CN110292591B - Compound lithospermum gel and preparation method and application thereof - Google Patents

Compound lithospermum gel and preparation method and application thereof Download PDF

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CN110292591B
CN110292591B CN201910534746.3A CN201910534746A CN110292591B CN 110292591 B CN110292591 B CN 110292591B CN 201910534746 A CN201910534746 A CN 201910534746A CN 110292591 B CN110292591 B CN 110292591B
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oil
lithospermum
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oil phase
gel
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CN110292591A (en
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王颖莉
贾颖
赵婧
王艳
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Shanxi Ruibolong Biotechnology Co ltd
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Shanxi University of Chinese Mediciine
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/07—Basidiomycota, e.g. Cryptococcus
    • A61K36/076—Poria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/19—Acanthaceae (Acanthus family)
    • A61K36/195—Strobilanthes
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/30—Boraginaceae (Borage family), e.g. comfrey, lungwort or forget-me-not
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A61K36/315—Isatis, e.g. Dyer's woad
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/34—Campanulaceae (Bellflower family)
    • A61K36/344—Codonopsis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/484—Glycyrrhiza (licorice)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/85—Verbenaceae (Verbena family)
    • A61K36/855—Clerodendrum, e.g. glorybower
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/35—Extraction with lipophilic solvents, e.g. Hexane or petrol ether

Abstract

The invention discloses a compound lithospermum gel and a preparation method and application thereof. The paint is prepared from the following components: compound arnebia oil mixed oil phase, surfactant, cosurfactant, water phase and other auxiliary agents; the compound lithospermum oil mixed oil phase is prepared by mixing the compound lithospermum oil and the oil phase; the preparation method of the compound lithospermum oil comprises the following steps: soaking pulverized radix Arnebiae, radix Codonopsis, Poria, folium Isatidis, radix Angelicae sinensis and Glycyrrhrizae radix in the oil phase, and percolating; the oil phase is at least one of olive oil, jojoba oil and sesame oil. The traditional Chinese medicine adopted by the invention has obvious anti-inflammatory effect, and the prepared gel preparation has transparent appearance and good stability; compared with the traditional gel preparation method, the invention directly adopts the oil phase percolate as the target drug to obtain the drug-loaded oil phase, simplifies the screening and preparation processes of the gel and improves the stability.

Description

Compound lithospermum gel and preparation method and application thereof
Technical Field
The invention relates to a compound lithospermum gel and a preparation method and application thereof, belonging to the field of traditional Chinese medicine preparations.
Background
Radix Arnebiae is dry root of Arnebia euchroma (Royle) Johnst or Arnebia guttata Bunge of Arnebia euchroma of Boraginaceae, and has pharmacological effects of resisting inflammation, virus and bacteria. The naphthoquinone component is the main effective component of radix Arnebiae, and is unstable and greatly affected by temperature, wherein alkannin has thermal instability, changes from red to purple black at above 60 deg.C, and changes rapidly with temperature rise, and the alkannin is destroyed, so the percolation extraction method has important significance for improving the stability of alkannin.
The microemulsion gel can enable the drug to quickly form higher concentration gradient at two sides of the skin, improve the transdermal rate of the drug, shorten the time lag, prolong the drug release time after transdermal administration and enable the blood concentration to be more stable. The gel preparation has uniform drug-loading distribution, certain viscosity, convenient use and carrying, long retention time, convenient absorption and high bioavailability.
Disclosure of Invention
The invention aims to provide a compound lithospermum gel and a preparation method and application thereof.
The compound lithospermum gel preparation takes lithospermum, codonopsis pilosula, poria, folium isatidis, angelica sinensis and liquorice extract as active ingredients, has obvious anti-inflammatory effect, and is transparent in appearance and good in stability. Compared with the traditional gel preparation method, the invention adopts the oil phase to directly percolate the traditional Chinese medicine, the obtained percolate is the target medicine and is used as the medicine-carrying oil phase of the gel preparation, the screening and preparation processes of the gel are simplified, and the stability is improved.
The invention provides a compound lithospermum gel which is prepared from the following components: compound arnebia oil mixed oil phase, surfactant, cosurfactant, water phase and other auxiliary agents;
the compound lithospermum oil mixed oil phase is prepared by mixing the compound lithospermum oil and the oil phase;
the preparation method of the compound lithospermum oil comprises the following steps: wetting the pulverized radix Arnebiae, radix Codonopsis, Poria, folium Isatidis, radix Angelicae sinensis and Glycyrrhrizae radix with the oil phase, placing into a percolating cylinder, soaking, and percolating;
the oil phase is at least one of olive oil, jojoba oil and sesame oil.
In the compound lithospermum gel, the compound lithospermum gel is prepared from the following components in parts by mass:
7-30 parts of compound lithospermum oil mixed oil phase; 30-60 parts of surfactant and 1-7 parts of cosurfactant; 30 parts of a water phase; 1-2 parts of other auxiliary agents.
