CN117298034A - Drug-loaded microemulsion-nanogel composite preparation for treating children eczema and preparation method and application thereof - Google Patents
Drug-loaded microemulsion-nanogel composite preparation for treating children eczema and preparation method and application thereof Download PDFInfo
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- CN117298034A CN117298034A CN202311020529.5A CN202311020529A CN117298034A CN 117298034 A CN117298034 A CN 117298034A CN 202311020529 A CN202311020529 A CN 202311020529A CN 117298034 A CN117298034 A CN 117298034A
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Abstract
The invention provides a modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children, which is formed by compositing nanogel and microemulsion; wherein the nanogel comprises the following components: 0.2 to 0.4 weight percent of honeysuckle extract, 0.3 to 0.6 weight percent of weeping forsythia extract, 0.1 to 0.2 weight percent of sodium tripolyphosphate, 1.0 to 2.0 weight percent of sodium carboxymethyl cellulose, 0.5 to 1 weight percent of chitosan and the balance of deionized water; the modified drug-loaded microemulsion comprises the following components: 0.1 to 0.2 weight percent of weeping forsythia volatile oil, 0.5 to 1 weight percent of bisabolol, 0.6 to 1.2 weight percent of tert-butylcyclohexanol, 2.5 to 5 weight percent of olive oil, 4.5 to 9 weight percent of isopropyl myristate, 0.1 to 0.2 weight percent of C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether, 20 to 40 weight percent of polyoxyethylene lauryl hydroxystearate and 20 to 40 weight percent of polyethylene glycol. According to the invention, the synergistic effect of each component is realized in a mode of a mixed system of modified drug-loaded microemulsion-nanogel, and the inhibition effect on the TRPV1 receptor is directly generated, so that the effect of treating both symptoms and root causes of eczema in children is achieved.
Description
Technical Field
The invention relates to the field of skin external products, in particular to a drug-loaded microemulsion-nanogel composite preparation for treating children eczema and a preparation method and application thereof.
Background
Eczema of children is a common skin inflammation, and symptoms thereof include itching, redness and swelling, dry skin and the like. The disease is mainly manifested by rough and hypertrophic skin, lichen lesions and pigmentation, and is frequently repeatedly used, seriously affecting the physical health and normal development of children.
Eczema in children causes severe itching sensation, is closely related to itching signaling pathways, and two main itching signaling pathways which are confirmed to be histamine-dependent itching signaling pathways and histamine-independent itching signaling pathways, wherein the two signaling pathways are related to a downstream signaling molecule capsaicin receptor (TRPV 1), and TRPV1 is expressed in nociceptors, skin keratinocytes and skin accessory cells and is closely related to local itching and pain sensation. TRPV1 is involved in acute itching mediated by histamine receptors H1 and H4 and in the itchy transition of pain stimuli in chronic itchy diseases, and thus sensitive skin is often accompanied by excessive reactions of peripheral nerve receptors, especially undesirable sensations such as burning and stinging due to the overactive TRPV 1.
The curative effect of the commercial medicines for treating the children eczema is not satisfactory, and the medicines have a plurality of side effects and adverse reactions. Corticoids, although taking effect quickly, are easy to relapse after stopping taking, for example, topical corticosteroids can lead to thinning of skin, generate side effects such as skin dryness, atrophy, telangiectasia, pigmentation and the like, and more serious corticoids can generate inhibition of hypothalamus-pituitary gland-adrenal axis or generate growth inhibition phenomenon, so that children are not suitable for large-dose and large-area long-term use. The safety of topical long-term use of the immunosuppressive drugs tacrolimus and pimecrolimus remains to be explored. Some lead and boric acid preparations have toxic and fertility-affecting side effects.
Therefore, the external medicine skin care product for treating the children eczema, which has good curative effect, quick response and small side effect, is developed and is an urgent need for infants suffering from eczema.
Disclosure of Invention
In order to solve the problems in the prior art, the invention provides a modified drug-loaded microemulsion-nanogel composite preparation for treating children eczema, a preparation method and application thereof, and the drug-loaded microemulsion-nanogel composite preparation can realize the synergistic effect of all components in a mode of a drug-loaded microemulsion-nanogel mixed system according to the pharmacological effect and physicochemical property characteristics of all active components, can directly inhibit TRPV1 receptors, and can achieve the effect of treating both symptoms and root causes of the children eczema.
The invention provides a modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children, which is characterized in that the preparation is formed by compositing nanogel and modified drug-loaded microemulsion, wherein the modified drug-loaded microemulsion is obtained by carrying out surface modification on the drug-loaded microemulsion by C16-C18 hydroxyalkyl hydroxy dimer linolenyl ether;
wherein the nanogel comprises the following components: 0.2 to 0.4 weight percent of honeysuckle extract, 0.3 to 0.6 weight percent of weeping forsythia extract, 0.1 to 0.2 weight percent of sodium tripolyphosphate, 1.0 to 2.0 weight percent of sodium carboxymethyl cellulose, 0.5 to 1 weight percent of chitosan and the balance of deionized water;
the modified drug-loaded microemulsion preparation raw material comprises the following components: 0.1 to 0.2 weight percent of weeping forsythia volatile oil, 0.5 to 1 weight percent of bisabolol, 0.6 to 1.2 weight percent of tert-butylcyclohexanol, 2.5 to 5 weight percent of olive oil, 4.5 to 9 weight percent of isopropyl myristate, 01 to 0.2 weight percent of C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether, 20 to 40 weight percent of polyoxyethylene lauryl hydroxystearate and 20 to 40 weight percent of polyethylene glycol.
