CN113144220B - Beta-cyclodextrin inclusion compound, gel preparation, preparation method and application thereof - Google Patents
Beta-cyclodextrin inclusion compound, gel preparation, preparation method and application thereof Download PDFInfo
- Publication number
- CN113144220B CN113144220B CN202110481369.9A CN202110481369A CN113144220B CN 113144220 B CN113144220 B CN 113144220B CN 202110481369 A CN202110481369 A CN 202110481369A CN 113144220 B CN113144220 B CN 113144220B
- Authority
- CN
- China
- Prior art keywords
- volatile oil
- beta
- inclusion compound
- cyclodextrin
- gel
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- 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)
- A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
- A61K36/236—Ligusticum (licorice-root)
-
- 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)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/534—Mentha (mint)
-
- 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
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- 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
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- 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]
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Mycology (AREA)
- Botany (AREA)
- Biotechnology (AREA)
- Alternative & Traditional Medicine (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Inorganic Chemistry (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Dermatology (AREA)
- Pulmonology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Cosmetics (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a beta-cyclodextrin inclusion compound, a gel preparation containing the inclusion compound, a preparation method and application thereof. The medicinal components included by the beta-cyclodextrin inclusion compound are mint volatile oil and ligusticum wallichii volatile oil. The inclusion compound increases the stability and solubility of the medicine, improves the utilization rate of the mint and ligusticum wallichii volatile oil smeared on the skin, reduces the pungent smell and plays a role in penetration promotion. In addition, a gel preparation containing the clathrate compound is provided, and the gel preparation can cover the pungent smell of the medicine, reduce the irritation and reduce the toxic and side effects; the volatilization loss amount of the medicine is reduced, and the utilization rate of the medicine is improved; can regulate the release speed and improve the bioavailability; protecting drug molecules, preventing volatile oil from deteriorating during long-term storage, and improving the stability of the drug; and the cost of medication is reduced and the effect of slow release can be realized. The preparation method of the gel preparation is simple and feasible, and can be applied to large-scale production.
Description
Technical Field
The invention belongs to the technology of medicinal preparations, and particularly relates to a beta-cyclodextrin inclusion compound, a gel preparation, a preparation method and application thereof.
Background
The mint volatile oil is an effective component extracted from fresh stems and leaves of mint through water distillation or subcritical low-temperature extraction, the main effective component of the mint volatile oil is menthol which can play a cooling role when being heated, and the mint volatile oil not only has the effects of cooling and relieving pain, but also can shrink capillaries and relieve symptoms such as headache, migraine and the like. The volatile oil of rhizoma Ligustici Chuanxiong is effective component extracted from rhizoma Ligustici Chuanxiong by water distillation or subcritical low temperature extraction, and its main components include ligustilide and ligustrazine, and it not only can dilate capillary vessel of head and promote blood circulation, but also has spasmolytic, antiasthmatic and sedative effects, and can effectively improve microcirculation and enhance immunity. The mint and the ligusticum wallichii have the effects of relieving fever, easing pain and resisting inflammation, and the mint volatile oil and the ligusticum wallichii volatile oil have good transdermal absorption effect.
Beta-cyclodextrin (beta-CD) is a cyclic oligosaccharide generated in starch, and cyclodextrin derivatives have the characteristics of internal hydrophobicity and external hydrophilicity, so that an inclusion compound is easily formed. The inclusion compound is an inclusion body formed by embedding drug molecules in a cavity structure of cyclodextrin molecules. The beta-cyclodextrin (beta-CD) in the cyclodextrin category has high encapsulation efficiency and low cost, and is widely applied to the pharmaceutical industry and the cosmetic industry. The chemical penetration enhancer can reversibly change the structure of the stratum corneum of the skin and promote the drug to be absorbed by capillary vessels through the skin. beta-CD is a novel chemical penetration enhancer, and can increase intercellular space by extracting lipid, thereby promoting drug penetration. The volatile oil penetration enhancer can enlarge the intercellular space, reduce the obstruction of skin to external drugs, and facilitate the transdermal diffusion of drugs in the percutaneous intercellular space.
The application combines two volatile oils without incompatibility, and the two volatile oils are mutually transdermal absorption enhancers while being used as effective components, so that the transdermal absorption efficiency can be improved, and a better drug absorption effect can be achieved. At present, no report related to cyclodextrin inclusion compounds containing mint volatile oil and ligusticum wallichii volatile oil is found.
Disclosure of Invention
The invention aims to: in order to solve the technical problems in the prior art, the application provides a beta-cyclodextrin inclusion compound, a gel preparation, and a preparation method and application thereof.
The technical scheme is as follows: the beta-cyclodextrin inclusion compound comprises the medicinal ingredients of mint volatile oil and ligusticum wallichii volatile oil, wherein the ratio of the total volume (ml) of the mint volatile oil and the ligusticum wallichii volatile oil to the mass (g) of beta-cyclodextrin is 1:6-10, and the volume ratio of the mint volatile oil to the ligusticum wallichii volatile oil is 3:1-10.
As a preferred technical scheme, the mass ratio of the total volume of the mint volatile oil and the ligusticum wallichii volatile oil to the beta-cyclodextrin is 1:8; the volume ratio of the mint volatile oil to the ligusticum wallichii volatile oil is 3:2.
