CN111821213A - Colorless transparent water-soluble ceramide 3 lipidosome and preparation method thereof - Google Patents
Colorless transparent water-soluble ceramide 3 lipidosome and preparation method thereof Download PDFInfo
- Publication number
- CN111821213A CN111821213A CN202010811801.1A CN202010811801A CN111821213A CN 111821213 A CN111821213 A CN 111821213A CN 202010811801 A CN202010811801 A CN 202010811801A CN 111821213 A CN111821213 A CN 111821213A
- Authority
- CN
- China
- Prior art keywords
- ceramide
- lipidosome
- polyethylene glycol
- castor oil
- colorless
- 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.)
- Withdrawn
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/68—Sphingolipids, e.g. ceramides, cerebrosides, gangliosides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
- A61K8/14—Liposomes; Vesicles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/72—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds
- A61K8/84—Cosmetics or similar toiletry preparations characterised by the composition containing organic macromolecular compounds obtained by reactions otherwise than those involving only carbon-carbon unsaturated bonds
- A61K8/86—Polyethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/92—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof
- A61K8/922—Oils, fats or waxes; Derivatives thereof, e.g. hydrogenation products thereof of vegetable origin
-
- 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
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/20—Chemical, physico-chemical or functional or structural properties of the composition as a whole
- A61K2800/30—Characterized by the absence of a particular group of ingredients
Abstract
The invention relates to a colorless transparent water-soluble ceramide 3 lipidosome and a preparation method thereof, and the ceramide 3 lipidosome comprises the following components in percentage by weight: 0.1-5% of ceramide 3, 1-10% of hydrogenated castor oil, 20-50% of polyethylene glycol-60, 30-60% of polyethylene glycol-100 and 4-15% of castor oil alcohol polyether-40. The preparation method comprises the steps of adding the mixed solution of the polyethylene glycol-60 and the polyethylene glycol-100 with fixed quantity and fixed speed at constant temperature, stirring at low speed, cooling, tabletting and forming to obtain the ceramide 3 lipidosome of the invention. The liposome is white semitransparent flaky solid, and can be dissolved by adding hot water and stirring to obtain colorless, odorless and transparent aqueous solution. The method solves the problem that the ceramide 3 is difficult to be applied to the water-based cosmetics at present. The ceramide lipid particle prepared by the invention has the advantages of small particle, good water dispersibility, colorless and transparent water dispersion, good stability, excellent biocompatibility, transdermal permeability and the like, is not limited by product dosage forms, can be applied to various cosmetics, has simple preparation process and is easy for industrial popularization.
Description
Technical Field
The invention relates to the field of cosmetics, in particular to a colorless transparent water-soluble ceramide 3 lipidosome and a preparation method thereof.
Background
Ceramide 3 is a compound formed by combining sphingoid and fatty acid through amide bond, is N-stearoyl-phytosphingosine, and plays important roles of moisturizing, anti-allergy, repairing, barrier, adhesion, moistening, antioxidation, anti-aging and the like in epidermal stratum corneum. The ceramide 3 has a structure similar to that of substances forming the horny layer of the skin, can quickly permeate into the skin and is combined with water in the horny layer to establish a protective net for the skin, lock water, moisten the skin and prevent dryness; is an important skin-activating component in the stratum corneum, can enhance the skin barrier, rebuild cells, help the renewal of the natural protective layer of the skin, and form an effective barrier to prevent water loss and reduce the influence of the external environment; improving sebum balance, helping damaged skin to relieve dryness, and especially requiring more ceramide in stimulated skin; can obviously enhance the adhesive force between keratinocytes, improve the degree of skin dryness and reduce the phenomenon of skin desquamation. Therefore, ceramide 3 supplementation is particularly important for the skin.
When ceramide 3 is used as a cosmetic in a liquid form, the portion improving skin absorption is limited. Because the molecular structure of the ceramide 3 is special, the ceramide has the characteristics of high melting point, low solubility, strong hydrophobicity, poor cell penetrating capability, instability caused by the influence of the surrounding environment and the like, and is not easy to be directly used in the formula of a skin care product. Even when dissolved in water, the aqueous solution thereof hardly forms a transparent liquid, and is unstable in water, and often forms an opaque or translucent opaque state, and in this case, separation or creaming occurs with time. Although the dispersion can be carried out by using a surfactant or the like, it is difficult to sufficiently reduce the particle diameter, and a dispersion having insufficient transparency may be obtained. These ceramide 3 products hardly penetrate the aged stratum corneum of the skin into stratum corneum cells, and it is difficult to achieve the desired effect in skin repair. In order to increase the stability of the product, ceramides are generally used in the form of emulsions and liposomes.