The invention also provides a preparation method of the modified drug-loaded microemulsion-nanogel composite preparation for treating the eczema of children, which comprises the following steps:
s1, weighing honeysuckle extract, weeping forsythiae extract, sodium tripolyphosphate and sodium carboxymethyl cellulose according to mass percentage, mixing, and adding deionized water for dissolution to obtain a mixture aqueous solution;
s2, weighing chitosan, dissolving the chitosan in a certain amount of deionized water, and regulating the pH value to 5.0 through a pH regulator to obtain a chitosan solution;
s3, slowly dripping the mixture water solution into the chitosan solution under the stirring condition to form nano gel;
s4, weighing fructus forsythiae volatile oil, bisabolol, tert-butyl cyclohexanol, olive oil, isopropyl myristate, C16-C18 hydroxyalkyl hydroxy dimer linol ether, polyoxyethylene lauryl stearate and polyethylene glycol according to mass percentage, and uniformly mixing to obtain modified drug-loaded emulsion;
s5, adding the modified drug-loaded emulsion into the nanogel system according to the mass ratio of 0.5:1-1:1, and stirring at uniform speed in the same direction to obtain the modified drug-loaded microemulsion-nanogel composite preparation.
Specifically, in step S2, the pH adjuster is acetic acid.
Specifically, the stirring condition in the step S3 is uniform-speed and same-direction stirring at a rotating speed of 2000 rpm.
Specifically, the polyethylene glycol in step S4 has a molecular weight of 400.
The invention also provides application of the modified drug-loaded microemulsion-nanogel composite preparation for treating the eczema of children in skin care products.
The invention also provides a skin care product with the effect of treating the eczema of children, which comprises 10-30 parts of the modified drug-loaded microemulsion-nanogel composite preparation prepared by the method, 0.1-5 parts of allantoin, 0.1-5 parts of panthenol, 0.01-0.2 part of sodium hyaluronate, 1-10 parts of humectant, 1-3 parts of emulsifier, 0.5-2 parts of thickener, 0.1-1 part of chelating agent, 0.1-0.5 part of pH regulator and 40-70 parts of deionized water.
Specifically, the humectant is prinsepia utilis royle oil, glycerol, propylene glycol and 1, 2-pentanediol with the mass ratio of 1-2:1-2:0.5-1.5:1; the emulsifier is cetyl stearyl alcohol and/or cetostearyl glucoside; the thickener is carbomer and/or behenyl alcohol; the chelating agent is disodium EDTA; the pH regulator is triethanolamine.
Specifically, the composition also comprises 0.01-0.03 part of preservative; wherein the preservative is p-hydroxyacetophenone and/or propyl hydroxybenzoate.
The invention also provides a preparation method of the skin care product with the effect of treating the children eczema, which is characterized in that: the method comprises the following steps:
s1, mixing allantoin, panthenol, sodium hyaluronate, a humectant, an emulsifier, a thickener and deionized water, heating and uniformly stirring to obtain a mixed solution A;
s2, cooling the mixed solution A, adding the modified drug-loaded microemulsion-nanogel composite preparation and the chelating agent, and uniformly stirring to obtain a mixed solution B;
and S3, adding a pH regulator into the mixed solution B, and uniformly stirring to obtain the skin care product with the effect of treating the eczema of children.
According to the different pharmacological effects and physicochemical properties of the active ingredients, the invention prepares the composite preparation in the form of nanogel and microemulsion respectively, and achieves the effect of treating both principal and secondary aspects of disease by utilizing the characteristics of different formulations.
The components of the modified drug-loaded microemulsion which play the role of efficacy are as follows: tert-butylcyclohexanol is a compound for skin conditioning, and is known as a 'sensitive regulator' by directly acting on a TRPV1 receptor to rapidly relieve skin problems such as sensitive redness; bisabolol has remarkable potential in improving problems such as skin redness, itching, dryness and the like, and can be applied to treatment of various skin problems; the active ingredients in forsythia volatile oil, such as acetone and methacrylate, can be directly combined with the TRPV1 receptor, and are realized by inhibiting the calcium channel activity of the TRPV1 receptor, and the sensitivity of the forsythia volatile oil to heat and chemical stimulus is reduced.
TRPV1 receptors are widely distributed in the nerve endings, hair follicles, sebaceous glands, blood vessels, epithelial cells and the like of the skin. The effective components need to penetrate the stratum corneum of the skin to exert the TRPV1 receptor inhibitory effect. In order to fundamentally cut off the pathogenesis source of eczema in children, isopropyl myristate, polyoxyethylene lauryl stearate and polyethylene glycol are selected to form a microemulsion system, and the functional components are wrapped in a microemulsion form to serve as channels of the functional components, so that the functional components can penetrate through skin stratum corneum, and a better TRPV1 receptor inhibition effect is exerted. In addition, the microemulsion is subjected to surface modification by the C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether, so that the permeability of the drug-loaded microemulsion is further improved, the deep penetration of the functional component into the skin is facilitated, and eczema is fundamentally treated.
The components of the nanogel which play the role of efficacy are as follows: the honeysuckle and the weeping forsythiae capsule have obvious anti-inflammatory effects, can relieve skin inflammation and red swelling caused by eczema, relieve illness and help to restore the health state of skin. Honeysuckle and weeping forsythiae capsule contain natural antibacterial substances, can inhibit bacterial growth, reduce infection risk and promote wound healing. In addition, the honeysuckle and the weeping forsythiae capsule have good moisturizing effect, can effectively moisten and soften skin, relieve itching and improve eczema symptoms, wherein the extracted active ingredients can relieve itching, help children reduce scratching behavior and improve sleep quality. Therefore, the active ingredients of honeysuckle and weeping forsythiae can be selected to quickly relieve the appearance symptoms of eczema of children.