The preparation method of the beta-cyclodextrin inclusion compound comprises the following steps:
(1) Weighing beta-cyclodextrin according to the formula ratio, adding distilled water, stirring and dissolving to obtain a saturated solution;
(2) Weighing the mint volatile oil and the ligusticum wallichii volatile oil according to the formula ratio, uniformly mixing, and fully dissolving by using absolute ethyl alcohol;
(3) Dripping the mixed solution of the mint volatile oil and the ligusticum wallichii volatile oil in the step (2) into a beta-cyclodextrin saturated solution under the water bath condition of 40-60 ℃;
(4) Continuously stirring for reaction after the dripping, continuously stirring to room temperature after the reaction is finished, and refrigerating;
(5) Refrigerating to allow the clathrate compound to fully settle, performing suction filtration, washing with petroleum ether for three times, washing off residual volatile oil on the surface, and drying to obtain the product.
In step (1), the temperature is preferably 40 to 60 ℃.
In the step (2), anhydrous ethanol with the volume equal to the total volume of the mint volatile oil and the ligusticum wallichii volatile oil is preferably added.
In the step (3), the preferable water bath condition is 50 ℃, the mixed solution of the mint volatile oil and the ligusticum wallichii volatile oil is dripped into the beta-cyclodextrin saturated solution at the speed of 3 mu L/s, and the saturated solution is stirred while adding.
In the step (4), preferably stirring for reaction for 30min; after the reaction, the mixture is stirred to room temperature and then refrigerated in a refrigerator at 4 ℃ for 24 hours.
And (5) drying in an oven at 45 ℃ for 8 hours to obtain the product.
A gel preparation containing the beta-cyclodextrin inclusion compound comprises the following components in 100 parts: 4 to 10 parts of sodium alginate, 0.5 to 5 parts of chitosan oligosaccharide, 0.2 to 1 part of sodium hyaluronate, 0.5 to 5 parts of beta-cyclodextrin inclusion compound, 3 to 20 parts of glycerol, 0.2 to 1 part of trisodium citrate, 0.1 to 1 part of water-soluble jojoba oil, 0.2 to 1 part of ethylene diamine tetraacetic acid, 0.005 to 0.5 part of calcium chloride, 0.1 to 1 part of preservative, 0.01 to 0.03 part of aromatic and deionized water in balance.
The preservative is selected from phenoxyethanol, ethylparaben and sodium benzoate; the aromatic is selected from herba Menthae volatile oil and flos Rosae Rugosae hydrosol.
The preparation method of the gel preparation comprises the following steps:
(1) Dissolving sodium alginate in a formula amount in deionized water;
(2) Dissolving chitosan oligosaccharide in a formula amount in deionized water, and adding the obtained clear transparent solution into the solution in the step (1) to obtain a mixture 1;
(3) Dissolving sodium hyaluronate with a formula amount in deionized water, and adding the sodium hyaluronate into the mixture 1 to obtain a mixture 2;
(4) Weighing the glycerol with the formula ratio, adding the glycerol into the mixture 2, and uniformly stirring the mixture in a water bath at the temperature of between 60 and 80 ℃ to obtain a mixture 3;
(5) Weighing beta-cyclodextrin inclusion compound, trisodium citrate, water-soluble jojoba oil, tetraethyl ethylenediamine and preservative in formula ratio, dissolving in deionized water, and stirring in water bath at 60-80 ℃ to fully dissolve to obtain a mixture 4;
(6) Stirring the mixture 3 and the mixture 4 in a water bath at the temperature of 60-80 ℃ until the mixture is uniformly mixed to form yellow, transparent, uniform and fine gel;
(7) To the gel was added a prescribed amount of CaCl at a concentration of 0.01g/mL 2 Adjusting the solution to a specified viscosity;
(8) Dripping a prescription amount of aromatic agent to adjust the smell of the gel;
(9) Homogenizing for 3-5 minutes in a high-speed dispersion homogenizer under the condition of 2000-4000 rap/min to obtain the gel containing the beta-cyclodextrin inclusion compound.
The gel can be uniformly applied to temple, and can be administered via acupoint to relieve symptoms caused by common cold, fever, fatigue and other environmental factors, such as headache, dizziness, and brain distention.
In the gel preparation components, sodium alginate (Al-Na for short) is heteropolysaccharide composed of beta-1,4-D-mannuronic acid (M) and a-1,4-D-guluronic acid (G), has rich sources and low cost, and can be used as an excellent matrix to form yellow transparent gel. It has excellent tissue compatibility and biodegradability, is not influenced by temperature, and has good thermal stability. Chitosan oligosaccharide, also called chitosan oligosaccharide and oligochitosan, is an oligosaccharide product with polymerization degree of 2-20, which is obtained by degrading chitosan through special biological enzyme technology, and the molecular weight is less than or equal to 3200Da. Has the advantages of good water solubility, large functional effect, high biological activity, easy absorption and utilization by organisms and the like. The sodium hyaluronate has a chemical formula of (C14H 20NO11 Na) n, has strong hygroscopicity, and can be dissolved in water. The aqueous solution is negatively charged, has high viscoelasticity and osmotic pressure at high concentration, and is easy to form gel with excellent properties. Meanwhile, the skin moisturizing cream is a good moisturizing agent, can meet the moisturizing requirements of skin in different seasons, and therefore can be widely applied to the field of medicines. The water-soluble Jojoba oil is derived from the plant Jojoba (Jojoba), has good permeability, is rich in vitamin D and protein, has good moistening and moisturizing effects, can maintain and adjust skin moisture, is effective in relieving, and has the effect of softening skin. Trisodium citrate, also known as sodium citrate, is derived from grains, is safe and reliable, can be biodegraded, and does not cause harm to human health. Can be used as acidity regulator, buffer and stabilizer, and has good pH regulation and buffering performance.