In recent years, solid lipid nanoparticles are used as a novel drug delivery carrier to replace traditional drug delivery systems such as liposome, microemulsion and polymer micelle. The solid lipid nanoparticle combines the advantages of other novel carrier systems, has the advantages of high biocompatibility and physical stability of the polymer nanoparticle, avoids medicament oxidation, degradation or leakage, can control medicament release, has good targeting property, has the advantages of low toxicity and simple operation of liposome and emulsion, and can be used for large-scale production. In addition, because the medicament of the solid lipid nanoparticle is wrapped in the lipid material, the problem of poor water solubility of the medicament is solved, and meanwhile, the half-life period of the medicament can be prolonged, so that the problems of low bioavailability and the like of other carrier systems are solved. The common preparation methods of the solid lipid nanoparticles at present include an emulsification evaporation-low temperature curing method, a microemulsion method, a film-ultrasonic method, a high-pressure homogenization method, an ultrasonic dispersion method and the like. However, the preparation techniques of these liposomes have various disadvantages such as complicated operation steps, large variation in repetitive effects, high use of organic solvents, and difficulty in mass production on a large scale. Moreover, the lipid particles prepared by the methods are difficult to prepare completely transparent, colorless and tasteless aqueous products, so that the wide application of the ceramide 3 in cosmetics is greatly limited, and particularly the application of the ceramide 3 in transparent aqueous products is limited.
Therefore, it is the focus of research to develop a new, stable, transparent and water-soluble ceramide 3 lipid particle to make it effectively exert skin care efficacy.
Disclosure of Invention
The invention aims to overcome the technical problems and provides a colorless and transparent water-soluble ceramide 3 lipidosome and a preparation method thereof. The method solves the problem that the ceramide 3 is difficult to use in the prior water-based cosmetics, and the ceramide lipid particle prepared by the method has the advantages of small particle size, good water dispersibility, colorless and transparent water dispersion, good stability, excellent biocompatibility, transdermal permeability and the like, is not limited by product formulations, can be applied to various cosmetics, has a simple preparation process, and is easy for industrial popularization.
In order to achieve the purpose, the invention is realized by the following technical scheme:
a colorless and transparent water-soluble ceramide 3 lipidosome comprises the following components in percentage by mass: 0.1-5% of ceramide 3, 1-10% of hydrogenated castor oil, 20-50% of polyethylene glycol-60, 30-60% of polyethylene glycol-100 and 4-15% of castor oil alcohol polyether-40.
Preferably, the colorless transparent water-soluble ceramide 3 lipidosome comprises the following components in percentage by mass: 1-3% of ceramide 3, 5-8% of hydrogenated castor oil, 30-40% of polyethylene glycol-60, 46-50% of polyethylene glycol-100 and 8-12% of castor oil alcohol polyether-40.
The preparation method of the colorless transparent water-soluble ceramide 3 lipidosome comprises the following steps:
(1) heating polyethylene glycol-60 and polyethylene glycol-100 according to a proportion to 80-85 ℃ for dissolving and dispersing uniformly to obtain a solution 1, and preserving heat for later use;
(2) weighing ceramide 3, hydrogenated castor oil and castor oil alcohol polyether-40 according to the proportion, heating to 105-115 ℃, and uniformly mixing to obtain a solution 2;
(3) cooling the solution 2 to 80-85 ℃, keeping the temperature at 80-85 ℃;
(4) stirring the solution 1 at a constant speed of 3000r/min under the condition of keeping the temperature at 80-85 ℃;
(5) dropwise adding the solution 2 into the solution 1 in the fourth step at the speed of 60 g/min;
(6) after the dripping is finished, reducing the rotating speed to 1000r/min, synchronously cooling to 50-60 ℃, wherein the cooling speed is 2 ℃/min;
(7) taking the feed liquid out of the pot, pouring the feed liquid into a forming tablet machine for tabletting and forming to obtain the ceramide 3 lipidosome of the invention.