According to the pharmacological effect and physicochemical property characteristics of the active ingredients, the efficacy of the composite preparation can be further ensured by further controlling the dosage of each ingredient;
firstly, tertiary butyl cyclohexanol, bisabolol and weeping forsythiae capsule volatile oil are wrapped in microemulsion, and the microemulsion is subjected to surface modification through C16-C18 hydroxyalkyl hydroxy dimer linol ether in the form of drug-loaded microemulsion, so that the microemulsion has good skin permeability, and the effect of inhibiting TRPV1 receptor is better exerted; the anti-inflammatory components of honeysuckle and weeping forsythiae capsule are formed and distributed in the network structure of the nanogel, which is favorable for exerting biological activity, directly resisting inflammation and relieving the appearance symptoms of eczema of children. The modified drug-loaded microemulsion and the nanogel are mixed to prepare the composite preparation, so that the synergistic effect of all the components is realized, the pathogenic source of the eczema of the children is cut off, the clinical symptoms of the eczema of the children are relieved rapidly, and the effect of treating both the symptoms and root causes of the eczema of the children is achieved.
The invention has the beneficial effects that:
(1) The active ingredients of tertiary butyl cyclohexanol, weeping forsythiae capsule volatile oil and bisabolol are wrapped in the microemulsion, so that the skin permeability of the active ingredients is enhanced, the effect of inhibiting TRPV1 receptors is better exerted, the inflammatory signal path of eczema of children is cut off, the etiology is fundamentally cut off, and the skin stinging and itching symptoms are rapidly relieved;
(2) After the drug-loaded microemulsion is modified by C16-C18 hydroxyalkyl hydroxy dimer linolenyl ether, the transdermal permeability of the microemulsion is further improved, and the deep penetration of the active ingredients into the skin is facilitated;
(3) The nano gel containing the honeysuckle and the weeping forsythiae capsule extract has positive charges on the surface, has strong affinity with skin, quickly ripens and wets the skin, and in addition, the honeysuckle extract and the weeping forsythiae capsule extract are distributed in the network structure inside the nano gel particles, so that the dispersion degree is high, the biological activity is favorably exerted, the inflammation is directly resisted, the dryness, the redness and the swelling of the skin and the inflammation of the skin are quickly improved, and the sterilization and the effect are improved.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present application, the drawings that are needed in the embodiments of the present application will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present application and should not be considered as limiting the scope, and other related drawings may be obtained according to these drawings without inventive effort for a person skilled in the art.
FIG. 1 is a schematic structural diagram of a modified drug-loaded microemulsion-nanogel composite formulation for treating eczema in children;
FIG. 2 is a graph showing the cumulative skin permeation curves of the various drug-loaded microemulsion-nanogel composite formulations prepared in example 3 and comparative example 1 and the external ointment prepared in comparative example 2;
FIG. 3 shows 24h skin hold-up of the various drug-loaded microemulsion-nanogel composite formulations prepared in example 3, comparative example 1, and the topical ointment prepared in comparative example 2;
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application more clear, the technical solutions in the embodiments of the present application will be clearly and completely described below. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
The preparation method of the honeysuckle extract and the weeping forsythiae capsule extract adopted in the invention comprises the following steps of;
(1) Preparation of honeysuckle extract
Reflux-decocting flos Lonicerae with 100ml water for 3 times, each time for 2 hr, filtering, mixing the 3 times of decoctions, concentrating the decoction at room temperature to obtain extract with relative density of 1.1-1.2, adding absolute ethanol to alcohol content of 75%, standing for 24 hr, filtering, concentrating the filtrate under reduced pressure to recover ethanol, and spray drying the concentrate to obtain flos Lonicerae extract.
(2) Preparation of fructus forsythiae extract
Pulverizing fructus forsythiae into coarse powder, adding 100ml of water, decocting under reflux for 1.5h for 3 times, filtering, mixing filtrates, concentrating the filtrate under reduced pressure at room temperature to obtain extract with relative density of 1.1-1.2, cooling, adding absolute ethanol to ethanol content of 60%, standing for 24h, filtering, concentrating the filtrate under reduced pressure to recover ethanol, and spray drying the concentrate to obtain fructus forsythiae extract.
Example 1
The embodiment provides a modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children, and the preparation method comprises the following steps:
s1, weighing and mixing 0.4g of honeysuckle extract, 0.6g of fructus forsythiae extract, 0.2g of sodium tripolyphosphate and 2g of sodium carboxymethylcellulose, and adding 50ml of deionized water for dissolution to obtain a mixture aqueous solution;
s2, weighing 1g of chitosan, dissolving in 50ml of deionized water, and adjusting the pH value to 5.0 through acetic acid to obtain a chitosan solution;
s3, slowly dripping the mixture water solution into the chitosan solution under the stirring condition of 2000rpm to form nano gel;
s4, weighing and uniformly mixing 0.2g of fructus forsythiae volatile oil, 1g of bisabolol, 1.2g of tert-butylcyclohexanol, 5g of olive oil, 9g of isopropyl myristate, 0.2g of C16-C18 hydroxyalkyl hydroxy dimer linol ether, 40g of polyoxyethylene lauryl stearate and 40g of polyethylene glycol 400 to obtain modified drug-loaded microemulsion;
s5, adding the modified drug-loaded emulsion into the nanogel system according to the mass ratio of 1:1, and uniformly stirring in the same direction to obtain the modified drug-loaded microemulsion-nanogel composite preparation.
Adding the modified drug-loaded microemulsion-nanogel composite preparation prepared in the example 1 into a nanogel system, and stirring at a constant speed in the same direction.
