CN111803445B - Preparation method of high-stability nano emulsion and nano emulsion gel - Google Patents

Preparation method of high-stability nano emulsion and nano emulsion gel Download PDF

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CN111803445B
CN111803445B CN202010660816.2A CN202010660816A CN111803445B CN 111803445 B CN111803445 B CN 111803445B CN 202010660816 A CN202010660816 A CN 202010660816A CN 111803445 B CN111803445 B CN 111803445B
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gel
nano emulsion
nano
emulsion
nanoemulsion
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CN111803445A (en
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郑寅
李辉
张福平
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Guizhou University
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    • A61K9/00—Medicinal preparations characterised by special physical form
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    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
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    • 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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    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

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

Preparation method of high-stability nano emulsion and nano emulsion gel
Technical Field
The invention belongs to the technical field of skin administration preparations, and particularly relates to a preparation method of a high-stability nano emulsion and a nano emulsion gel.
Background
The nano-emulsion gel is a special gel formulation formed by mixing the nano-emulsion and a gel matrix according to a certain proportion, and the formulation reduces the mobility of the nano-emulsion and improves the applicability of the nano-emulsion. However, the nanoemulsion gel in the prior art has the following technical problems: (1) the influence of pH on the zeta potential of the nano emulsion drops is not considered in the preparation process of the prior formulations; (2) the existing preparation method of the nano-emulsion gel has the defects that the nano-emulsion is prepared and then is mixed with the gel matrix with the same mass and complete crosslinking, so that the uniform distribution of nano-emulsion drops in the nano-emulsion gel cannot be ensured, and the longitudinal and transverse uniform delivery of the preparation in the skin cannot be ensured.
At present, the citral-terbinafine compound nanoemulsion gel is prepared in the prior art, and the content of the thickener is regulated to find that the nanoemulsion gel gradually transits from a transdermal drug delivery system to a local drug delivery system along with the increase of the content of the thickener (1%, 2% and 3%), and the quantity of the transdermal drug accumulated for 24 hours is extremely reduced (P) remarkably<0.01), wherein the citral content is 1021 μ g/cm2Reduced to 353 mug/cm2Terbinafine prepared by 213 mu g/cm2Reduced to 74.3. mu.g/cm2(ii) a Marking the nanoemulsion droplets with BBOT, laser confocal microscopy tracing the drug distribution shows that as the thickener content increases, although the drug tends to deposit in the epidermis and dermis layers, the distribution is not uniform, i.e. the drug delivery depth is not uniform and there is still a significant amount of drug entering the dermis layer.
Another prior art currently prepares terbinafine nanoemulsion gel (1% carbomer 940, w/w) with carbomer 940 gel matrix, transdermal tests found that the transdermal rate of the prepared nanoemulsion gel within 24h was significantly higher (P <0.01) than the commercial terbinafine gel formulation (lanmeili), and in vitro skin candida albicans infection treatment tests found that the fungus clearance rate of the terbinafine nanoemulsion gel was significantly higher than that of lanmeili group (P < 0.01).
However, the nano-emulsion gel prepared by the prior art has poor dynamic stability on one hand, and on the other hand, the method of fully mixing the nano-emulsion and gel matrix with equal mass and complete crosslinking is still adopted for preparing the nano-emulsion gel, so that the nano-emulsion droplets can not be uniformly dispersed in the gel matrix, and the problem of nonuniform longitudinal and transverse distribution of delivered drugs in the skin is caused.
Disclosure of Invention
In order to solve the technical problems, the invention provides a preparation method of nano-emulsion gel, which can improve the dynamic stability of the nano-emulsion gel and improve the dispersion uniformity of nano-emulsion droplets.
The invention aims to provide a preparation method of a high-stability nano emulsion.
Another object of the present invention is a method for preparing a nanoemulsion gel using the above-mentioned high stability nanoemulsion.
The preparation method of the high-stability nano emulsion according to the embodiment of the invention comprises the following steps:
(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 drug 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 homogenizing condition of 8000-.