In the compound lithospermum gel, the mass ratio of the total mass of the compound lithospermum oil to the oil phase can be 1: 1-12;
the mass ratio of the lithospermum to the codonopsis pilosula to the poria cocos to the folium isatidis to the angelica sinensis to the liquorice is 5-1: 0-2: 1:1: 4-1: 1, specifically 3:1:1:1:3: 1;
the particle size of the crushed lithospermum, codonopsis pilosula, poria cocos, folium isatidis, angelica sinensis and liquorice can be 40-80 meshes.
When the radix codonopsis is 0, the mass ratio of the lithospermum to the poria cocos to the folium isatidis to the angelica sinensis to the liquorice can be 5-1: 1:1: 4-1: 1.
in the compound lithospermum gel, in order to avoid blockage caused by expansion after lithospermum, codonopsis pilosula, poria cocos, folium isatidis, angelica sinensis and liquorice are directly filled into a percolation cylinder to be contacted with oil phase, before the lithospermum, codonopsis pilosula, poria cocos, folium isatidis, angelica sinensis and liquorice are filled into the percolation cylinder, the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice are fully wetted by the oil phase, and the wetting time can be 6-24 hours, specifically 12 hours, 6-12 hours, 12-24 hours or 10-20 hours; when the oil phase is used for moistening, the mass of the oil phase is 2-5 times of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice, and specifically can be 2 times or 2-4 times;
the dipping time can be 12 h-48 h, and specifically can be 48h or 24 h-48 h; when the oil phase is adopted for impregnation, the mass of the oil phase is 2-4 times, specifically 3 times, of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice;
during the percolation, the mass ratio of the oil phase to the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice can be 3-8: 1, and specifically can be 5: 1.
In the compound lithospermum gel, the surfactant comprises polyoxyethylene 40 hydrogenated castor oil and/or span 80; specifically polyoxyethylene 40 hydrogenated castor oil and span80 (also called span80), wherein the mass ratio of the polyoxyethylene 40 hydrogenated castor oil to the span80 can be 1.5-2.5: 1;
the cosurfactant comprises glycerin and/or PEG 400;
the water phase is phosphate buffer solution, distilled water or water, and the water can be specifically deionized water;
the other auxiliary agent is at least one of rose essential oil, phenoxyethanol and ethylparaben;
the compound lithospermum gel has uniform particle size distribution, the particle size is 10nm-100nm, the pH value is 6-6.8, and the stability is high.
The invention also provides a preparation method of the compound lithospermum gel, which comprises the following steps: 1) wetting the pulverized radix Arnebiae, radix Codonopsis, Poria, folium Isatidis, radix Angelicae sinensis, and Glycyrrhrizae radix with the oil phase, placing into a percolating cylinder, soaking, and percolating to obtain the compound radix Arnebiae oil;
2) mixing the compound lithospermum oil and the oil phase to obtain a mixed oil phase of the compound lithospermum oil;
3) mixing the surfactant and the co-surfactant;
4) and (3) uniformly mixing the substances obtained by the steps 2) and 3), and then dropwise adding the water phase and the other auxiliary agents to obtain the compound lithospermum gel.
In the preparation method, in order to avoid blockage caused by expansion after the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice are directly filled into a percolation cylinder to be contacted with oil phase, the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice are fully wetted by the oil phase before being filled into the percolation cylinder, and the wetting time can be 6-24 hours; when the oil phase is used for moistening, the mass of the oil phase is 2-5 times of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice;
the dipping time can be 12-48 h; when the oil phase is adopted for impregnation, the mass of the oil phase is 2-4 times of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the dyers woad leaf, the angelica sinensis and the liquorice,
during percolation, the mass ratio of the oil phase to the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice can be 3-8: 1.
In the invention, the oil phase is used for percolation to obtain the compound lithospermum oil phase containing the effective components, thereby realizing the enrichment of the effective components, improving the stability of the effective components and simplifying the processes of prescription screening and preparation.
The compound lithospermum gel is applied to preparing anti-inflammatory drugs and delayed hypersensitivity resistant drugs.
The compound lithospermum gel is a traditional Chinese medicine external preparation and has the effects of resisting acute inflammation and delayed hypersensitivity.
The invention has the following advantages:
1. the 6 traditional Chinese medicines in the compound lithospermum gel are all high-safety traditional Chinese medicines;
2. the compound lithospermum gel adopts a direct oil phase percolation method to obtain a drug-loaded oil phase containing effective components, so that the stability of the effective components is improved, and the prescription screening and preparation processes are simplified;
3. the compound lithospermum gel has uniform particle size distribution, the particle size is 10nm-100nm, the pH value is 6-6.8, and the stability is high;
4. the compound lithospermum gel has obvious acute inflammation resistance: the compound lithospermum gel can reduce the ear swelling of mice caused by dimethylbenzene; the compound lithospermum gel can reduce the increase of the permeability of the skin capillary vessels of the abdomen of the mouse caused by the dimethylbenzene; the compound lithospermum gel can reduce the increase of the permeability of capillary vessels in the abdominal cavity of a mouse caused by acetic acid;
5. the compound lithospermum gel has the following effects on delayed hypersensitivity (DTH): the compound lithospermum gel has a regulating effect on T lymphocyte subsets; the compound lithospermum gel can reduce the ear swelling of a DTH mouse caused by 1-chloro-2, 4-Dinitrobenzene (DNCB); the compound lithospermum gel can reduce spleen and thymus enlargement of a DTH mouse caused by DNCB.