Example 2
The embodiment provides a modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children, and the preparation method comprises the following steps:
s1, weighing and mixing 0.3g of honeysuckle extract, 0.5g of fructus forsythiae extract, 0.15g of sodium tripolyphosphate and 1.5g of sodium carboxymethylcellulose, and adding 50ml of deionized water for dissolution to obtain a mixture aqueous solution;
s2, weighing 0.75g of chitosan, dissolving the chitosan in 50ml of deionized water, and adjusting the pH value to 5.0 through acetic acid to obtain a chitosan solution;
s3, slowly dripping the mixture water solution into the chitosan solution under the stirring condition of 2000rpm to form nano gel;
s4, weighing and uniformly mixing 0.15g of fructus forsythiae volatile oil, 0.75g of bisabolol, 0.9g of tert-butylcyclohexanol, 4g of olive oil, 6.5g of isopropyl myristate, 0.15g of C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether, 30g of polyoxyethylene dodecyl stearate and 30g of polyethylene glycol 400 to obtain modified drug-loaded microemulsion;
s5, adding the modified drug-loaded microemulsion into the nanogel system according to the mass ratio of 0.75:1, and stirring at uniform speed in the same direction to obtain the modified drug-loaded microemulsion-nanogel composite preparation prepared in the example 2.
Example 3
The embodiment provides a modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children, and the preparation method comprises the following steps:
s1, weighing and mixing 0.2g of honeysuckle extract, 0.3g of fructus forsythiae extract, 0.1g of sodium tripolyphosphate and 1.0g of sodium carboxymethylcellulose, and adding 50ml of deionized water for dissolution to obtain a mixture aqueous solution;
s2, weighing 0.5g of chitosan, dissolving the chitosan in 50ml of deionized water, and adjusting the pH value to 5.0 through acetic acid to obtain a chitosan solution;
s3, slowly dripping the mixture water solution into the chitosan solution under the stirring condition of 2000rpm to form nano gel;
s4, weighing and uniformly mixing 0.1g of fructus forsythiae volatile oil, 0.5g of bisabolol, 0.6g of tert-butylcyclohexanol, 2.5g of olive oil, 4.5g of isopropyl myristate, 0.1g of C16-C18 hydroxyalkyl hydroxy dimer linol ether, 20g of polyoxyethylene lauryl stearate and 20g of polyethylene glycol 400 to obtain modified drug-loaded microemulsion;
s5, adding the modified drug-loaded microemulsion into the nanogel system according to the mass ratio of 0.5:1, and stirring at uniform speed in the same direction to obtain the modified drug-loaded microemulsion-nanogel composite preparation prepared in the example 3.
Determination of particle size and distribution and Zeta potential
The particle size distribution of the nanogel obtained in example 1 was examined by a laser dynamic light scattering method (malvern laser particle sizer 3000), and the result showed that the particle size of the nanogel was within a range of 85±9.2nm, and the Zeta potential of the nanogel was examined by a Zeta potential analyzer, and the result showed that the Zeta potential of the nanogel was within a range of 32.2±7.3 mv. The particle size of the modified drug-loaded microemulsion/nanogel mixed system is 132+/-10.5 nm and the zeta potential is 21.3+/-11.2 mv measured by a laser scattering method.
Referring to fig. 1, fig. 1 is a schematic structural diagram of a drug-loaded microemulsion-nanogel composite preparation for treating eczema in children prepared in this example 3, wherein the composite preparation is obtained by compounding the above active ingredients in different forms according to the pharmacological effects and physicochemical properties of the active ingredients, so as to achieve synergistic effects of the active ingredients, cut off the pathogenic source of eczema in children and rapidly relieve clinical symptoms of eczema in children, and achieve the effect of treating both symptoms and root causes of eczema in children. As can be seen from fig. 1, the invention wraps tert-butylcyclohexanol, bisabolol and weeping forsythiae capsule volatile oil in microemulsion, and the microemulsion is subjected to surface modification by using C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether in the form of drug-loaded microemulsion, so that the microemulsion has good skin permeability, and the effect of inhibiting TRPV1 receptor is better exerted; the anti-inflammatory components of honeysuckle and weeping forsythiae capsule are formed and distributed in the network structure of the nanogel, which is favorable for exerting biological activity, directly resisting inflammation and relieving the appearance symptoms of eczema of children. The composite preparation obtained by mixing the drug-loaded microemulsion and the nanogel realizes the synergistic effect of all the components, cuts off the incidence source of the eczema of the children and rapidly relieves the clinical symptoms of the eczema of the children, thereby achieving the effect of treating both the symptoms and root causes of the eczema of the children.
Comparative example 1
The comparative example provides a drug-loaded microemulsion-nanogel composite preparation, which is prepared by a method which is mainly different from that of the embodiment 3: the drug-loaded microemulsion is not modified by C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether, and the specific preparation method comprises the following steps:
s1, weighing and mixing 0.2g of honeysuckle extract, 0.3g of fructus forsythiae extract, 0.1g of sodium tripolyphosphate and 1.0g of sodium carboxymethylcellulose, and adding 50ml of deionized water for dissolution to obtain a mixture aqueous solution;
s2, weighing 0.5g of chitosan, dissolving the chitosan in 50ml of deionized water, and adjusting the pH value to 5.0 through acetic acid to obtain a chitosan solution;
s3, slowly dripping the mixture water solution into the chitosan solution under the stirring condition of 2000rpm to form nano gel;
s4, weighing 0.1g of fructus forsythiae volatile oil, 0.5g of bisabolol, 0.6g of tert-butyl cyclohexanol, 2.5g of olive oil, 4.5g of isopropyl myristate, 20g of polyoxyethylene lauryl stearate and 20g of polyethylene glycol 400, and uniformly mixing to obtain a drug-carrying microemulsion;
s5, adding the drug-loaded microemulsion into the nanogel system according to the mass ratio of 0.5:1, and uniformly stirring in the same direction to obtain the modified drug-loaded microemulsion-nanogel composite preparation prepared in comparative example 1.