In the preparation process of the high-stability nano emulsion, firstly, a medicament is dissolved into an organic solvent to form an oil phase; then mixing the emulsifier with 1, 2-propylene glycol in a specific ratio to obtain a mixed surfactant; mixing the mixed surfactant with the drug dissolved solution of the oil phase, and adjusting the pH of the system to 7.2-7.5 by adopting an alkaline solution to greatly increase the OH of the water phase－Content of the nano emulsion droplets makes the surfaces of the nano emulsion droplets adsorb more OH-And the Zeta potential absolute value of the nano emulsion drop is increased, so that the nano emulsion drop is more stable and cannot be polymerized after being placed for a long time.
Preferably, in the step (1), the solvent is one of ethyl acetate, isopropyl myristate, cinnamaldehyde, citral, eugenol and carvacrol. The organic solvent provided by the invention is non-toxic or low-toxicity organic solvent as a carrier of the medicine.
Preferably, in the step (1), the weight ratio of the drug to the solvent is 1: 8-12. The weight ratio of the drug to the solvent provided by the present invention is within the above range, and the drug can be dissolved in the solvent better, thereby forming a uniform and stable drug solution.
Preferably, in the step (2), the emulsifier is one of polyoxyethylene hydrogenated castor oil RH40, polyoxyethylene hydrogenated castor oil RH60, Tween-80, Tween-60, Tween-20, castor oil polyoxyethylene ether EL-40 and span-80. The emulsifier in the invention has the functions of emulsification and solubilization, remarkably reduces the tension of the interface between the drug and the water phase, and increases the solubility of the drug in water by utilizing the emulsification, thereby effectively improving the curative effect of the drug.
Preferably, in the step (3), one of 0.5-2mol/L sodium hydroxide solution, 0.5-2mol/L potassium hydroxide solution and 0.8-1.2mol/L sodium carbonate solution is used for adjusting the pH. Further preferably, the pH is adjusted to 7.2-7.4.
The invention takes sodium hydroxide, potassium hydroxide or sodium carbonate solution with specific concentration as a pH regulator to regulate the pH of a system to between 7.2 and 7.5, preferably to between 7.2 and 7.4, thereby increasing the OH of an aqueous phase－Content of the nano emulsion droplets makes the surfaces of the nano emulsion droplets adsorb more OH-And increasing the Zeta potential absolute value of the nano emulsion drop.
The invention provides a method for preparing nano-emulsion gel by using the nano-emulsion, which comprises the following steps:
(1) adding a thickening agent into the high-stability nano emulsion obtained by the method, and uniformly stirring to obtain a nano emulsion crude gel;
(2) and (2) adding triethanolamine into the coarse nano-emulsion gel obtained in the step (1), and stirring at the temperature of 20-25 ℃ at the speed of 60-120r/min for 6-12h to obtain the nano-emulsion gel.
According to the preparation method of the nano-emulsion gel, the nano-emulsion is prepared by the method, then the nano-emulsion is used as a water phase, the thickening agent is added to prepare the nano-emulsion crude gel, and finally the cross-linking degree is adjusted by triethanolamine to prepare the nano-emulsion gel. The method provided by the invention overcomes the technical problem that the nano-emulsion and the gel matrix are respectively prepared in the preparation method of the nano-emulsion gel in the prior art, and then the fully crosslinked gel matrix is uniformly mixed with the nano-emulsion with equal mass, so that the uniform dispersion of nano-emulsion droplets can not be ensured, the nano-emulsion droplets are ensured to be uniformly dispersed in the nano-emulsion gel matrix, the transverse and longitudinal uniform delivery of the medicine in the nano-emulsion gel in the skin is ensured, and the slow release effect of the medicine is improved.
Preferably, in step (1), the thickener is carbomer 934, carbomer 940 or carbomer 971.
