol.

3. The method of claim 1, wherein in step (1), the weight ratio of the drug to the solvent is 1: 8-12.

4. The method for preparing nanoemulsion gel according to claim 1, wherein in step (2), the emulsifier is one of polyoxyethylene hydrogenated castor oil RH400, polyoxyethylene hydrogenated castor oil RH60, tween-80, tween-60, tween-20, castor oil polyoxyethylene ether EL-40, and span-80.

5. The method of claim 1, wherein in step (3), the pH is adjusted using one of a sodium hydroxide solution of 0.5-2mol/L, a potassium hydroxide solution of 0.5-2mol/L, and a sodium carbonate solution of 0.8-1.2 mol/L.

6. The method of preparing a nanoemulsion gel of claim 1, wherein in step (1), the thickener is carbomer 934, carbomer 940 or carbomer 971.

7. The method of claim 1, wherein in step (1), the thickener is added in an amount of 0.5 to 1.5 wt% of the nanoemulsion.

8. The method of claim 1, wherein in step (1) the thickener is added in an amount of 3-4 wt% of the nanoemulsion.

9. The method of claim 1, wherein the triethanolamine is added in an amount of 0.02 to 0.08g/L in step (2).

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