Has the advantages that: compared with the prior art, the method has the following advantages: the inclusion compound increases the stability and solubility of the medicine, improves the utilization rate of the mint and ligusticum wallichii volatile oil smeared on the skin, reduces the pungent smell and plays a role in permeation promotion. In addition, a gel preparation containing the clathrate compound is provided, and the gel preparation can cover the pungent smell of the medicine, reduce the irritation and reduce the toxic and side effects; the volatilization loss amount of the medicine is reduced, and the utilization rate of the medicine is improved; can regulate the release speed and improve the bioavailability; protecting drug molecules, preventing volatile oil from deteriorating during long-term storage, and improving the stability of the drug; and the cost of medication is reduced and the effect of slow release can be realized. The preparation method of the gel preparation is simple and feasible, and can be applied to large-scale production.
Drawings
FIG. 1 is a standard curve of the concentration of volatile oil of herba Menthae and rhizoma Ligustici Chuanxiong;
FIG. 2 is a TLC chart of the inclusion compound of volatile oil beta-CD of peppermint and Szechuan lovage rhizome; wherein, 1 is a mint and ligusticum wallichii volatile oil sample, 2 is an ultrasonic-treated mint and ligusticum wallichii volatile oil beta-CD inclusion compound supernatant, 3 is a blank beta-CD sample, and 4 is an ultrasonic-treated mint and ligusticum wallichii volatile oil beta-CD inclusion compound supernatant;
FIG. 3 is a UV full wavelength scan of the volatile oil, the supersonic supernatant of the beta-CD inclusion compound of peppermint/Ligusticum wallichii volatile oil, blank beta-CD, and the non-supersonic supernatant of the beta-CD inclusion compound of peppermint/Ligusticum wallichii volatile oil;
FIG. 4 is a transmission electron microscope image of beta-CD and its inclusion compound of volatile oil of herba Menthae and rhizoma Ligustici Chuanxiong;
FIG. 5 shows the cumulative transdermal penetration of volatile oils of herba Menthae and rhizoma Ligustici Chuanxiong;
FIG. 6 is a UV scan of the sample after transdermal penetration;
FIG. 7 is a gel microscopic electron microscope image of the inclusion compound of volatile oil beta-cyclodextrin containing herba Menthae and rhizoma Ligustici Chuanxiong.
Detailed Description
The present application will be described in detail with reference to specific examples.
The beta-cyclodextrin in the examples was purchased from national pharmaceutical group chemical agents, ltd; sodium hyaluronate was purchased from Dongchen group; sodium alginate, tetraethyl ethylenediamine, jojoba oil, trisodium citrate, calcium chloride and chitosan oligosaccharide are all purchased from Shanghai Michelin Biochemical technology Co., ltd; fragrances were purchased from the Beijing Aminomato Act technologies, inc.
Example 1
The preparation of the beta-cyclodextrin inclusion compound comprises the following steps:
(1) Weighing 4g of beta-cyclodextrin in a 100mL beaker, adding distilled water, and stirring and dissolving in a water bath at 60 ℃ until a saturated solution is obtained;
(2) Mixing herba Menthae volatile oil 300 μ L and rhizoma Ligustici Chuanxiong volatile oil 200 μ L, and dissolving with anhydrous alcohol 500 μ L;
(3) Slowly dripping the volatile oil of the mint and the ligusticum wallichii into the beta-cyclodextrin saturated solution at the speed of 20 mu L/s in water bath at the temperature of 50 ℃;
(4) Stirring for 30min, continuing stirring to room temperature, and refrigerating at 4 deg.C for 24 hr;
(5) Fully settling the inclusion compound under the refrigeration condition of 4 ℃, performing suction filtration, washing with a proper amount of petroleum ether, and drying the obtained solid in a baking oven of 45 ℃ for 8 hours to obtain the solid beta-cyclodextrin inclusion compound containing the volatile oil of the mint and the ligusticum wallichii.
Example 2
A method for preparing a gel formulation containing the beta-cyclodextrin inclusion compound prepared in example 1, comprising the steps of:
(1) Dissolving 4g of sodium alginate in deionized water, and performing ultrasonic treatment for 10 minutes under the condition of the power of 250W to fully dissolve the sodium alginate;
(2) Taking 0.5g of chitosan oligosaccharide, dissolving in deionized water, and adding the obtained clear and transparent solution into the solution 1) to obtain a mixture 1;
(3) Dissolving 0.2g of sodium hyaluronate for 5 minutes under the ultrasonic condition with the power of 250W, and adding the sodium hyaluronate into the mixture 1 to obtain a mixture 2;
(4) Weighing 3g of glycerol, adding the glycerol into the mixture 2, and uniformly stirring the mixture in a water bath at the temperature of 80 ℃ to obtain a mixture 3;
(5) Weighing the beta-cyclodextrin inclusion compound (0.5 g) containing the mint and ligusticum wallichii volatile oil prepared in the embodiment 1, trisodium citrate (0.2 g), water-soluble jojoba oil (0.1 g), tetraethylammonium oxalate (0.2 g) and a preservative (0.1 g) to be dissolved in a proper amount of deionized water, and stirring the mixture under the condition of water bath at the temperature of 80 ℃ to fully dissolve the mixture to obtain a mixture 4;
(6) Stirring the mixture 3 and the mixture 4 for 15 minutes under the condition of 80 ℃ water bath until the mixture is uniformly mixed to form yellow transparent uniform fine gel;
(7) To the gel was added 0.5mL of CaCl at a concentration of 0.01g/mL 2 Adjusting the solution to a specified viscosity;
(8) Adding aromatic (50 μ L) dropwise to adjust gel smell;
(9) Homogenizing for 3 min at 2000rap/min in high speed homogenizer to obtain beta-cyclodextrin inclusion gel containing volatile oil of herba Menthae and rhizoma Ligustici Chuanxiong.