Preferably, in step (1), the thickener is added in an amount of 0.5 to 1.5 wt% of the nanoemulsion. The thickener of the present invention is suitable for transdermal drug delivery system when the content of the thickener is 0.5-1.5 wt%.
Preferably, in step (1), the thickener is added in an amount of 3 to 4 wt% of the nanoemulsion. The thickener in the present invention is suitable for topical administration systems at a content of 3-4 wt%.
Preferably, in the step (1), the stirring temperature is 20-25 ℃, the stirring speed is 60-120r/min, and the stirring time is 6-12 h.
Preferably, in the step (2), the triethanolamine is added in an amount of 0.02 to 0.08 g/L.
According to the invention, triethanolamine is used as a cross-linking agent, and the triethanolamine can perform sufficient cross-linking reaction with a large amount of carboxyl in carbomer by using amino in molecules under the condition of the addition amount, so that gel is formed; the gel is uniformly crosslinked and is a uniform liquid crystal gel, and nano emulsion drops in the gel are uniformly dispersed; triethanolamine has alkalinity, can neutralize acidity of carbomer molecules, helps to maintain Zeta potential level of nanoemulsion droplets in nanoemulsion gel, and enhances stability of nanoemulsion gel; the triethanolamine is cheap, easy to obtain and convenient to popularize and apply.
The invention has the beneficial effects that:
the preparation method of the high-stability nano emulsion provided by the invention uses alkaliAdjusting pH of the water phase to 7.2-7.5 with the aqueous solution to keep the system weakly alkaline and increase OH in the nanoemulsion-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 fully crosslink the nano emulsion crude gel, 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.
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, it is obvious that the drawings in the following description are only some embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the drawings without creative efforts.
FIG. 1 is a Zeta potential value of the nanoemulsion obtained in comparative example 1;
FIG. 2 is a Zeta potential value of the nanoemulsion obtained in example 1;
FIG. 3 is the Zeta potential values of the nanoemulsion obtained in example 2;
figure 4a is the particle size distribution of the nanoemulsion gel of example 7 before centrifugation;
FIG. 4b is the particle size distribution of the nanoemulsion gel of example 7 after centrifugation;
figure 5a is the particle size distribution of the nanoemulsion gel of example 8 before centrifugation;
FIG. 5b is the particle size distribution of the nanoemulsion gel of example 8 after centrifugation;
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;
FIG. 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;
FIG. 8 is a schematic of the drug distribution in the nanoemulsion gel of example 9 within 2h of the skin;
FIG. 9 is a schematic of the drug distribution in the skin of comparative example 4 nanoemulsion gel 2 h;
FIG. 10 is a schematic representation of the drug distribution in the skin of nanoemulsion gel 2h of example 10;
fig. 11 is a schematic of the drug distribution in the skin of comparative example 5 nanoemulsion gel 2 h.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.
Example 1
A preparation method of the high-stability nano emulsion comprises the following steps:
(1) dissolving terbinafine in 10 times of citral to obtain medicinal solution;
(2) mixing castor oil polyoxyethylene ether EL-40 and 1, 2-propylene glycol according to the weight ratio of 5:1 to obtain a mixed surfactant;
(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 5:1 to obtain a mixed solution, taking 6 parts of the mixed solution, adding water to 20 parts by weight of the mixed solution under the high-speed homogenization condition of 8000r/min, adding 1mol/L sodium hydroxide solution to adjust the pH value to 7.2, and carrying out high-speed homogenization for 10min to form the high-stability nano emulsion.
Example 2
A high-stability nanoemulsion was prepared in the same manner as in example 1, except that the pH was adjusted to 7.5 in step (3).
Example 3
A preparation method of the high-stability nano emulsion comprises the following steps:
(1) dissolving artemisinin into carvacrol of which the weight is 10 times that of the artemisinin to obtain a medicine dissolving solution;
(2) mixing emulsifier Tween-80 and 1, 2-propylene glycol according to a weight ratio of 9:1 to obtain a mixed surfactant;
(3) and (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 9:1 to obtain a mixed solution, taking 9 parts of the mixed solution, adding water to 20 parts by weight of the mixed solution under the condition of high-speed homogenization at 10000r/min, adding 2mol/L potassium hydroxide solution to adjust the pH value to 7.3, and performing high-speed homogenization for 10min to form the high-stability nano emulsion.