Drawings
FIG. 1 shows a phenomenon in the process of dropping distilled water.
Fig. 2 is a pseudo-ternary phase diagram of RH40: Span 80: 6:4 in combination with PEG 400.
Figure 3 is a pseudo-ternary phase diagram for RH40: Span80 ═ 6:4 in combination with glycerol.
Fig. 4 is a pseudo-ternary phase diagram of RH40: Span 80: 7:3 in combination with PEG 400.
Fig. 5 is a pseudo-ternary phase diagram of RH40: Span80 ═ 7:3 in combination with glycerol.
FIG. 6 is a ternary phase diagram for different surfactants used in combination with co-surfactants.
FIG. 7 is the appearance chart of the microemulsion gels of formula 4 and formula 5 in example 1.
FIG. 8 is a distribution diagram of the particle size of the microemulsion gel of lithospermum of formula 4 in example 1 of the present invention.
Detailed Description
The experimental procedures used in the following examples are all conventional procedures unless otherwise specified.
Materials, reagents and the like used in the following examples are commercially available unless otherwise specified.
In the following examples, the medicinal materials: gromwell (Hebei Quantai pharmaceuticals Co., Ltd., batch No. 1604001), radix Codonopsis (Codonopsis pilosula (Hebei Quantai pharmaceuticals Co., Ltd., batch No. 1703001), Poria (Hebei Quantai pharmaceuticals Co., Ltd., batch No. 1614003), folium Isatidis (Hebei Quantai pharmaceuticals Co., Ltd., batch No. 1708001), radix Angelicae sinensis (Hebei Quantai pharmaceuticals Co., Ltd., batch No. 1712004), and radix Glycyrrhizae (Hebei Quantai pharmaceuticals Co., Ltd., batch No. 1712002).
Reagent: extra virgin olive oil (commercially available, spain, date of manufacture 2018/04/03, origin), jojoba oil (commercially available, german, date of manufacture 2018/07/30), sesame oil (commercially available, shanxi, origin); polyoxyethylene 40 hydrogenated castor oil (BASF corporation, lot # 89940824U0), span80 (tsujin san xin chemical limited, lot # 20180705), polyethylene glycol 400 (tsujin science and technology limited, lot # 20161005), glycerol (tsujin feng boat chemical reagent science and technology limited, lot # 20180528), 1, 2-propanediol (tsujin boat chemical reagent science and technology limited, lot # 20160514), rose essential oil (guangzhou dong bio-science and technology limited, lot # DTCK1891C), phenoxyethanol (shandong you sog chemical technology limited, lot # 20180717), ethyl paraben (ibo bio-technology limited, lot # 20180526).
Xylene (Shanghai Kangfeng chemical Co., Ltd., batch No. 20190116), physiological saline (Shijiazhuang Siyao Co., Ltd., batch No. 1806092005), Evans blue (Yuanye Bion., batch No. L04J9J62864), compound dexamethasone acetate cream (Huarun Sanjiu medicine Co., Ltd., batch No. 20190214), 1-chloro-2, 4-dinitrobenzene (Saen chemical technology Co., Ltd., batch No. FI160116), mouse CD4 enzyme-linked immunoassay kit (Shanghai enzyme-linked Biotechnology Co., Ltd., batch No. m1038374), and mouse CD8 enzyme-linked immunoassay kit (Shanghai enzyme-linked Biotechnology Co., Ltd., batch No. m 1038372).
In the examples described below, Zetaszier Nano-90 (Malvern, UK), DNM-9602 enzyme-labeled analyzer (Beijing Prolang technologies, Inc.), CP24C analytical balance (Shanghai Oghai Spongiao, Inc.), TU-1810 ultraviolet-visible spectrophotometer (Beijing Puji general instruments, Inc.), SC-02 low-speed centrifuge (Kagaku scientific instruments, Inc., Anhui), model 78-1 magnetically heated stirrer (Ronghua instruments, Inc., of Jintan, Jiangsu province).
In the following examples, SPF grade ICR mice, male and female halves, with a body mass of 18g-22g, were purchased from Shanghai Seipaibikha laboratory animals Co., Ltd, and the certification numbers: 20180006000161, production license number of experimental animal: SCXK (Shanghai) 2018 and 0006.