Compared with the prior art, the invention has the following advantages and effects:
(1) the ceramide 3 lipidosome of the invention is a monolayer lipidosome formed by polyethylene glycol-60 and polyethylene glycol-100, and the ceramide 3 and hydrogenated castor oil are distributed in a membrane vesicle through castor oil alcohol polyether-40 to form a stable nano-scale solid lipidosome.
(2) The ceramide 3 lipidosome prepared by the method is a white semitransparent flaky solid, is convenient to use, and can be prepared into a colorless, tasteless and transparent aqueous solution only by adding a proper amount of product into hot water at 85-90 ℃ for heat preservation for 30 min. Can be conveniently applied to various transparent cosmetic systems, and can also be prepared into products of different formulations to expand the application of the ceramide 3.
(3) Through special proportion and specific process, the ceramide 3 is highly dispersed, so that the ceramide 3 lipidosome is about 10nm, and the particle size distribution range is narrow and uniform. The active ingredients can be released and absorbed better. The ceramide 3 lipid particle has good self-permeability, can easily penetrate the aged stratum corneum of skin to reach stratum corneum cells, supplement the deficiency of skin ceramide, perform deep repair, establish a perfect skin barrier, better exert the effects of moisturizing, anti-allergy and the like, and enhance the expected using effect of the ceramide 3.
(4) The ceramide 3 lipidosome of the invention improves the content and stability of ceramide in the formula, does not change color at high temperature and does not precipitate at low temperature. The product does not form opaque or translucent opaque state after long-term storage, and does not separate or emulsify.
(5) The ceramide 3 lipidosome of the invention is free of thickening agent and preservative, safe, non-irritant, more comfortable to use, free of greasy feeling on skin after use, natural in moisture retention and water-tender in skin.
(6) The ceramide 3 lipidosome of the invention has simple production process, high production efficiency and low production cost, and is beneficial to industrial production.
Drawings
FIG. 1 is a TEM image of ceramide 3 lipoplasts according to example 1 of the present invention.
FIG. 2 is a particle size distribution diagram of ceramide 3 lipoplasts in examples 1 to 3 of the present invention.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
| Formulation of | Example 1 | EXAMPLE 2 | EXAMPLE 3 |
| Polyethylene glycol-60 | 32% | 40% | 30% |
| Polyethylene glycol-100 | 50% | 46% | 47% |
| Ceramide 3 | 2% | 1% | 3% |
| Hydrogenated castor oil | 7% | 5% | 8% |
| Ricinoleic alcohol polyether-40 | 9% | 8% | 12% |
The preparation method of the colorless transparent water-soluble ceramide 3 lipidosome comprises the following steps:
(1) heating polyethylene glycol-60 and polyethylene glycol-100 according to a proportion to 80-85 ℃ for dissolving and dispersing uniformly to obtain a solution 1, and preserving heat for later use;
(2) weighing ceramide 3, hydrogenated castor oil and castor oil alcohol polyether-40 according to the proportion, heating to 105-115 ℃, and uniformly mixing to obtain a solution 2;
(3) cooling the solution 2 to 80-85 ℃, keeping the temperature at 80-85 ℃;
(4) stirring the solution 1 at a constant speed of 3000r/min under the condition of keeping the temperature at 80-85 ℃;
(5) dropwise adding the solution 2 into the solution 1 in the fourth step at the speed of 60 g/min;
(6) after the dripping is finished, reducing the rotating speed to 1000r/min, synchronously cooling to 50-60 ℃, wherein the cooling speed is 2 ℃/min;
(7) taking the feed liquid out of the pot, pouring the feed liquid into a forming tablet machine for tabletting and forming to obtain the ceramide 3 lipidosome of the invention.
The ceramide 3 liposome described in examples 1 to 3 was subjected to physicochemical detection, and the detection indexes obtained were as follows:
1. stability test
10% of ceramide 3 lipidosome of the embodiment 1 to 3 is added into hot water with the temperature of 85 to 90 ℃ for heat preservation for 30min to prepare colorless, tasteless and transparent aqueous solution, and performance stability detection is respectively carried out, wherein the performance stability detection comprises a heat resistance test, a cold resistance test and a centrifugation test.