Example 4
A preparation method of the high-stability nano emulsion comprises the following steps:
(1) dissolving naftifine in ethyl acetate with the weight being 12 times that of naftifine to obtain a medicine dissolving solution;
(2) mixing emulsifier Tween 60 and 1, 2-propylene glycol according to a weight ratio of 8:1 to obtain a mixed surfactant;
(3) and (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 8:1 to obtain a mixed solution, taking 9 parts of the mixed solution, adding water to 20 parts by weight of the mixed solution under the high-speed homogenization condition of 11000r/min, adding 0.5mol/L potassium hydroxide solution to adjust the pH value to 7.4, and carrying out high-speed homogenization for 30min to form the high-stability nano emulsion.
Example 5
A preparation method of the high-stability nano emulsion comprises the following steps:
(1) dissolving ivermectin in ethyl acetate with the weight 8 times that of the ivermectin to obtain a medicine dissolving solution;
(2) mixing emulsifier polyoxyethylene hydrogenated castor oil RH40 and 1, 2-propylene glycol according to the weight ratio of 7:1 to obtain a mixed surfactant;
(3) and (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 7:1 to obtain a mixed solution, taking 8 parts of the mixed solution, adding water to 20 parts by weight of the mixed solution under the high-speed homogenization condition of 12000r/min, adding 0.8mol/L sodium carbonate solution to adjust the pH value to 7.2, and homogenizing at a high speed for 20min to form the high-stability nano emulsion.
Example 6
A preparation method of the high-stability nano emulsion comprises the following steps:
(1) dissolving terbinafine in 12 times of cinnamaldehyde to obtain a medicine solution;
(2) mixing emulsifier castor oil polyoxyethylene ether EL-40 and 1, 2-propylene glycol according to the weight ratio of 6:1 to obtain a mixed surfactant;
(3) and (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 6:1 to obtain a mixed solution, taking 7 parts of the mixed solution, adding water to 20 parts by weight of the mixed solution under the condition of high-speed homogenization at 10000r/min, adding 1.2mol/L sodium carbonate solution to adjust the pH value to 7.2, and homogenizing at a high speed for 60min to form the high-stability nano emulsion.
Example 7
A nanoemulsion gel is prepared by the following steps:
(1) adding the thickening agent carbomer 934 into the high-stability nano emulsion obtained in the example 1, and stirring at the temperature of 20 ℃ at the speed of 120r/min for 6 hours, wherein the adding amount of the carbomer 934 is 1 wt% of the nano emulsion, so as to obtain nano emulsion crude gel;
(2) and (2) adding triethanolamine into the coarse nano-emulsion gel obtained in the step (1), wherein the adding amount of the triethanolamine is 0.02g/L, and stirring at the temperature of 20 ℃ at the speed of 120r/min for 6h to obtain the nano-emulsion gel.
Example 8
A nanoemulsion gel was prepared in the same manner as in example 7, except that carbomer was added in an amount of 3 wt% of the nanoemulsion in step (1).
Example 9
A nanoemulsion gel is prepared by the following steps:
(1) taking the high-stability nano emulsion obtained in the example 1, adding a thickening agent carbomer 934, wherein the addition amount of the carbomer 934 is 4 wt% of the nano emulsion, and stirring at the temperature of 20 ℃ at the speed of 120r/min for 6 hours to obtain a nano emulsion crude gel;
(2) and (2) adding triethanolamine into the coarse nano-emulsion gel obtained in the step (1), wherein the adding amount of the triethanolamine is 0.08g/L, and stirring at the temperature of 25 ℃ at the speed of 60r/min for 12h to obtain the nano-emulsion gel.