Comparative example 2
The comparative example provides a topical ointment, which is prepared by a method which is different from that of example 3 in that: the functional components are directly mixed and then prepared into ointment, and the ointment is compounded in different preparation forms according to the pharmacological effect and physicochemical property characteristics of each functional component.
Weighing 0.2g of honeysuckle extract, dissolving 0.3g of weeping forsythiae extract in 50ml of water, and preserving heat at 70 ℃ to serve as a water phase for standby; weighing 0.1g of weeping forsythiae volatile oil, 0.1g of bisabolol, 0.5g of tert-butylcyclohexanol, 0.5g of glyceryl monostearate, 1.5g of stearyl alcohol, 2.5g of white vaseline, 1.2g of glycerol and 0.5g of polyoxyethylene lauryl stearate, stirring and mixing uniformly at 70 ℃, slowly adding into the water phase, and stirring while adding to obtain the external ointment.
Application example
A skin care product with a function of treating eczema in children, which is prepared from the modified drug-loaded microemulsion-nanogel composite preparation described in the application example 3, comprises the following components in parts by mass:
20 parts of modified drug-loaded microemulsion-nanogel composite preparation, 3 parts of allantoin, 2 parts of panthenol, 0.1 part of sodium hyaluronate, 5 parts of humectant, 2 parts of emulsifier, 1 part of thickener, 0.5 part of chelating agent, 0.3 part of pH regulator and 55 parts of deionized water.
The humectant is prinsepia utilis royle oil, glycerol, propylene glycol and 1, 2-pentanediol with the mass ratio of 1.5:1:1:1; the emulsifier is cetylstearyl glucoside; the thickening agent is behenyl alcohol; the chelating agent is disodium EDTA; the pH regulator is triethanolamine.
A preparation method of a skin care product with the effect of treating eczema of children comprises the following steps:
s1, mixing allantoin, panthenol, sodium hyaluronate, prinsepia utilis royle oil, glycerol, propylene glycol, 1, 2-pentanediol, cetostearyl glucoside, behenyl alcohol and deionized water, heating and uniformly stirring to obtain a mixed solution A; the heating temperature is 75 ℃, and the stirring speed is 110rpm;
s2, cooling the mixed solution A, adding the modified drug-loaded microemulsion-nanogel composite preparation prepared in the embodiment 3 and EDTA disodium, and uniformly stirring to obtain a mixed solution B; the stirring rate was 60rpm;
s3, adding triethanolamine into the mixed solution B, and uniformly stirring to obtain a skin care product with the effect of treating the eczema of children; the temperature of the cooling is 40 ℃, and the stirring speed is 40rpm.
Skin penetration test
The skin permeability was measured by using the drug-loaded microemulsion-nanogel composite formulations prepared in example 3 and comparative example 1, respectively, and the external ointment prepared in comparative example 2.
The skin permeability of the external ointment prepared in comparative example 2 was examined for the various drug-loaded microemulsion/nanogel composite formulations prepared in example 3 and comparative example 1, respectively, using bisabolol as an index ingredient in this test.
(1) High performance liquid chromatography for measuring bisabolol content
High performance liquid chromatography is adopted to measure the content of the bisabolol, and the liquid chromatography conditions are as follows: the chromatographic column was a C18 column (4.6 mm. Times.250 mm. Times.5 μm); the sample injection amount is 10 mu L; the detection wavelength is 220nm; the mobile phase is methanol-water (85:15); flow rate: 1.0mL/min.
(2) In vitro transdermal test
After shaving the skin of the abdomen of the rat, the rat is sheared, and the rat is fixed between the supply tank and the receiving tank with proper size, the stratum corneum faces the supply tank, and the stratum basale faces the receiving surface. And (3) injecting physiological saline receiving solution containing 5% ethanol into the receiving tank, wherein the water bath temperature is 32 ℃, and stirring at a constant speed of 300 r/min. Wherein 2ml of the modified drug-loaded microemulsion/nanogel composite preparation prepared in example 3 was administered to a supply tank, sealed with a sealing film, and perforated with a plurality of small holes. After the start of the experiment, 0.5ml was sampled at 0.5h,1h,2h,4h,6h,8h,12h,24h, respectively, and immediately after each sampling fresh receiving liquid of the same volume was fed in and air bubbles in the receiving tank were removed. Filtering the obtained receiving solution with 0.45 μm microporous membrane, measuring bisabolol content with high performance liquid chromatography, and calculating cumulative permeation (Qn):
wherein Qn is accumulated permeation quantity per unit area at time t, cn is drug mass concentration at time t, ci is drug mass concentration of the receiving liquid at the time of the ith sampling, vi is sampling volume, V is receiving chamber volume, A is effective diffusion area (3.14 cm 2 )。
And drawing a cumulative permeation curve by taking the medicine Qn as an ordinate and t as an ordinate. After termination of the experiment, the mouse skin was removed, the skin surface was rinsed with water and the skin was ground with a small amount of mobile phase methanol-water (85:15). Transferring the ground slurry into a centrifuge tube, centrifuging at high speed, pouring the supernatant into a volumetric flask, re-extracting the precipitate with a proper amount of mobile phase, mixing the supernatants, determining the bisabolol content with the mobile phase, and calculating the skin retention for 24 hours.