Heat resistance test: the samples are put into an electric heating constant temperature incubator at the temperature of (40 days 1) DEG C for 24 hours, and after the temperature is recovered, whether phenomena of discoloration, turbidity, taste change, precipitation, creaming and the like exist or not is observed, and the detection results show that the adverse results do not appear in the testing process of the ceramide 3 lipidosome in the embodiments 1 to 3, and the stability is good.
Cold resistance test: the sample is put into a refrigerator at 1 ℃ of (-5 to-10) DEG C for 24 hours, and after the temperature is restored to the room temperature, whether phenomena of discoloration, turbidity, taste change, precipitation, creaming and the like exist or not is observed, and the detection result shows that the adverse results do not appear in the testing process of the ceramide 3 lipid plasmid described in the embodiments 1 to 3, and the stability is good.
And (3) centrifugal test: the sample is placed in a centrifuge and tested for 30min at the rotating speed of 3000r/min, the separation and layering conditions of the sample are observed, and the detection result shows that the poor results do not appear in the testing process of the ceramide 3 lipidosome in the embodiments 1 to 3, so that the stability of the ceramide 3 lipidosome testing liquid is good.
The results show that the ceramide 3 lipidosome of the invention improves the content and the stability of ceramide in the formula, does not change color at high temperature and does not precipitate at low temperature. The product does not form opaque or translucent opaque state after long-term storage, and does not separate or emulsify.
Light transmittance test
10% of ceramide 3 lipidosome of the embodiment 1 to 3 is added into hot water with the temperature of 85 to 90 ℃ for heat preservation for 30min, and the colorless, tasteless and transparent aqueous solution is prepared. The light transmittance in the visible light region (380-780 nm) is measured by an ultraviolet visible spectrophotometer (Shimadzu UV-2550), and the result is shown in Table 1:
| item | EXAMPLE 1 | EXAMPLE 2 | EXAMPLE 3 |
| Light transmittance (%) | 96.91 | 97.12 | 96.65 |
The result shows that the light transmittance of the aqueous dispersion of 10 mass percent ceramide 3 lipidosome is higher than 96 percent, and the transparency is extremely high, which indicates that the ceramide 3 lipidosome prepared by the invention can be conveniently applied to various transparent cosmetic systems.
3. Structural characterization
A10% aqueous solution of the ceramide 3 lipoplasmid of example 1 was prepared, dropped onto a special copper mesh, evaporated naturally, allowed to stand to deposit particles on the copper mesh, and the morphology was observed by a transmission electron microscope (JEM-2100), and the results are shown in FIG. 1. As can be seen, the ceramide 3 lipid particle has a spherical appearance and a uniform size of about 10 nm.
4. Average particle size test
The particle size distributions of examples 1 to 3 were measured by a laser particle size analyzer (MalvernZS-90), and the results are shown in FIG. 2. As can be seen from the figure, the average particle size of example 1 is 8.5nm, the average particle size of example 2 is 7.7nm, the average particle size of example 3 is 9.8nm, and the particle size distribution of the ceramide 3 lipid particle of the present invention is very narrow and the particles are relatively uniform. From these data, it can be seen that the ceramide 3 lipidosome of the present invention is a very small nanoparticle, ensuring dispersion stability and solution transparency.
Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art will understand that various changes, modifications and substitutions can be made without departing from the spirit and scope of the invention as defined by the appended claims. Any modification, equivalent replacement, or improvement made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (3)
1. A colorless and transparent water-soluble ceramide 3 lipidosome is characterized by comprising the following components in percentage by mass: 0.1-5% of ceramide 3, 1-10% of hydrogenated castor oil, 20-50% of polyethylene glycol-60, 30-60% of polyethylene glycol-100 and 4-15% of castor oil alcohol polyether-40.
2. The colorless and transparent water-soluble ceramide 3 lipidosome according to claim 1, which comprises the following components in percentage by mass: 1-3% of ceramide 3, 5-8% of hydrogenated castor oil, 30-40% of polyethylene glycol-60, 46-50% of polyethylene glycol-100 and 8-12% of castor oil alcohol polyether-40.
3. The colorless and transparent water-soluble ceramide 3 lipidosome according to claim 1 or 2, which comprises the following steps:
(1) heating polyethylene glycol-60 and polyethylene glycol-100 according to a proportion to 80-85 ℃ for dissolving and dispersing uniformly to obtain a solution 1, and preserving heat for later use;
(2) weighing ceramide 3, hydrogenated castor oil and castor oil alcohol polyether-40 according to the proportion, heating to 105-115 ℃, and uniformly mixing to obtain a solution 2;
(3) cooling the solution 2 to 80-85 ℃, keeping the temperature at 80-85 ℃;
(4) stirring the solution 1 at a constant speed of 3000r/min under the condition of keeping the temperature at 80-85 ℃;
(5) dropwise adding the solution 2 into the solution 1 in the fourth step at the speed of 60 g/min;
(6) after the dripping is finished, reducing the rotating speed to 1000r/min, synchronously cooling to 50-60 ℃, wherein the cooling speed is 2 ℃/min;
(7) taking the feed liquid out of the pot, pouring the feed liquid into a forming tablet machine for tabletting and forming to obtain the ceramide 3 lipidosome of the invention.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010811801.1A CN111821213A (en) | 2020-08-13 | 2020-08-13 | Colorless transparent water-soluble ceramide 3 lipidosome and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010811801.1A CN111821213A (en) | 2020-08-13 | 2020-08-13 | Colorless transparent water-soluble ceramide 3 lipidosome and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111821213A true CN111821213A (en) | 2020-10-27 |
Family
ID=72918865
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010811801.1A Withdrawn CN111821213A (en) | 2020-08-13 | 2020-08-13 | Colorless transparent water-soluble ceramide 3 lipidosome and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111821213A (en) |
-
2020
- 2020-08-13 CN CN202010811801.1A patent/CN111821213A/en not_active Withdrawn
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Yang et al. | Encapsulating plant ingredients for dermocosmetic application: An updated review of delivery systems and characterization techniques | |
| Lasoń et al. | Influence of process parameters on properties of Nanostructured Lipid Carriers (NLC) formulation. | |
| CN107397714A (en) | With anti-blue light contamination and the elite breast of desalination microgroove effect and its preparation and application | |
| KR101363757B1 (en) | Double layered capsule for cosmetics and method of manufacturing the same | |
| EP2471539B1 (en) | Transdermal composition of phosphatidylcholine and method for producing same | |
| CN111544317B (en) | Anti-aging composition cationic nano-liposome and preparation method and application thereof | |
| CN106619149A (en) | Method for preparing nicotinamide-coated multivesicular liposomes | |
| CN113164368B (en) | High-content and sustained-release retinoid capsule and wrinkle-improving composition containing same | |
| Rosli et al. | Formulation and characterization of nanostructured lipid carrier encapsulated Zingiber zerumbet oil using ultrasonication technique | |
| CN114917133A (en) | Supramolecular solvent liposome and preparation method and application thereof | |
| CN114848533A (en) | Preparation method of nano-liposome efficiently-coated composite ceramide | |
| KR100904370B1 (en) | Cosmetic Composition containing Nanoliposomes | |
| AU2018272337B2 (en) | Emulsified liposome composition and preparation method therefor | |
| CN116850073A (en) | Active substance eutectic solvent liposome face cream and preparation method thereof | |
| KR101694987B1 (en) | Oil-in-water solubilized cosmetic composition comprising hydrolyzed jojoba ester oil | |
| CN111821213A (en) | Colorless transparent water-soluble ceramide 3 lipidosome and preparation method thereof | |
| CN115429713A (en) | Moisturizing, repairing and anti-aging composition containing ceramide and preparation method thereof | |
| CN116098830A (en) | Preparation method and application of hydroxy pinacolone retinoic acid ester supermolecule liposome preparation | |
| KR102369527B1 (en) | Cosmetic composition with excellent skin anti-aging effect by containing ferrocene nanocapsules loaded with tocopherol | |
| CN115634175A (en) | Composition for preparing microbead essence, microbead essence and preparation method of microbead essence | |
| KR20070069250A (en) | Nanodermal gel containing nanowater and transdermal delivery adhensive sheet type gel and method thereof | |
| CN113456592A (en) | Antiseptic and anti-inflammatory liposome and preparation method thereof | |
| CN112190576A (en) | Composition of skin external preparation, skin external preparation and preparation method thereof | |
| KR102622315B1 (en) | Method for manufacturing nanovesicles stably capturing high content of high-molecular Polysaccharide | |
| JP4592347B2 (en) | External preparation composition |
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 | ||
| WW01 | Invention patent application withdrawn after publication | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20201027 |