Example 3
A gel formulation containing the beta-cyclodextrin inclusion compound prepared in example 1, prepared in the same manner as in example 2, and having the following composition: 10g of sodium alginate, 5g of chitosan oligosaccharide, 0.6g of sodium hyaluronate, 5g of beta-cyclodextrin inclusion compound, 20g of glycerol, 1g of trisodium citrate, 1g of water-soluble jojoba oil, 1g of ethylene diamine tetraacetic acid, 5mL of CaCl2 solution with the concentration of 0.01g/mL, 1g of preservative, 300 mu L of aromatic and deionized water in a full amount (100 g).
Example 4
The preparation method of the gel preparation containing the beta-cyclodextrin inclusion compound prepared in example 1 is the same as that of example 2, and the gel preparation comprises the following components: 8g of sodium alginate, 4g of chitosan oligosaccharide, 0.6g of sodium hyaluronate, 3g of beta-cyclodextrin inclusion compound, 15g of glycerol, 0.6g of trisodium citrate, 0.6g of water-soluble jojoba oil, 0.6g of ethylenediamine tetraacetic acid, 3mL of CaCl2 solution with the concentration of 0.01g/mL, 0.8g of preservative, 150 mu L of aromatic and deionized water are added to the total amount (100 g).
Screening of mint and ligusticum wallichii volatile oil inclusion process
Establishing a volatile oil standard curve:
according to the mint volatile oil: the volume ratio of the ligusticum wallichii volatile oil =3:2 is measured and 500 mu L of volatile oil is measured, the volatile oil is diluted by absolute ethyl alcohol according to the following concentration gradient, the absorbance under different concentrations is respectively measured, a standard curve is drawn, and the experimental result is shown in table 1.
TABLE 1 determination of absorbance values of volatile oil ethanol solutions of different concentrations
A standard curve was established as shown in figure 1.
The blank recovery rate of the volatile oil is determined as follows:
taking the volume ratio of the mint volatile oil: 1ml of ligusticum wallichii volatile oil = 3:2; taking 1mL of absolute ethyl alcohol, and fully dissolving volatile oil; placing 5g of beta-CD in a round-bottom flask filled with zeolite, adding 100mL of distilled water, and heating to fully dissolve the beta-CD; dropwise adding the volatile oil mixed solution into a round-bottom flask, connecting with a volatile oil tester, and extracting volatile oil by adopting a water vapor extraction method until the oil amount in the volatile oil tester is not increased; standing for a period of time, and recording the amount of recovered volatile oil; the volume of the recovered volatile oil was 0.92mL.
The blank recovery rate of the volatile oil is calculated according to the following formula:
determining the utilization rate of the volatile oil and the inclusion rate of beta-CD:
mixing 0.04g of the clathrate compound with 4ml of absolute ethyl alcohol; after being uniformly mixed, the mixture is subjected to ultrasonic treatment for 20min by an ultrasonic cleaning instrument under the conditions of 25 ℃ and 40 kHZ; passing the sample through a 0.22mm organic film after ultrasonic treatment; and (3) measuring the absorbance of the sample after the film is passed by using an ultraviolet spectrophotometer under the condition that the lambda =264nm, and calculating the content of the volatile oil.
The volatile oil utilization rate calculation formula is as follows:
the calculation formula of the cyclodextrin inclusion rate is as follows:
beta-CD inclusion assay design
The test adopts an orthogonal test method, determines three factors which mainly affect inclusion time, inclusion temperature and wall material and core material proportion, selects three levels to carry out investigation test, takes comprehensive scores of cyclodextrin inclusion rate and volatile oil utilization rate as evaluation indexes, and screens and determines the inclusion process.
The comprehensive score = beta-cyclodextrin inclusion rate x 20% + volatile oil utilization rate x 80%.
The levels of the factors for the orthogonality test are shown in table 2.
TABLE 2 is the orthogonal test horizon
Tests 1-9 were arranged according to the L9 (3^4) orthogonal table, the specific test method was as follows:
weighing beta-CD according to the prescription amount, adding 10 times of deionized water, and stirring to dissolve the beta-CD into a saturated solution; diluting the volatile oil with anhydrous ethanol according to 1:1; then dropwise adding the mixture into a beta-cyclodextrin saturated solution under the condition of water bath at a set temperature; stirring for a set time, and continuing stirring to room temperature; refrigerating in a refrigerator at 4 ℃ for 24h; and after the inclusion compound is completely separated out, carrying out suction filtration. Washing with appropriate amount of petroleum ether for three times to remove surface residual volatile oil; drying in a 45 ℃ oven for 8h to obtain the clathrate compound product. The volatile oil quantity, the volatile oil utilization rate and the cyclodextrin inclusion rate are respectively measured.
The protocol for runs 1-9 is as follows:
the experiment 1 is that the inclusion time is 30min, and the inclusion temperature is 40 ℃; 3g of beta-cyclodextrin;
experiment 5 is inclusion time of 60min, and inclusion temperature is 50 ℃; 5g of beta-cyclodextrin;
experiment 7 is that the inclusion time is 90min, and the inclusion temperature is 40 ℃; 5g of beta-cyclodextrin;
the experiment 8 is that the inclusion time is 90min, and the inclusion temperature is 50 ℃; 3g of beta-cyclodextrin;
experiment 9 is that the inclusion time is 90min, and the inclusion temperature is 60 ℃; 4g of beta-cyclodextrin.