The skin permeation curves and 24-hour skin hold-up of comparative example 1 and comparative example 2 were measured in the same manner and compared with the measurement results of example 3.
Referring to fig. 2 and 3, fig. 2 is a graph showing skin cumulative permeation curves of the various drug-loaded microemulsion-nanogel composite formulations prepared in example 3 and comparative example 1 and the external ointment prepared in comparative example 2;
FIG. 3 shows the 24-hour skin hold-up of the external ointment prepared in comparative example 2, for different drug-loaded microemulsion-nanogel composite formulations prepared in example 3, comparative example 1; as can be seen from the test results, the cumulative permeation of the preparation example 3 is far greater than that of the preparation example 1, and the cumulative permeation of the preparation example 2 is the smallest, which shows that the modified drug-loaded microemulsion/nanogel composite preparation prepared in the preparation example 3 has stronger skin permeability due to the modification of the surface of the microemulsion by C16-C18 hydroxyalkyl hydroxy dimer linolenyl ether, and can promote the skin permeability of the forsythia volatile oil, the bisabolol and the tert-butylcyclohexanol which are wrapped in the microemulsion. While example 3 has a higher skin permeability to maximize skin hold-up (fig. 3), it is helpful for treatment of eczema in children.
Evaluation of drug efficacy
(1) In vitro test of mouse eczema model
A plurality of white laboratory mice (balb/c mice) with a weight of 18-20g and male and female halves were selected and randomly grouped according to sex weight, which were respectively a normal control group, a model control group, a dexamethasone acetate soft-extract control group, a comparative example 1 group, a comparative example 2 group and an example 3 group, each group being 6.
1 day before the experiment, the back of the mouse was dehaired to an area of about 3cm 2 . In the experiments the other groups (except the normal group) were sensitized once with 7% dinitrochlorobenzene solution (pyruva-raw oil=4:1) in the dehairing zone. At the same time, each group was applied to the dehairing area of the mice according to the dose, and the administration was carried out 1 time a day for 11 days continuously. And the normal control group and the model control group are coated with the same amount of microemulsion/nanogel matrix without the drug on the dehairing area. Groups (except normal groups) were challenged 1 time every 2 days after day 6 by applying acetone solution to the inner side of the right ear of the mice. Killing the mice after the 3 rd excitation, then using a puncher to punch out equal-area lugs at the same parts of the two ears of the mice, weighing on an analytical balance, taking the weight difference of the two ears as the response value of the contact eczema of the mice, and calculating the inhibition rate, wherein the calculation formula is that：
Eczema response value = right ear weight-left ear weight
Inhibition ratio= (model control group ear average eczema response value-administration group ear average eczema response value)/model control group ear average eczema response value;
the test results are shown in table 1:
table 1 eczema test results
| Group of | Coating quantity (g/kg) | Eczema response value (mg) | Inhibition ratio (%) |
| Normal control group | 10 | 0.43±0.22 | / |
| Model control group | 10 | 23.17±1.58 | / |
| Dexamethasone acetate group | 10 | 13.23±1.91 | 42.9 |
| Comparative example 1 | 10 | 14.62±1.07 | 36.9 |
| Comparative example 2 | 10 | 18.33±1.89 | 20.8 |
| Example 3 | 10 | 11.04±1.29 | 52.3 |
As a result, it was found that the eczema inhibitory rate of example 3 of the present invention was 52.3%, which was higher than that of comparative examples 1 and 2, and slightly higher than that of the dexamethasone acetate group.
(2) Skin irritation test
Selecting adult healthy New Zealand rabbits, and dehairing 2 pieces of the adult healthy New Zealand rabbits with sodium sulfide symmetrically on two sides of the back before the test, wherein each piece has an area of 9cm 2 . Of which 4 were the complete skin test groups; after the other 4 dehairing areas were sterilized with alcohol, they were rubbed with sandpaper to cause local abrasion, and the test group was used for broken skin. The modified drug-carrying microemulsion/nanogel prepared in example 3 was applied to the left side of the back after depilation, the microemulsion/nanogel without drug was applied to the right side, and as a blank, the drug-carrying microemulsion/nanogel was administered 3 times per day for 7 consecutive days at a daily dose (10 g modified drug-carrying microemulsion/nanogel/kg body weight), the test substance was washed with warm water after the last application for 24 hours, and the presence or absence of local erythema and edema reactions within 1-72 hours after the removal of the test substance was observed, and the stimulation response was scored according to a prescribed method, and the stimulation intensity was evaluated with an average score. The stimulation response scoring criteria were as follows: 0 point without erythema; mild erythema was barely visible for 1 minute; poisoning erythema, visible 2 minutes; severe erythema 3 minutes; red purple spots with scab formation of 4 minutes; no edema 0 score; mild edema was barely visible for 1 minute; toxic edema, visible as 2 minutes; severe edema, skin lifting, clear contourDividing the definition into 3 points; severe edema, skin doming, and enlargement or blister collapse for 4 minutes. The skin irritation light evaluation criteria were as follows: no stimulation for 0-0.5 min; mild stimulation 0.5-3; moderately stimulating for 3-6 min; strong stimulation for 6-8 minutes; the test results are shown in Table 2.
Table 2 skin irritation test
The results show that the average value of the stimulus response of each group is very low and no stimulus response exists after 7 days of continuous administration; in the experimental process, abnormal conditions such as activities, diet, feces and the like of experimental animals are not found, and abnormal secretions are not found in eyes, noses and the like; no pigmentation was found at the application site, indicating that the composite preparation prepared according to the present invention was not irritating to the skin.