Example 1 preparation of Compound Lithospermum erythrorhizon gel
Preparing compound lithospermum gel:
1. preparation of compound lithospermum oil
Weighing the medicinal materials according to a certain proportion (such as lithospermum: radix codonopsis: poria cocos: folium isatidis: angelica sinensis: liquorice: 3:1), crushing (the particle size can be 40-80 meshes), sieving, mixing uniformly, fully wetting in a beaker by 2 times of the mass of olive oil, placing in a percolation cylinder after sealing for 12h, soaking in 3 times of the mass of olive oil for 48h, and percolating by 5 times of the mass of the olive oil, thus obtaining the compound lithospermum oil.
2. Preparation of compound lithospermum oil mixed oil phase
Diluting compound arnebia oil (such as compound arnebia oil: jojoba oil mass ratio of 1:4) with jojoba oil to obtain compound arnebia oil mixed oil phase.
3. Screening of surfactants
Polyoxyethylene 40 hydrogenated castor oil (RH40) was the main surfactant, which was adjusted with Span80 (Span 80). The maximum amount of the compound lithospermum oil mixed oil phase which can be carried by 1g of mixed surfactant is used as an evaluation index to screen the surfactant combination. The results are shown in table 1, and the surfactant combination RH40, Span 80-6: 4 and RH40, Span 80-7: 3 which is larger in the amount that 1g of mixed surfactant can carry the mixed oil phase of the compound lithospermum oil are selected as the alternative surfactants of the compound lithospermum gel.
TABLE 1 amount of oil mixture phase of compound arnebia oil with turbidity phenomenon when mixed with 1g surfactant
Figure RE-GDA0002167807270000051
4. Screening of cosurfactant
Using common cosurfactant such as anhydrous ethanol, 1, 2-propylene glycol, glycerol, and polyethylene glycol 400(PEG-400) as alternative cosurfactantmWhen the ratio is 9:1 (K)mIs the mass ratio of the surfactant and the cosurfactant) and the maximum amount of the mixture of the surfactant and the cosurfactant which can carry the mixed oil phase of the compound arnebia oil and is 0.5g is taken as an evaluation index to screen the cosurfactant. The results are shown in table 2, and 0.5g of the mixture of the surfactant and the cosurfactant is selected to be capable of carrying the mixed oil of the compound lithospermum oil, and is used as the alternative cosurfactant of the compound lithospermum gel compared with a large amount of glycerol and PEG 400.
TABLE 2 amount of oil phase mixture of compound arnebia oil with turbidity after mixing
Figure RE-GDA0002167807270000052
Figure RE-GDA0002167807270000061
5. Prescription screening
With mixtures of surfactants and cosurfactants (K)m) The compound lithospermum oil mixed oil phase and the distilled water are three vertexes to draw a pseudo-ternary phase diagram. Respectively mixing surfactant and cosurfactant at ratio (K) of 10:0, 9:1, 8:1, and 7:1mValue) of the components are mixed,mixing the mixture and the mixed oil phase of compound arnebia oil uniformly according to the mass ratio of 1:9-9:1, and dripping distilled water in the mixing process to obtain the result KmThe mass ratio of the compound lithospermum oil to the mixed oil phase is 1:9-4:6, the gel state appears, and the emulsification or layering phenomenon appears when the mass ratio is 5:5-9:1, as shown in figure 1. The gel region is drawn by a pseudo-ternary phase diagram method, which is shown in fig. 2-5.
In the experimental process, the phenomenon of emulsification is found to be easy to occur when the water phase is more than 30 percent, so that the proportion of the fixed water phase is 30 percent, and the pseudo-ternary phase diagram is converted into the ternary phase diagram. The ternary phase diagram of different surfactant and co-surfactant combinations is shown in figure 6.
Because the ternary phase diagram of different surfactants and cosurfactants used together is small in difference, five different points with the same combined use ratio of the compound lithospermum oil mixed oil phase, the surfactant and the cosurfactant are selected in the ternary phase diagram for testing according to the principle that the oil phase ratio is large (see table 3). The appearance of the compound lithospermum gel with the prescription 4 and the prescription 5 prepared by the invention is shown in figure 7. The pH of the gel is 6-6.8, the particle size distribution of radix Arnebiae microemulsion gel is shown in figure 8, and the particle size is 10-100 nm.
TABLE 3 composition of each part based on 1g
Figure RE-GDA0002167807270000062
Example 2 study of the Effect of Compound Lithospermum erythrorhizon gel on acute inflammation
The influence research of the acute inflammation is carried out on the compound lithospermum gel prepared by the prescription 4 in the table 3 in the embodiment 1 of the invention:
1. model experiment of mouse auricle swelling caused by xylene
(1) Method of producing a composite material
Mice were randomly divided into 6 groups after 1 week of adaptive feeding, and each group had ten males and females in half. The front and back surfaces of the auricle of the blank group and the model group are evenly smeared with 40 mg/piece of distilled water, the positive medicine group is smeared with 40 mg/piece of compound dexamethasone acetate cream, the blank gel group is smeared with 40 mg/piece of blank gel, the low gel group is smeared with 40 mg/piece of low-concentration compound lithospermum gel (containing 2.65 percent of lithospermum compound oil), the high gel group is smeared with 40 mg/piece of high-concentration compound lithospermum gel (containing 5.30 percent of lithospermum compound oil, formula 4, 26.5 percent x (dilution multiple of jojoba oil) 1/5 is 5.30 percent), and the left auricle of each group is used as a control. After administration for 6 days, except for blank groups, 20 microlitre of dimethylbenzene is uniformly coated on the right and back surfaces of the right auricle of the mouse in each group after administration for 1 hour on the 6 th day to establish an ear swelling model, after modeling for 20min, both ears are cut off, ear sheets at the same parts of the left and right auricles are taken down along the edges of the auricles by a 6mm puncher to measure the quality, the ear swelling degree is calculated, and the ear swelling inhibition rate is calculated.
Swelling degree of ear-right ear-left ear
The inhibition rate of ear swelling is (degree of swelling of model group ear-degree of swelling of administration group ear)/degree of swelling of model group ear × 100%
(2) Statistical analysis method
Statistical analysis is carried out on experimental data by SPSS software, the experimental data accord with normal distribution and uniform variance, one-way ANOVA (one-way ANOVA) method is used for multi-sample average comparison, LSD (least squares) method is used for pairwise comparison among groups, and the inspection level alpha is 0.05. The resulting values are expressed as Mean ± standard deviation (Mean ± SD).
(3) Results and discussion
The results are shown in Table 4. Compared with the blank group, the ear swelling degree of the model group is increased, and the difference has statistical significance (P is less than 0.01); compared with the model group, the ear swelling degree of the positive drug group, the blank gel group and the compound lithospermum gel group (low concentration and high concentration) are all reduced, and the difference has statistical significance (P is less than 0.01); compared with the gel group, the ear swelling degree difference between the high gel group and the blank gel group is significant (P < 0.05). The compound lithospermum gel is shown to reduce mouse ear swelling caused by xylene.
TABLE 4 Effect of Compound Lithospermum erythrorhizon gel on swelling of mouse auricle caused by paraxylene
Figure RE-GDA0002167807270000071
Note: compared to the blank group: delta p is less than 0.05, delta p is less than 0.01; compared to the model set: p <0.05, p < 0.01; ratio to blank gel: # p <0.05, # p < 0.01.
2. Model for hyperfiltration of capillary vessels of abdominal skin of mouse caused by dimethylbenzene
(1) Method of producing a composite material
The middle part of the abdomen of the mouse is depilated by 8 percent sodium sulfide after the mouse is adaptively fed for 1 week, the depilated area is about 2cm multiplied by 2cm, the mouse is randomly divided into 5 groups after 24 hours, and each group has ten males and females in half. Blank group and model group were applied with distilled water 45mg/cm on abdomen2The dexamethasone acetate cream with 45mg/cm is coated on the abdomen of the positive drug group2Blank gel group the abdomen was coated with 45mg/cm blank gel2The compound radix Arnebiae gel group is applied to abdomen at 45mg/cm2. Each group was dosed 3 times daily for 6 days. On the sixth day, 0.1mL/10g of 0.5% Evans blue physiological saline solution was injected into the tail vein, except for the blank group, 30 μ L/mouse xylene was applied to the abdominal skin of the mouse for each group after lh administration, 20min later, the skin (about 1.5 cm. times.1.5 cm) of the abdominal locus coeruleus was removed, cut into pieces, placed in 5mL of acetone-physiological saline (7:3) and soaked for 48h, centrifuged at 3000r/min for 15min, and the supernatant was taken and the absorbance value was measured at 590nm with a spectrophotometer.
(2) Statistical analysis method
Statistical analysis is carried out on experimental data by SPSS software, the experimental data accord with normal distribution and uniform variance, one-way ANOVA (one-way ANOVA) method is used for multi-sample average comparison, LSD (least squares) method is used for pairwise comparison among groups, and the inspection level alpha is 0.05. The resulting values are expressed as Mean ± standard deviation (Mean ± SD).
(3) Results and discussion
The results are shown in Table 5. Compared with the blank group, the permeability of the skin capillary vessels of the model group is increased, and the difference has statistical significance (P < 0.01); compared with the model group, the permeability of the skin capillary vessel of the positive drug group, the blank gel group and the compound lithospermum gel group (low concentration and high concentration) is reduced, and the difference has statistical significance (P is less than 0.01); compared with the gel groups, the compound lithospermum gel group has no significant difference with the blank gel group.
TABLE 5 influence of Compound Lithospermum erythrorhizon gel on the permeability of mouse skin capillary due to paraxylene
Figure RE-GDA0002167807270000081
Note: compared to the blank group:△p＜0.05，△△p is less than 0.01; compared to the model set: p <0.05, p < 0.01.