Example 10
A nanoemulsion gel was prepared in the same manner as in example 9, except that carbomer was added in an amount of 1.5 wt% of the nanoemulsion in step (1).
Comparative example 1
A nanoemulsion was prepared in the same manner as in example 1, except that, in step (3), the pH was adjusted to 6.9.
Comparative example 2
A nanoemulsion gel was prepared in the same manner as in example 7, except that, in step (1), the nanoemulsion obtained in comparative example 1 was used.
Comparative example 3
A nanoemulsion gel was prepared in the same manner as in example 7, except that, in step (1), the nanoemulsion obtained in comparative example 1 was used.
Comparative example 4
A nanoemulsion gel is prepared by the following steps:
(1) preparing a nano emulsion: the preparation method is the same as that of example 1;
(2) preparing a gel matrix: taking carbomer 934, adding water, wherein the weight of carbomer is 8 wt% of the weight of water, and stirring at the temperature of 20 ℃ at the speed of 120r/min for 6 hours to obtain a gel matrix;
(3) and (3) uniformly mixing the nano emulsion obtained in the step (1) and the gel matrix obtained in the step (2) in equal weight, adding triethanolamine, wherein the adding amount of the triethanolamine is 0.08g/L, and stirring at the temperature of 25 ℃ at the speed of 60r/min for 12 hours to obtain the nano emulsion gel.
The preparation method provided in comparative example 4 is a conventional preparation method.
Comparative example 5
A nanoemulsion gel was prepared in the same manner as in comparative example 4, except that the carbomer was 3% by weight of the water in step (2).
Test examples
Effect of pH on Zeta potential of nanoemulsion
The nanoemulsions obtained in example 1, example 2 and comparative example 1 were tested for Zeta potential absolute values and the results are shown in fig. 1-3.
In the preparation method of the nano emulsion provided by the comparative example 1, in the step (3), the pH is adjusted to 6.9, the pH in the example 1 is adjusted to 7.2, the pH in the example 2 is adjusted to 7.5, and as can be seen from the graphs in FIGS. 1-3, the Zeta potential absolute value of the nano emulsion in the comparative example 1 is about 0.83mv, the Zeta potential absolute value of the nano emulsion obtained in the example 1 is about 8.26mv, and the Zeta potential absolute value of the nano emulsion obtained in the example 2 is about 21.13mv, and the Zeta potential absolute value of the nano emulsion obtained by the method provided by the invention is obviously larger than that of the nano emulsion in the comparative example 1. The preparation method of the nano emulsion provided by the invention can greatly increase OH of the water phase by adjusting the pH of the system to 7.2-7.5 by using an alkaline solution-Content of the nano emulsion droplets makes the surfaces of the nano emulsion droplets adsorb more OH-And the Zeta potential absolute value of the nano emulsion drop is increased, so that the nano emulsion drop is more stable and cannot be polymerized after being placed for a long time.
2. Dynamic stability of nanoemulsion gel obtained by different preparation methods
The particle size distributions of the nanoemulsion gels obtained in example 7, example 8, comparative example 2 and comparative example 3 before and after centrifugation at a centrifugation rate of 12000r/min were examined, and the results are shown in FIGS. 4a to 7 b.