The results of the data obtained in runs 1-9 are shown in Table 3.
TABLE 3 orthogonal test data sheet
An orthogonal test table was obtained from the experimental data, as shown in table 4.
TABLE 4 orthogonal test Table
Analysis by SPSS23.0 software analysis of variance was performed on the results of the orthogonal test, the results of which are shown in table 5.
TABLE 5 analysis of variance table for orthogonal tests
The variance analysis and the visual analysis are carried out on the experimental result to obtain the inclusion temperature which has significant difference (P) to the experimental result<0.05 The inclusion time and the ratio of the mass and the volume of the core material to the wall material have no significant difference (P) to the experiment>0.05 Thus selecting B) 2 Factors, since the utilization of volatile oil is the main influencing factor, A is selected according to the synthesis 1 、C 2 Two factors. Thus finally determining that the beta-CD inclusion process is A 1 B 2 C 2 Namely, the inclusion temperature is 50 ℃, the inclusion time is 30min, and the mass-volume ratio of the core material to the wall material is 1:8.
verification of inclusion process of volatile oil in examples
TLC method for qualitative analysis of inclusion compound
Preparing volatile oil sample solution for test. Precisely measuring the mint volatile oil: and (3) putting 100ul of the ligusticum wallichii volatile oil =3:2 into a 10ml volumetric flask, diluting with ethanol, and fixing the volume to a scale to obtain the finished product.
Preparing a supernatant solution of a beta-cyclodextrin inclusion compound containing the mint and ligusticum wallichii volatile oil after ultrasonic treatment for a test sample. Weighing 0.1g of beta-CD inclusion compound, adding 10mL of absolute ethyl alcohol, performing ultrasonic treatment for 20min, and passing through an organic membrane of 0.22 mu m to obtain the beta-CD inclusion compound.
Preparing blank beta-CD sample solution for test. Weighing 0.1g of blank beta-CD, adding 10mL of absolute ethyl alcohol, fully mixing and standing for 20min, and passing through an organic film with the thickness of 0.22 mu m to obtain the beta-CD.
Preparing a sample of a supernatant solution of a beta-cyclodextrin inclusion compound containing mint and ligusticum wallichii volatile oil without ultrasonic treatment. Weighing 0.1g of inclusion compound, adding 10mL of absolute ethyl alcohol, fully mixing and standing for 20min, and passing through an organic film with the thickness of 0.22 mu m to obtain the clathrate compound.
The 4 sample solutions were spotted on a silica gel plate, and developed using petroleum ether (60 to 90 ℃) and ethyl acetate as developing agents in a volume ratio of 10.
After the development, the film was taken out, dried, and inspected under an ultraviolet lamp, and the results are shown in FIG. 2.
And (4) conclusion: as can be seen from FIG. 2, the supernatant of beta-cyclodextrin inclusion compound containing volatile oil of herba Menthae and rhizoma Ligustici Chuanxiong after ultrasonic treatment has the same spots at the same positions by using volatile oil sample solution as control, which indicates that the volatile oil has not changed in property after inclusion; the blank beta-CD sample solution and the supernatant solution of the non-ultrasonic beta-cyclodextrin inclusion compound containing the volatile oil of the mint and the ligusticum wallichii have no spots, which shows that the volatile oil is completely included.
And (3) performing qualitative analysis on the inclusion compound by using a UV full-wavelength scanning method:
and (3) taking the volatile oil sample solution to be tested, and diluting the volatile oil sample solution with absolute ethyl alcohol according to a certain proportion to obtain the volatile oil sample solution.
Taking a supernatant solution of the ultrasonic-treated beta-cyclodextrin inclusion compound containing the mint and the ligusticum wallichii volatile oil to be tested, and diluting the supernatant solution with absolute ethyl alcohol according to a certain proportion to obtain the oral liquid.
Taking blank beta-CD sample solution as test solution.
Collecting non-ultrasonic supernatant solution of beta-cyclodextrin inclusion compound containing volatile oil of herba Menthae and rhizoma Ligustici Chuanxiong.
The four test solutions were scanned with a full wavelength of 190-400nm by UV spectrophotometer, and the results are shown in FIG. 3.
And (4) conclusion: taking the volatile oil sample solution as a contrast, the clathrate compound supernatant solution after ultrasonic treatment has peaks at the same wavelength, and the peak types are basically consistent, which indicates that the properties of the clathrated volatile oil are not changed; the blank beta-CD sample solution and the supernatant solution of the non-ultrasonic inclusion compound have no characteristic peak, which indicates that the volatile oil is completely included.
Qualitative analysis of the inclusion compound of the mint and ligusticum wallichii volatile oil beta-cyclodextrin by a scanning electron microscope (TEM) experimental method:
and respectively taking a proper amount of beta-cyclodextrin and the inclusion compound to observe the morphological characteristics of the beta-cyclodextrin and the inclusion compound.
The scanning electron microscope results are shown in FIG. 4.
The electron microscope result shows that black round dot-shaped objects are in the inclusion compound, and the inclusion compound is not of a blank structure, so that the inclusion compound is formed.