3. Acetic acid induced mouse peritoneal capillary hyperfiltration model.
(1) Method of producing a composite material
The pretreatment of the mice and the treatment of the mouse abdominal skin capillary permeability hyperfunction model caused by xylene in 2 are randomly divided into 6 groups, and each group has half of ten males and females. Blank group and model group were applied with distilled water 45mg/cm on abdomen2The dexamethasone acetate cream with 45mg/cm is coated on the abdomen of the positive drug group2Blank gel group the abdomen was coated with 45mg/cm blank gel2The low-concentration compound radix Arnebiae gel is applied to abdomen at 45mg/cm2The high gel group is coated with high concentration compound radix Arnebiae gel 45mg/cm on abdomen2Each group was administered 3 times daily for 6 days. On the sixth day, 0.1mL/10g of 0.5% Evans blue physiological saline solution is injected into the tail vein, except the blank group, all the other groups after the Ih administration are all caused inflammation by injecting 0.2mL of 0.6% acetic acid physiological saline solution into the abdominal cavity, after 20min, the abdominal cavity is cut off and washed by 6mL of physiological saline for a plurality of times, the equal amount of washing liquid is collected and diluted, the washing liquid is centrifuged at 3000r/min for 15min, and the supernatant is taken and used for measuring the absorbance value at 590nm by using a spectrophotometer.
(2) Statistical analysis method
Statistical analysis is carried out on experimental data by SPSS software, the experimental data accord with normal distribution and uniform variance, one-way ANOVA (one-way ANOVA) method is used for multi-sample average comparison, LSD (least squares) method is used for pairwise comparison among groups, and the inspection level alpha is 0.05. The resulting values are expressed as Mean ± standard deviation (Mean ± SD).
(3) Results and discussion
The results are shown in Table 6. Compared with the blank group, the permeability of the capillary vessels in the abdominal cavity of the model group is increased, and the difference has statistical significance (P is less than 0.05); compared with the model group, the permeability of the abdominal capillary vessels of the high-concentration compound lithospermum gel group is reduced, the difference has statistical significance (P is less than 0.05), and the positive medicine, the blank gel and the low-concentration compound lithospermum gel have the effect of reducing the increase of the permeability of the abdominal capillary vessels caused by acetic acid, but the difference has no statistical significance; there was no significant difference between the gel groups. The compound lithospermum gel can reduce the increase of the permeability of the capillary vessels in the abdominal cavity of the mouse caused by acetic acid.
TABLE 6 influence of compound radix Arnebiae gel on permeability of capillary blood vessel in abdominal cavity of mouse caused by acetic acid
Figure RE-GDA0002167807270000091
Note: compared to the blank group:△p＜0.05，△△p is less than 0.01; compared to the model set: p <0.05, p < 0.01.
Example 3 study of Effect of Compound Lithospermum erythrorhizon gel on delayed hypersensitivity
The influence of delayed hypersensitivity on the compound lithospermum gel prepared by the formula 4 in the table 3 in the example 1 of the invention was studied:
delayed Type Hypersensitivity (DTH) is an important index for measuring the cellular immune function of an animal body, DTH is specific cellular immunity mediated by T cells under the action of antigen substances, when some chemical haptens such as 1-fluoro-2, 4-Dinitrobenzene (DNFB) and 1-chloro-2, 4-Dinitrobenzene (DNCB) are contacted with skin, the chemical haptens can be combined with skin proteins to form complete antigens, so that T lymphocytes sensitive to the haptens are induced to proliferate and diffuse to blood and tissues from lymph nodes, and when the animal body is contacted with the same allergens again, Langerhans cells capture the allergens and migrate to a dermis layer to be presented to the specific T lymphocytes, release inflammatory cytokines and initiate skin inflammation. Therefore, the DNCB-induced DTH model has important significance for researching the functions of T lymphocytes and cytokines thereof in inflammatory and immune diseases.
1. Experimental method and statistical analysis method
The right middle part of the abdomen of the mouse is depilated by 8 percent sodium sulfide after the mouse is adaptively fed for 1 week, the depilated area is about 2cm2cm, and after 24 hours, randomly dividing the obtained product into 6 groups, wherein each group comprises ten males and females in half. Blank group and model group were applied with distilled water 45mg/cm on abdomen2The dexamethasone acetate cream with 45mg/cm is coated on the abdomen of the positive drug group2Blank gel group the abdomen was coated with 45mg/cm blank gel2The low-concentration compound radix Arnebiae gel is applied to abdomen at 45mg/cm2The high gel group is coated with high concentration compound radix Arnebiae gel 45mg/cm on abdomen2. Each group was administered 3 times daily for 7 consecutive days. On the 2 nd day and the 3 rd day of depilation, 0.1mL of 5% DNCB acetone solution is uniformly smeared on the abdomen of each mouse except the blank group for sensitization, 2h after smearing the drug on the 7 th day, 0.1mL of 1% DNCB acetone solution is uniformly smeared on the right auricle of each mouse except the blank group for excitation, the left auricle is smeared with acetone solution for comparison, the blank group is smeared on the auricle of both auricles of the mouse for acetone solution, blood is taken after excitation for 24h, the left auricle is placed for 0.5h and then centrifuged for 15min at 3500r/min, and the upper serum is taken to measure the Cluster of Differentiation 4(CD4+) and the Cluster of Differentiation 8(CD8+) in the mouse serum by a microplate reader; cutting off double ears to calculate ear swelling degree and ear swelling inhibition rate; spleen and thymus are dissected out, visceral index is calculated, and SPSS software is adopted to carry out statistical analysis on experimental data.