(3) Anti-inflammatory test for relief
Hyaluronidase is a hydrolase for degrading hyaluronic acid, is a main component of extracellular matrix of connective tissue of an organism, and is related to most of type I allergic reactions and type IV allergic reactions mediated by IgE and T cells, so that in vitro inhibition experiments of the hyaluronidase can reflect the properties of corresponding products, such as relieving, antiallergic, anti-inflammatory and the like, of skin to a certain extent.
The soothing efficacy is mainly characterized by evaluating the inhibition rate of the test sample on the hyaluronidase. The experimental principle of inhibiting the hyaluronidase is that the hyaluronidase and an enzyme substrate are subjected to catalytic reaction, the absorbance is changed after an active substance is added, and the inhibition rate of the hyaluronidase inhibitor is reversed according to the change of the absorbance.
The hyaluronidase activity of the experiment is used as a detection tool, negative control, positive control and sample groups are respectively designed, 3 biological repetitions are designed for each group, a compound preparation is adopted to react with hyaluronidase and a substrate, absorbance is measured at 530nm, the hyaluronidase activity is detected, and the higher the inhibition rate is, the better the effect is indicated. The various drug-loaded microemulsion-nanogel composite formulations prepared in example 3 and comparative example 1 and the external ointment prepared in comparative example 2 were used as test samples, and the experimental results are shown in table 3:
TABLE 3 inhibition of hyaluronidase Activity
| Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | |
| Average inhibition rate | 84.5 | 79.2 | 86.7 | 34.9 | 28.6 |
As can be seen from the experimental results in Table 3, compared with comparative examples 1-2, examples 1-3 have a certain inhibition rate on hyaluronidase, which indicates that the compound preparation provided by the invention has a certain relieving and anti-inflammatory effect. And when the drug-loaded microemulsion is not modified by C16-C18 hydroxyalkyl hydroxy dimer linol ether, for example, comparative example 1, the inhibition rate of hyaluronidase is obviously lower than that of examples 1-3, which indicates that the modified drug-loaded microemulsion-nanogel can exert better synergistic effect.
(3) Antibacterial property test
According to the detection method of annex C of the sanitary standard of disposable sanitary products (GB 15979-2002), antibacterial tests are carried out, test strains comprise staphylococcus aureus and escherichia coli, the action time is 2min, the tests are repeated for three times, and the average antibacterial rate is calculated. If the average bacteriostasis rate is more than or equal to 50%, the composite preparation has bacteriostasis, and the result is shown in Table 4:
table 4 antibacterial test results
| Example 1 | Example 2 | Example 3 | Comparative example 1 | Comparative example 2 | |
| Average inhibition of Staphylococcus aureus% | 72.4 | 68.3 | 64.8 | 34.9 | 0 |
| Average inhibition rate of colibacillus% | 67.1 | 71.7 | 69.5 | 40.7 | 0 |
| Whether or not there is an antibacterial effect | Has the following components | Has the following components | Has the following components | Has the following components | Without any means for |
From the experimental results in Table 3, the modified drug-loaded nano gel composite preparation provided by the invention has an antibacterial effect, and has a good inhibition effect on staphylococcus aureus and escherichia coli.
(4) Antipruritic test
Dextran is a high molecular glucose polymer that can cause mast cells to release histamine to induce inflammatory projection, causing skin itching in mice. While histamine can promote the synthesis and secretion of proinflammatory cytokines and chemokines such as IL-1A, IL1B, IL-6, IL-8 or RANTES by various cells and tissues, and promote itch caused by anaphylactic-inflammatory reaction. Histamine also stimulates nerve endings in the skin, directly causing itching and releases Substance P (SP), promoting degranulation of mast cells to release histamine further causing itching. At the same time, scratching by itching can lead to the release of inflammatory mediators, increasing the severity of itching.
The test provides a certain pharmacological basis by establishing a dextran-induced mouse itching model and observing the itching relieving effect of a sample to be tested. The number of test model mice was 50, and the mice were randomly divided into five groups of 10 mice each, each half of which was male and female, including a deionized water treated model group, a compound dexamethasone acetate cream treated group, and eczema cream treated groups of examples 1-3. Mice were dehaired on the back, given 0.2 g/each for 5 consecutive days, given 0.02% dextran by tail vein after 1h last, and observed for the number of scratches occurring within 30min for each group.
Itching relieving rate (%) = (number of scratching in model group-number of scratching in sample group)/number of scratching in model group ×100%.
The experimental results are shown in table 5:
table 5 antipruritic test results
| Group of | Average number of scratching for 30min | Antipruritic rate (%) |
| Model control group | 47 | / |
| Dexamethasone acetate group | 24 | 60.4 |
| Comparative example 1 | 28 | 31.5 |
| Comparative example 2 | 31 | 29.7 |
| Example 1 | 16 | 59.4 |
| Example 2 | 17 | 56.1 |
| Example 3 | 13 | 57.8 |
As can be seen from the results in Table 5, the dextran had a very good itching effect on mice, the number of scratching times occurring within 30min was very remarkable in the group, and the number of scratching times of mice was remarkably reduced by re-injecting the dextran after the administration of the dexamethasone acetate cream group and the examples 1 to 3, indicating that the dexamethasone acetate cream group and the examples 1 to 3 had a remarkable inhibitory effect on itching of mice caused by the dextran. And the compound preparation prepared in the examples 1-3 has little difference with the antipruritic effect of dexamethasone acetate cream.
The above is only an example of the present application, and is not intended to limit the scope of the present application, and various modifications and variations will be apparent to those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principles of the present application should be included in the scope of the present application.