Content uniformity verification test of the mint and ligusticum wallichii volatile oil beta-cyclodextrin inclusion compound:
mixing four different batches of inclusion compound containing mint and ligusticum wallichii volatile oil beta-cyclodextrin 0.04g with 4ml of absolute ethyl alcohol; mixing uniformly, and performing ultrasonic treatment for 20min at 25 deg.C and 40kHZ with ultrasonic cleaning instrument; passing through a 0.22mm organic membrane, measuring the absorbance for three times under the condition that the lambda =264nm after passing through the membrane, obtaining the content of four batches of volatile oil, and the verification result is shown in table 6:
TABLE 6 Experimental verification results of content uniformity of volatile oil beta-cyclodextrin inclusion compound of herba Menthae and rhizoma Ligustici Chuanxiong
And (4) conclusion: the verification shows that no significant difference (P > 0.05) exists among the groups, and the content of samples in different batches is uniform and has no significant difference.
Example 2 verification of the prepared gel preparation containing the beta-cyclodextrin inclusion compound of the volatile oils of mint and ligusticum wallichii
Gel skin cumulative permeation measurement in the examples:
healthy mice were weighed to 18. + -.1 g. Shaving off hair, and peeling off skin to obtain isolated skin. Removing subcutaneous fat and mucus tissue, repeatedly washing with PBS, and drying skin surface water with filter paper. 0.5g of the gel sample prepared in the example was weighed.
The test conditions are as follows: setting the condition of T =32 ℃ by using a Franz diffusion cell; penetration area 2.2mm 2 (ii) a The receiving cell medium was 6.5mL of a 20% ethanol physiological saline solution with a stirring rate of 300 rpm/min.
The testing steps are as follows: the excised rat skin was fixed between a diffusion cell and a receiving cell, and 0.5g of the gel sample prepared in the example was added to the skin on one side of the diffusion cell. The liquid level of the receiving pool is just in contact with the lower layer of the skin. The magnetic stirrer and the thermostatic water bath are started. 2mL samples are taken 15min, 30min, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after the experiment is started, and after sampling, 20% ethanol PBS solution with equal volume and equal temperature is added. The sample taken out is filtered by a microporous membrane with the diameter of 0.45 mu m, the concentration of the medicine is measured by ultraviolet spectrophotometry, and the cumulative permeation quantity of the medicine is calculated according to a formula.
The skin cumulative permeation quantity Q is calculated as follows:
C n for the nth sampling of drug concentration (ml/ml)
C i For the ith sampling of drug concentration (ml/ml)
V is the liquid volume (ml) of the receiving tank
V' is the sampling volume (ml)
A is the penetration area (cm) 2 )
The cumulative skin permeation of the drug as a function of time is shown in fig. 5.
As can be seen from the slope of the curve in FIG. 5, the drug has the fastest penetration rate in 2-4 h, the cumulative penetration rate in 24h is 1.2301 μ L, and the drug penetration rate is 20.82%.
Ultraviolet full-wavelength scanning analysis of the transdermal drug:
the transdermal sample solution was diluted appropriately and subjected to full wavelength scanning in the wavelength range of 190-400nm under an ultraviolet spectrophotometer, the results are shown in fig. 6.
And (4) conclusion: the volatile oil sample solution is used as a contrast, the transdermal drug solution has peaks at the same wavelength, and the peak types are basically consistent, which indicates that the properties of the transdermal volatile oil are not changed.
Quality control of the gel:
appearance: the yellow color is transparent, fine and uniform, and has light fragrance; it can be kept colloidal at normal temperature, and does not dry or liquefy.
The pH measurement of the gel containing the mint and ligusticum wallichii volatile oil beta-cyclodextrin inclusion compound is as follows:
0.5g of the gel prepared in example was weighed, diluted with 10 to 15 times of distilled water to dissolve it, and the pH was measured with a pH meter.
The pH value of the gel containing the mint and ligusticum wallichii volatile oil beta-cyclodextrin inclusion compound prepared in the determination example is 6.8, the gel has small irritation to human skin and high affinity.
The gel microscopic electron microscope particle size detection of the volatile oil beta-cyclodextrin inclusion compound containing the mint and the ligusticum wallichii:
the gel prepared in a few embodiments is taken on a clean glass slide, a cover glass is used for lightly pressing the gel to ensure that the gel is thin and transparent, the area of the thin layer is equivalent to that of the cover glass, 3 pieces of the gel are coated, and the whole visual field under the cover glass is immediately inspected under a microscope of 50-100 times, so that the condensation phenomenon cannot occur, and particles larger than 180 mu m cannot be detected.
The micrograph is shown in FIG. 7.
And (4) conclusion: the gel particles of the beta-cyclodextrin inclusion compound containing the volatile oil of the mint and the ligusticum wallichii, which is prepared in the test example, are uniformly distributed, and no particles with the particle size of more than 180 mu m appear.
The gel stability test of the beta-cyclodextrin inclusion compound containing the mint and ligusticum wallichii volatile oil comprises the following steps:
test subjects: the gel containing the volatile oil beta-cyclodextrin inclusion compound of the mint and the szechuan lovage rhizome prepared in the embodiment.
The test principle is as follows: and testing the pH value and the viscosity value of the gel before testing, determining the corresponding parameter range when the product is qualified, and observing the appearance and the property of the product. And testing parameters of each group of samples after the stability test, and observing whether the appearance of the samples is changed or not, thereby judging whether the product stability is good or not.
The test method comprises the following steps:
1) And (3) centrifugal stability test: and (3) taking 20g of 3 groups of samples, placing the samples in a centrifugal machine, keeping the rotating speed of 2500r/min, centrifuging the samples for 10min, taking out the samples, testing whether the pH values and the viscosity values of the samples are changed, observing whether the gel is layered or not, and comparing the appearance of the samples, namely whether the color and the smell are changed or not.