2. Experimental results and discussion
(1) Influence of compound lithospermum gel on DTH mouse T cell subset caused by DNCB
CD4+ T cells and CD8+ T cells are two subsets of T cells, CD4+ T cells are also called helper T cells (Th), and have the function of assisting humoral and cellular immunity; CD8+ T cells, also called suppressor T cells (Ts), have both cytostatic and humoral immune functions. Delayed-type hypersensitivity reactions locally develop specific CD4+ cell activation and aggregation, secreting and releasing large amounts of inflammatory cytokines that trigger monocyte infiltration, lymphocytotoxicity, and local exudation and edema.
The experimental data are all in accordance with normal distribution and uniform variance, the multi-sample mean comparison is carried out by using one-way ANOVA (one-way ANOVA) method, the groups are compared in pairs by using LSD (least squares) method, and the inspection level alpha is 0.05. The values obtained are expressed as Mean. + -. standard deviation (Mean. + -. SD) and the results are shown in Table 7. Compared with a blank group, the CD4+ of the model group is increased, the CD8+ is reduced, the ratio of CD4+/CD8+ is obviously increased, and the difference has statistical significance (P is less than 0.05, and P is less than 0.01), which indicates that DNCB has stronger cytotoxicity to CD8 +; compared with the model group, the compound lithospermum gel group (low concentration and high concentration) has the advantages that CD4+, CD4+/CD8+ are reduced, CD8+ is increased, the difference has statistical significance (P <0.05, P <0.01), the toxic effect of DNCB on CD8+ can be antagonized by the compound lithospermum gel, the steady state of a T cell subgroup is recovered, and the cellular immune function of a mouse is in an immune suppression state; compared with the gel groups, the high gel group has significant difference (P <0.05, P <0.01) with the blank gel group, namely CD8+ and CD4+/CD8 +. The compound lithospermum gel has a regulating effect on T lymphocyte subsets.
TABLE 7 Effect of Compound Lithospermum erythrorhizon gel on T cell subsets of DTH mice caused by DNCB
Figure RE-GDA0002167807270000111
Note: compared to the blank group:△p＜0.05，△△p is less than 0.01; compared to the model set: p <0.05, p < 0.01;
ratio to blank gel:#p＜0.05，##p＜0.01。
(2) influence of compound lithospermum gel on DTH mouse ear swelling caused by DNCB
DNCB is a hapten, and the diluent is smeared on abdominal wall skin to form complete antigen with skin protein to stimulate T lymphocytes to proliferate into sensitized lymphocytes, and is smeared on ears after 4-7 days to locally generate DTH, wherein the peak is reached in 24-48 h after antigen attack, so that the swelling degree of the ears is measured 24h after the excitation.
The experimental data are all in accordance with normal distribution and uniform variance, the multi-sample mean comparison is carried out by using one-way ANOVA (one-way ANOVA) method, the groups are compared in pairs by using LSD (least squares) method, and the inspection level alpha is 0.05. The values obtained are expressed as Mean. + -. standard deviation (Mean. + -. SD) and the results are shown in Table 8. Compared with the blank group, the ear swelling degree of the model group is obviously increased, and the difference has statistical significance (P is less than 0.01); compared with the model group, the compound lithospermum gel group (low concentration and high concentration) has reduced ear swelling degree, the difference has statistical significance (P is less than 0.05, P is less than 0.01), the blank gel group and the positive medicine group can reduce the ear swelling of the DTH mice caused by DNCB, but the difference is not obvious; compared with the gel group, the ear swelling degree difference between the high gel group and the blank gel group is significant (P < 0.05). The compound lithospermum gel is shown to reduce the ear swelling of the DTH mice caused by DNCB.
TABLE 8 Effect of Compound Lithospermum erythrorhizon gel on DNCB-induced ear swelling in DTH mice
Figure RE-GDA0002167807270000112
Note: compared to the blank group: delta p is less than 0.05, delta p is less than 0.01; compared to the model set: p <0.05, p < 0.01; ratio to blank gel: # p <0.05, # p < 0.01.
(3) Influence of compound lithospermum gel on organ index of DTH mouse caused by DNCB
DTH is a T lymphocyte dependent response that is primarily characterized by the appearance of a delayed inflammatory response in the sensitized body at the site of antigen attack. The thymus and spleen are the main immune organs of the body, wherein the spleen is the place where immune cells are settled and is also the place for immune response; the thymus is the major site of T cell development. When the organism generates hypersensitivity, spleen and thymus are swollen, the mass of the spleen and thymus is increased, and the organ index can reflect the strength of the immune function of the organism to a certain extent.
The results after statistics of the experimental data are shown in Table 9. Compared with the blank group, the spleen index and the thymus index of the model group are increased, and the difference has statistical significance (P <0.05 and P < 0.01); compared with the model group, the spleen index and the thymus index of the compound lithospermum gel group (low concentration and high concentration), the blank gel group and the positive drug group are both reduced, and the difference has statistical significance (P <0.05, P < 0.01); compared with the gel groups, the thymus index difference between the high gel group and the blank gel group is significant (P < 0.05). The compound lithospermum gel is shown to reduce enlargement of spleen and thymus of a DTH mouse caused by DNCB.
TABLE 9 Effect of Compound Lithospermum erythrorhizon gel on organ index of DTH mouse caused by DNCB
Figure RE-GDA0002167807270000121
Note: compared to the blank group: delta p is less than 0.05, delta p is less than 0.01; compared to the model set: p <0.05, p < 0.01; ratio to blank gel: # p <0.05, # p < 0.01.

Claims (7)

1. A compound lithospermum gel is prepared from the following components: compound arnebia oil mixed oil phase, surfactant, cosurfactant, water phase and other auxiliary agents;
the components are as follows in parts by mass: 7-30 parts of compound lithospermum oil mixed oil phase; 30-60 parts of surfactant and 1-7 parts of cosurfactant; 30 parts of water phase and 1-2 parts of other auxiliary agents;
the compound lithospermum oil mixed oil phase is prepared by mixing the compound lithospermum oil and the oil phase;
the preparation method of the compound lithospermum oil comprises the following steps: wetting the pulverized radix Arnebiae, radix Codonopsis, Poria, folium Isatidis, radix Angelicae sinensis and Glycyrrhrizae radix with the oil phase, placing into a percolating cylinder, soaking, and percolating;
the mass ratio of the lithospermum to the codonopsis pilosula to the poria cocos to the folium isatidis to the angelica sinensis to the liquorice is 5-1: 1-2: 1:1: 4-1: 1;
the oil phase is at least one of olive oil, jojoba oil and sesame oil;
the surfactant is polyoxyethylene 40 hydrogenated castor oil and span 80; the mass ratio of the polyoxyethylene 40 hydrogenated castor oil to the span80 is 1.5-2.5: 1
The cosurfactant is glycerol or PEG 400.
2. The compound lithospermum gel of claim 1, which is characterized in that: the mass ratio of the total mass of the compound lithospermum oil to the oil phase is 1: 1-12;
the particle size of the crushed lithospermum, codonopsis pilosula, poria cocos, folium isatidis, angelica sinensis and liquorice is 40-80 meshes.
3. The compound lithospermum gel as claimed in claim 1 or 2, which is characterized in that: the wetting time is 6-24 h; when the oil phase is used for moistening, the mass of the oil phase is 2-5 times of the total mass of the lithospermum, the poria cocos, the folium isatidis, the angelica sinensis, the codonopsis pilosula and the liquorice;
the dipping time is 12-48 h; when the oil phase is adopted for impregnation, the mass of the oil phase is 2-4 times of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice;
during percolation, the mass ratio of the oil phase to the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice is 3-8: 1.
4. The compound lithospermum gel as claimed in claim 1 or 2, which is characterized in that: the water phase is phosphate buffer solution, distilled water or water;
the other auxiliary agent is at least one of rose essential oil, phenoxyethanol and ethylparaben.
5. The preparation method of the compound lithospermum gel of any one of claims 1 to 4, comprising the following steps: 1) wetting the pulverized radix Arnebiae, radix Codonopsis, Poria, folium Isatidis, radix Angelicae sinensis, and Glycyrrhrizae radix with the oil phase, placing into a percolating cylinder, soaking, and percolating to obtain the compound radix Arnebiae oil;
2) mixing the compound lithospermum oil and the oil phase to obtain a mixed oil phase of the compound lithospermum oil;
3) mixing the surfactant and the co-surfactant;
4) and 2) uniformly mixing the mixed oil phase of the compound lithospermum oil obtained in the step 2) with the mixture obtained in the step 3), and then dropwise adding the water phase and the other auxiliary agents to obtain the compound lithospermum gel.
6. The method of claim 5, wherein: the wetting time is 6-24 h; when the oil phase is used for moistening, the mass of the oil phase is 2-5 times of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice;
the dipping time is 12-48 h; when the oil phase is adopted for impregnation, the mass of the oil phase is 2-4 times of the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice;
during percolation, the mass ratio of the oil phase to the total mass of the lithospermum, the codonopsis pilosula, the poria cocos, the folium isatidis, the angelica sinensis and the liquorice is 3-8: 1.
7. Use of the compound lithospermum gel of any one of claims 1 to 4 in the preparation of anti-inflammatory drugs, anti-delayed type hypersensitivity drugs.
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