The nanoemulsion gel of figure 4a has a particle size distribution of 17.67 ± 1.84nm,
the nanoemulsion gel particle size distribution of fig. 4b is 35.37 ± 1.67 nm;
the nanoemulsion gel particle size distribution of figure 6a is 28.35 + -1.62 nm,
the nanoemulsion gel particle size distribution of fig. 6b is 97.03 ± 1.91 nm;
the nanoemulsion gel particle size distribution of figure 5a is 18.24 + -1.36 nm,
the nanoemulsion gel particle size distribution of fig. 5b is 25.71 ± 1.49 nm;
the nanoemulsion gel particle size distribution of figure 7a is at 27.52 + -1.91 nm,
the nanoemulsion gel particle size distribution of fig. 7b is 66.82 ± 0.98 nm;
as can be seen from the comparison between fig. 4a and 4b and fig. 6a and 6b and the comparison between fig. 5a and 5b and fig. 7a and 7b, under the premise of the same thickener content, the nanoemulsion obtained by adjusting the pH to 7.2 and 7.5 is used as the water phase, and then the particle size of the nanoemulsion gel obtained by the method provided by the invention is not obviously increased before and after centrifugation, and the dynamic stability is good; the nano-emulsion gel prepared by taking the nano-emulsion obtained by adjusting the pH to 6.9 as the water phase has obviously increased particle size before and after centrifugation and poor dynamic stability. This also demonstrates that the kinetic stability of the resulting nanoemulsion gel can be significantly improved by adjusting the pH to 7.2-7.5 during the preparation of the nanoemulsion.
3. Drug sustained release effect of nano-emulsion gel obtained by different preparation methods
The nanoemulsion gels obtained in example 9, example 10, comparative example 4 and comparative example 5 were labeled with fluorescent drug delivery in skin for 2h, and the results are shown in fig. 8 to 11.
As can be seen from the results of fig. 8 to 11, the thickener prepared by the method provided in example 9 of the present invention delivers the drug uniformly in the skin and most of the drug remains in the epidermal layer in 2h of 4 wt% of the nanoemulsion gel, while the drug delivery in 2h of the same amount of the thickener obtained in comparative example 4 is not uniform in the skin and a large amount of the drug enters the dermal layer; the thickener prepared by the method provided by the embodiment 10 of the invention has the advantages that the drug is uniformly delivered in the skin and most of the drug is uniformly delivered to the true cortex in 1.5 wt% of the nanoemulsion gel 2h, while the drug is not uniformly delivered in the skin in the nanoemulsion gel 2h with the same content of the thickener obtained by the comparative example 5, and the local drug aggregation phenomenon is obvious. This shows that the nanoemulsion gel prepared by the method provided by the invention can be delivered uniformly in the skin and accurately deliver the drug under the same other conditions. The nanoemulsion gels obtained by the traditional method are delivered unevenly and non-uniformly in the skin, and local drug aggregation phenomenon can occur.
4. Dispersivity of nano emulsion in nano emulsion gel obtained by different preparation methods
And (3) determining the dispersibility of the nanoemulsion in the nanoemulsion gel in the gel matrix by adopting a high performance liquid chromatography. Under chromatographic conditions, C18 reverse phase chromatography, mobile phase (methanol: water, 8:2, v/v), flow rate of 1.1mL/min and pH 3.5; establishing high performance liquid chromatography for measuring the contents of model drugs (citral and terbinafine) in the nanoemulsion gel (standard curve y of citral is 3 × 10)-7x-0.0122，r20.9992; standard curve y 2 x 10 of terbinafine content-7x-0.0385，r20.9998). Then, the drug content of each gram of the nano-emulsion gel obtained by the preparation methods of the invention in 5 batches of the embodiment 10 and the comparative example 5 is respectively quantitatively analyzed at random under the condition of the high performance liquid chromatography, and the embodiment 10 should be 40mg/g of citral and 4mg/g of terbinafine under the condition of uniform dispersion; comparative example 5 citral 20mg/mL, terbinafine 2 mg/mL.
The test results are: the content of citral in the nanoemulsion gel obtained in the embodiment 10 is 40.18 +/-0.36 mg/g; terbinafine is 4.12 plus or minus 0.23 mg/g; the nano-emulsion gel obtained in the comparative example 5 has the citral content of 25.12 +/-12.22 mg/g; terbinafine is 2.32 + -3.44 mg/g. The test results show that the content of the drug per gram of the gel in the obtained nanoemulsion gel by adopting the method of the invention is uniform and stable, while the content of the drug per gram of the gel in the nanoemulsion gel prepared by adopting the method of the comparative example and the traditional method is large in discrete degree and nonuniform.
The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended 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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