2) High temperature stability test: and (3) taking 3 groups of 20g samples, placing the samples in an oven at 40 ℃ overnight, taking out the samples, placing the samples at room temperature for 24 hours, recovering the samples to the normal temperature, and testing whether the physical and chemical properties and the appearance of the samples are changed or not.
3) Low temperature stability experiment: and (3) taking 20g of 3 groups of samples, placing the samples in a refrigerator at 4 ℃ for freezing overnight, taking out the samples, placing the samples at room temperature for 24 hours, and recovering the samples to the room temperature, and detecting whether the physical and chemical properties and the appearance of the samples are changed.
And (3) test results:
1) And (3) centrifugal stability test: the sample is not layered and has good state, and the physical and chemical properties are not changed.
2) High temperature stability test: the physical and chemical properties of the sample were not changed and the state was good.
3) Low-temperature stability test: the physical and chemical properties of the sample were not changed and the state was good.
And (4) conclusion: experiments prove that the beta-cyclodextrin inclusion compound containing the mint and ligusticum wallichii volatile oil prepared in the embodiment has better gel stability.
Claims (9)
1. The gel preparation of the beta-cyclodextrin inclusion compound is characterized by comprising the following components in 100 parts: 4-10 parts of sodium alginate, 0.5-5 parts of chitosan oligosaccharide, 0.2-1 part of sodium hyaluronate, 0.5-5 parts of beta-cyclodextrin inclusion compound, 3-20 parts of glycerol, 0.2-1 part of trisodium citrate, 0.1-1 part of water-soluble jojoba oil, 0.2-1 part of ethylenediamine tetraacetic acid, 0.005-0.5 part of calcium chloride, 0.1-1 part of preservative, 0.01-0.03 part of aromatic and deionized water in balance; the beta-cyclodextrin inclusion compound comprises the medicinal ingredients of mint volatile oil and ligusticum wallichii volatile oil, wherein the mass ratio of the total volume of the mint volatile oil and the ligusticum wallichii volatile oil to the beta-cyclodextrin is 1 to 6 to 10, and the volume ratio of the mint volatile oil to the ligusticum wallichii volatile oil is 3.
2. The gel formulation of claim 1, wherein the mass ratio of the total volume of the mint volatile oil and the ligusticum wallichii volatile oil to the beta-cyclodextrin is 1:8; the volume ratio of the mint volatile oil to the ligusticum wallichii volatile oil is 3:2.
3. The gel formulation of claim 1, wherein said beta-cyclodextrin inclusion compound is prepared by a process comprising the steps of:
(1) Weighing beta-cyclodextrin according to the formula ratio, adding distilled water, stirring and dissolving to obtain a saturated solution;
(2) Weighing the mint volatile oil and the ligusticum wallichii volatile oil according to the formula ratio, uniformly mixing, and fully dissolving by using absolute ethyl alcohol;
(3) Dripping the mixed solution of the mint volatile oil and the ligusticum wallichii volatile oil in the step (2) into a beta-cyclodextrin saturated solution under the water bath condition of 40-60 ℃;
(4) Continuously stirring for reaction after the dripping, continuously stirring to room temperature after the reaction is finished, and refrigerating;
(5) Refrigerating to allow the clathrate compound to fully settle, performing suction filtration, washing with petroleum ether for three times, washing off residual volatile oil on the surface, and drying to obtain the product.
4. The gel formulation of claim 3, wherein in step (2), absolute ethanol is added in an amount equal to the total volume of the mint volatile oil and the ligusticum wallichii volatile oil; in the step (3), the water bath condition is 50 ℃, and the mixed solution of the mint volatile oil and the ligusticum wallichii volatile oil is dripped into the beta-cyclodextrin saturated solution at the speed of 3 mu L/s.
5. The gel formulation of claim 3, wherein in step (4), the reaction is stirred for 30min; stirring to room temperature, and refrigerating in a refrigerator at 4 deg.C for 24 hr; and (5) drying in an oven at 45 ℃ for 8h to obtain the product.
6. The gel formulation of claim 1, wherein said preservative is selected from the group consisting of phenoxyethanol, ethylparaben, sodium benzoate; the aromatic is selected from herba Menthae volatile oil and flos Rosae Rugosae hydrosol.
7. The gel formulation of claim 1, wherein the gel formulation is applied to temple and administered to the temple to achieve relief of symptoms of headache, dizziness, and bloating caused by cold, fever, fatigue, and other environmental factors.
8. A method of preparing a gel formulation according to claim 1, comprising the steps of:
(1) Dissolving sodium alginate in a formula amount in deionized water;
(2) Dissolving chitosan oligosaccharide in a formula amount in deionized water, and adding the obtained clear transparent solution into the solution in the step (1) to obtain a mixture 1;
(3) Dissolving sodium hyaluronate with a formula amount in deionized water, and adding the sodium hyaluronate into the mixture 1 to obtain a mixture 2;
(4) Weighing the glycerol with the formula ratio, adding the glycerol into the mixture 2, and stirring the mixture uniformly in a water bath at the temperature of between 60 and 80 ℃ to obtain a mixture 3;
(5) Weighing beta-cyclodextrin inclusion compound, trisodium citrate, water-soluble jojoba oil, ethylene diamine tetraacetic acid and preservative in formula ratio, dissolving in deionized water, and stirring under the water bath condition of 60-80 ℃ to fully dissolve to obtain a mixture 4;
(6) Stirring the mixture 3 and the mixture 4 in a water bath at the temperature of 60-80 ℃ until the mixture is uniformly mixed to form yellow, transparent, uniform and fine gel;
(7) To the gel was added a prescribed amount of CaCl at a concentration of 0.01g/mL 2 Adjusting the solution to a specified viscosity; dripping a prescription amount of aromatic to adjust the gel smell; homogenizing to obtain gel containing beta-cyclodextrin inclusion compound.