Claims (10)
1. The modified drug-carrying microemulsion-nanogel composite preparation for treating the eczema of children is characterized by being formed by compositing nanogel and modified drug-carrying microemulsion, wherein the modified drug-carrying microemulsion is obtained by carrying out surface modification on the drug-carrying microemulsion by C16-C18 hydroxyalkyl hydroxy dimer linolenyl ether;
wherein the nanogel comprises the following components: 0.2 to 0.4 weight percent of honeysuckle extract, 0.3 to 0.6 weight percent of weeping forsythia extract, 0.1 to 0.2 weight percent of sodium tripolyphosphate, 1.0 to 2.0 weight percent of sodium carboxymethyl cellulose, 0.5 to 1 weight percent of chitosan and the balance of deionized water;
the modified drug-loaded microemulsion comprises the following components: 0.1 to 0.2 weight percent of weeping forsythia volatile oil, 0.5 to 1 weight percent of bisabolol, 0.6 to 1.2 weight percent of tert-butylcyclohexanol, 2.5 to 5 weight percent of olive oil, 4.5 to 9 weight percent of isopropyl myristate, 01 to 0.2 weight percent of C16-C18 hydroxyalkyl hydroxy dimer linoleyl ether, 20 to 40 weight percent of polyoxyethylene lauryl hydroxystearate and 20 to 40 weight percent of polyethylene glycol.
2. The method for preparing the modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children as claimed in claim 1, which is characterized by comprising the following steps:
s1, weighing honeysuckle extract, weeping forsythiae extract, sodium tripolyphosphate and sodium carboxymethyl cellulose according to mass percentage, mixing, and adding deionized water for dissolution to obtain a mixture aqueous solution;
s2, weighing chitosan, dissolving the chitosan in a certain amount of deionized water, and regulating the pH value to 5.0 through a pH regulator to obtain a chitosan solution;
s3, slowly dripping the mixture water solution into the chitosan solution under the stirring condition to form nano gel;
s4, weighing fructus forsythiae volatile oil, bisabolol, tert-butyl cyclohexanol, olive oil, isopropyl myristate, C16-C18 hydroxyalkyl hydroxy dimer linol ether, polyoxyethylene lauryl stearate and polyethylene glycol according to mass percentage, and uniformly mixing to obtain modified drug-loaded emulsion;
s5, adding the modified drug-loaded emulsion into the nanogel system according to the mass ratio of 0.5:1-1:1, and stirring at uniform speed in the same direction to obtain the modified drug-loaded microemulsion-nanogel composite preparation.
3. The method for preparing the modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children according to claim 2, wherein the pH regulator in the step S2 is acetic acid.
4. The method for preparing the modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children according to claim 2, wherein the stirring condition in the step S3 is uniform-speed and same-direction stirring at a rotating speed of 2000 rpm.
5. The method for preparing a modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children according to claim 2, wherein the molecular weight of the polyethylene glycol in the step S4 is 400.
6. The use of the modified drug-loaded microemulsion-nanogel composite preparation for treating eczema in children according to claim 1 in skin care products.
7. The skin care product with the effect of treating the eczema of children is characterized by comprising 10-30 parts of the modified drug-loaded microemulsion-nanogel composite preparation of claim 1, 0.1-5 parts of allantoin, 0.1-5 parts of panthenol, 0.01-0.2 part of sodium hyaluronate, 1-10 parts of humectant, 1-3 parts of emulsifier, 0.5-2 parts of thickener, 0.1-1 part of chelating agent, 0.1-0.5 part of pH regulator and 40-70 parts of deionized water.
8. The skin care product with the effect of treating eczema of children according to claim 7, wherein the humectant comprises prinsepia utilis royle oil, glycerol, propylene glycol and 1, 2-pentanediol in a mass ratio of 1-2:1-2:0.5-1.5:1; the emulsifier is cetyl stearyl alcohol and/or cetostearyl glucoside; the thickener is carbomer and/or behenyl alcohol; the chelating agent is disodium EDTA; the pH regulator is triethanolamine.
9. The skin care product with the effect of treating eczema of children according to claim 7, further comprising 0.01-0.03 parts of preservative; wherein the preservative is p-hydroxyacetophenone and/or propyl hydroxybenzoate.
10. The method for preparing the skin care product with the effect of treating the eczema of children according to claim 7, wherein the method is characterized by comprising the following steps of: the method comprises the following steps:
s1, mixing allantoin, panthenol, sodium hyaluronate, a humectant, an emulsifier, a thickener and deionized water, heating and uniformly stirring to obtain a mixed solution A;
s2, cooling the mixed solution A, adding the modified drug-loaded microemulsion-nanogel composite preparation and the chelating agent, and uniformly stirring to obtain a mixed solution B;
and S3, adding a pH regulator into the mixed solution B, and uniformly stirring to obtain the skin care product with the effect of treating the eczema of children.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311020529.5A CN117298034A (en) | 2023-08-14 | 2023-08-14 | Drug-loaded microemulsion-nanogel composite preparation for treating children eczema and preparation method and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311020529.5A CN117298034A (en) | 2023-08-14 | 2023-08-14 | Drug-loaded microemulsion-nanogel composite preparation for treating children eczema and preparation method and application thereof |
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| Publication Number | Publication Date |
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| CN117298034A true CN117298034A (en) | 2023-12-29 |
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| CN202311020529.5A Pending CN117298034A (en) | 2023-08-14 | 2023-08-14 | Drug-loaded microemulsion-nanogel composite preparation for treating children eczema and preparation method and application thereof |
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| Country | Link |
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| CN (1) | CN117298034A (en) |
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- 2023-08-14 CN CN202311020529.5A patent/CN117298034A/en active Pending
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