9. The method for preparing a gel formulation according to claim 8, wherein in the step (7), the homogenizing is performed under 2000 to 4000rap/min for 3~5 minutes by a high speed dispersion homogenizer.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110481369.9A CN113144220B (en) | 2021-04-30 | 2021-04-30 | Beta-cyclodextrin inclusion compound, gel preparation, preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110481369.9A CN113144220B (en) | 2021-04-30 | 2021-04-30 | Beta-cyclodextrin inclusion compound, gel preparation, preparation method and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN113144220A CN113144220A (en) | 2021-07-23 |
| CN113144220B true CN113144220B (en) | 2022-11-08 |
Family
ID=76872723
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110481369.9A Active CN113144220B (en) | 2021-04-30 | 2021-04-30 | Beta-cyclodextrin inclusion compound, gel preparation, preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113144220B (en) |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1799557B (en) * | 2005-01-05 | 2010-05-26 | 代龙 | Chinese medicinal gel formulation, its preparation process and quality control method |
| CN105106292A (en) * | 2015-09-11 | 2015-12-02 | 任汉学 | Polysaccharide biomedical colloidal fluid and preparation method |
| CN108524344A (en) * | 2017-03-01 | 2018-09-14 | 广州佰盛利和化妆品有限公司 | A kind of penetrating white formula of purification containing lemon and its preparation process |
| CN108042812A (en) * | 2018-01-31 | 2018-05-18 | 江苏卫生健康职业学院 | A kind of rhizoma chuanxiong volatile oil hydroxypropyl-beta-cyclodextrin inclusion and preparation method thereof |
| CN108785124A (en) * | 2018-05-12 | 2018-11-13 | 徐州医科大学 | Cream type cosmetic base that is a kind of pure natural and having bacteriostasis |
| CN110075032B (en) * | 2019-05-24 | 2021-12-10 | 山东大学 | Xanthan gum/sodium alginate composite oil-in-water emulsion rich in functional factors and preparation method thereof |
| CN110200832A (en) * | 2019-07-19 | 2019-09-06 | 云南绿新生物药业有限公司 | A kind of preparation method of water solubility cannabidiol shower cream |
| CN111000767A (en) * | 2019-12-19 | 2020-04-14 | 郑远元 | Chitosan nano moisturizing repair liquid for feet and preparation method thereof |
-
2021
- 2021-04-30 CN CN202110481369.9A patent/CN113144220B/en active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN113144220A (en) | 2021-07-23 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112315846B (en) | Schizophyllum commune polysaccharide liposome and preparation method and application thereof | |
| CN110882201A (en) | Itching-relieving skin-care cream and preparation method thereof | |
| CN113350234A (en) | Preparation method and application of allergy-relieving repair compound | |
| CN113018202A (en) | Dendrobium officinale polysaccharide/astragalus polysaccharide composite hydrogel as well as preparation method and application thereof | |
| CN105031207A (en) | Sugar-free pulse-activating decoction oral liquid and preparation method thereof | |
| CN113144220B (en) | Beta-cyclodextrin inclusion compound, gel preparation, preparation method and application thereof | |
| CN112754994A (en) | Ginsenoside liposome and preparation method thereof | |
| CN113133956B (en) | Guarana and clove essential oil composite nanoemulsion for resisting skin aging | |
| CN107759710B (en) | Preparation method of ambary hemp extract and application of ambary hemp extract in tobacco | |
| CN115531257A (en) | Plant essential oil composition and skin care product added with same | |
| CN111358722B (en) | Skin care product containing grape skin residue extract and preparation method thereof | |
| CN111323508B (en) | Method for determining content of 2, 4-dihydroxy-6-methoxyacetophenone in blumea balsamifera oil | |
| CN110812249B (en) | Glabridin cubic liquid crystal nanoparticles and application thereof in resisting skin photodamage | |
| CN106727154A (en) | Anti-acne gel and its preparation technology | |
| CN108324647B (en) | Skin care emulsion and preparation method thereof | |
| CN111214385A (en) | Nanoparticle emulsion loaded with skin nutrient and preparation method thereof | |
| CN113599445A (en) | Sugar-free apricot kernel and perilla cold granules and preparation method thereof | |
| CN113143788A (en) | Multi-effect composition and face cream with moisturizing, repairing and relieving functions | |
| CN113759011A (en) | Method for establishing characteristic spectrum of starwort root and preparation thereof | |
| CN115590819B (en) | Red fennel liposome, preparation method and gel paste thereof | |
| CN110179741A (en) | A kind of wormwood face cream of natural moisture preserving and preparation method thereof | |
| CN111265443A (en) | Anti-aging essence skin care lotion containing codonopsis pilosula extract and preparation method of anti-aging essence skin care lotion | |
| CN117618318B (en) | Disposable massage cream and preparation method thereof | |
| CN108918739B (en) | Pretreatment method and high performance liquid chromatography method for determining alkannin in O/W type lithospermum skin milk | |
| CN115737494B (en) | Antioxidant moisturizing skin care product and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |