A preparation method and application of retinol derivatives

Abstract

The present invention belongs to the technical field of preparation of retinol derivatives, and specifically relates to a preparation method and application of retinol derivatives. The preparation method provided by the present invention comprises the following steps: 1) mixing hydroxyethyl cellulose powder, water, inorganic acid and oxidant, heating for reaction, cooling after the reaction, filtering, washing and drying to obtain oxidized cellulose; 2) mixing retinol powder and hydroxy silicone oil, and filtering after stirring to obtain hydroxy silicone oil-coated retinol; 3) mixing oxidized cellulose, hydroxy silicone oil-coated retinol, catalyst and first organic solvent, heating for reaction, ultrasonic treatment of reaction liquid after the reaction, filtering after the ultrasonic treatment, concentrating the filtrate and extracting with a second organic solvent, and drying the extract to obtain the retinol derivative. The retinol derivative prepared by the present invention has excellent light and heat stability.

Description

Technical Field

[0001] The invention belongs to the technical field of preparation of retinol derivatives, and specifically relates to a preparation method of a retinol derivative and application thereof. Background Art

[0002] Retinol (also known as vitamin A) can be oxidized into retinal by alcohol dehydrogenase in the body, and then oxidized into retinoic acid by acetaldehyde dehydrogenase. After entering the skin, it is taken up from the extracellular matrix by retinoic acid-related binding protein (cytosolic RA binding protein), transported to the cell nucleus, activating related target genes, causing gene expression or inhibition, and ultimately leading to changes in the structure and function of the epidermis and dermis. Retinoic acid has multiple alternating single and double bond configurations, which can bind to a variety of RA receptors in cells, causing a wide range of physiological effects. Retinoic acid is generally used in the medical field.

[0003] Retinol, retinal and retinyl esters are generally used in the cosmetics field. Common retinol ester compounds include retinol acetate, retinol palmitate, hydroxypinacolone retinoic acid ester and retinol retinoic acid. Among them, retinal is less used, while retinol and retinyl esters are widely used, with significant effects in anti-aging, acne removal, whitening and anti-oxidation. However, there is still a problem of stability.

[0004] As a polyol compound, retinol has multiple highly reactive double bonds and is very sensitive to light and heat. Therefore, how to improve the light and heat stability of retinol has become a major research hotspot. Summary of the invention

[0005] Therefore, the technical problem to be solved by the present invention is to overcome the problem of poor photothermal stability of retinol, and further provide a preparation method of retinol derivatives and applications thereof.

[0006] In order to solve the above problems, the scheme of the present invention is as follows:

[0007] A method for preparing a retinol derivative comprises the following steps:

[0008] 1) mixing hydroxyethyl cellulose powder, water, inorganic acid and oxidant, heating for reaction, cooling after the reaction, filtering, washing and drying to obtain oxidized cellulose;

[0009] 2) mixing retinol powder and hydroxy silicone oil and stirring them, and filtering them after stirring to obtain retinol coated with hydroxy silicone oil;

[0010] 3) mixing the oxidized cellulose, the hydroxy silicone oil-coated retinol, the catalyst and the first organic solvent, heating for reaction, subjecting the reaction solution to ultrasonic treatment after the reaction, filtering after the ultrasonic treatment, concentrating the filtrate, extracting with the second organic solvent, and drying the extract to obtain the retinol derivative.

[0011] In an optional embodiment, the mass ratio of the hydroxyethyl cellulose powder, water, inorganic acid and oxidant is 100:(200-400):(5-20):(100-140).

[0012] In an optional embodiment, the inorganic acid is selected from a sulfuric acid solution, and the mass fraction of the sulfuric acid solution is 30-45%;

[0013] The oxidizing agent is selected from potassium permanganate.

[0014] In an optional embodiment, the heating reaction temperature in step 1) is 160-220° C., preferably 180° C., and the heating reaction time is 1-5 h.

[0015] In an optional embodiment, after the reaction in step 1) is completed, the temperature is lowered to room temperature, filtered, the filter cake is washed with deionized water until the washing water is colorless, and dried to obtain oxidized cellulose.

[0016] In an optional embodiment, the molar ratio of hydroxyethyl cellulose powder to potassium permanganate is 1:(0.03-1.1), preferably 1:0.1. In addition, the hydroxyethyl cellulose powder and potassium permanganate can be dried before use, for example, dried in an oven at 60-160° C. for 24 hours, preferably dried at 120° C. for 24 hours.

[0017] In an optional embodiment, the mass ratio of the retinol powder to the hydroxy silicone oil is 100:(150-250);

[0018] In step 2), the stirring rate is 150-300 rpm and the stirring time is 0.5-3 h.

[0019] The present invention does not specifically limit the molecular weight of the hydroxy silicone oil. Optionally, the molecular weight of the hydroxy silicone oil is 300-500.

[0020] In an optional embodiment, the mass ratio of the oxidized cellulose, the hydroxy silicone oil-coated retinol, the catalyst and the first organic solvent is (80-120): (80-120): (8-15): (200-400).

[0021] In an optional embodiment, the heating reaction temperature in step 3) is 45-60° C., and the heating reaction time is 1-5 h;

[0022] The ultrasonic power during the ultrasonic treatment is 100-500 W, preferably 300 W, and the ultrasonic time is 0.5-3 h. The ultrasonic temperature is not specifically limited in the present invention, and can be 0-40° C. If not limited, the ultrasonic treatment is performed at room temperature.

[0023] In an optional embodiment, the mass ratio of the oxidized cellulose to the hydroxy silicone oil-encapsulated retinol is 1:(1-5), preferably 1:3.

[0024] In an optional embodiment, the first organic solvent can be distilled using potassium permanganate before being added, and the fraction is added with molecular sieves and stored in a dry reagent bottle or flask.

[0025] In an optional embodiment, the filtration in step 3) is a conventional filtration step in the art. The filtration step can also be performed by dialysis or ultrafiltration using an ultrafiltration membrane, for example, ultrafiltration using a membrane with a molecular weight cutoff of 100-1000Da, preferably 300Da.

[0026] In an optional embodiment, the catalyst is selected from at least one of potassium carbonate and sodium carbonate;

[0027] The first organic solvent is selected from at least one of acetone, carbon tetrachloride, and tetrahydrofuran;

[0028] The second organic solvent is selected from at least one of acetone and dichloromethane.

[0029] The present invention also provides an application of the retinol derivative prepared by the above-mentioned preparation method in cosmetics.

[0030] The technical solution of the present invention has the following advantages:

[0031] The preparation method of the retinol derivative provided by the present invention is firstly to oxidize the hydroxyethyl cellulose powder with an oxidant to form active groups such as carboxyl groups on the cellulose, and then to mix the retinol powder and hydroxy silicone oil to coat the surface of the retinol with hydroxy silicone oil, and then to mix the oxidized cellulose, the retinol coated with hydroxy silicone oil, the catalyst and the organic solvent, and to heat the reaction, and to react and bond the carboxyl groups on the cellulose with the hydroxy silicone oil and the hydroxyl groups on the retinol, and the entanglement of the polymer chains on the cellulose and the silicone oil can shield the effect of light on the retinol, and due to the influence of steric hindrance, the configuration of the retinol is fixed on the long chain of cellulose, and at the same time, combined with the protection of the outer silicone oil of the retinol, under the double protection, the light and heat stability of the retinol is greatly improved. In addition, the hydroxyethyl cellulose can also play the role of sustained release of retinol, giving the skin time to establish immune tolerance, and the prepared retinol derivatives can produce retinoic acid even if they are acted on by biological enzymes, and the configuration types are reduced, reducing allergic reactions. DETAILED DESCRIPTION

[0032] The following examples are provided for further understanding of the present invention, but are not intended to limit the best mode of implementation and do not limit the scope of protection of the present invention.

[0033] The experimental steps or conditions not specified in the following embodiments of the present invention can be implemented according to the conventional experimental steps and conditions used in the existing literature in the field. The reagents or instruments used without specifying the manufacturer are all conventional reagents or instruments that can be purchased commercially.

[0034] Example 1

[0035] This embodiment provides a method for preparing a retinol derivative, comprising the following steps:

[0036] 1) 100 g of hydroxyethyl cellulose powder, 300 g of water, 10 g of 40% sulfuric acid and 110 g of potassium permanganate were mixed and reacted at 180° C. for 4 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with deionized water until the washing water was colorless and dried to obtain oxidized cellulose.

[0037] 2) 100 g of retinol powder and 200 g of hydroxy silicone oil (molecular weight of 500) were mixed and stirred at a stirring rate of 200 rpm for 1.0 h. After the stirring was completed, the mixture was filtered to obtain retinol coated with hydroxy silicone oil;

[0038] 3) 100 g of oxidized cellulose, 100 g of hydroxy silicone oil-coated retinol, 10 g of potassium carbonate and 300 g of acetone were mixed, and heated at 50° C. for reaction for 1.0 h. After the reaction, the reaction solution was subjected to ultrasonic treatment at a power of 300 W and a time of 1.0 h. After the ultrasonic treatment, the solution was filtered, the filtrate was concentrated and extracted with dichloromethane, and the extract was freeze-dried to obtain the retinol derivative.

[0039] Example 2

[0040] This embodiment provides a method for preparing a retinol derivative, comprising the following steps:

[0041] 1) 100 g of hydroxyethyl cellulose powder, 300 g of water, 12 g of 40% sulfuric acid and 120 g of potassium permanganate were mixed and reacted at 170° C. for 4 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with deionized water until the washing water was colorless and dried to obtain oxidized cellulose.

[0042] 2) 100 g of retinol powder and 180 g of hydroxy silicone oil (molecular weight of 500) were mixed and stirred at a stirring rate of 200 rpm for 1.5 h. After the stirring was completed, the mixture was filtered to obtain retinol coated with hydroxy silicone oil;

[0043] 3) 110 g of oxidized cellulose, 100 g of hydroxy silicone oil-coated retinol, 10 g of potassium carbonate and 300 g of acetone were mixed, and heated at 50° C. for reaction for 1.5 h. After the reaction, the reaction solution was subjected to ultrasonic treatment at a power of 300 W and a time of 1.0 h. After the ultrasonic treatment, the solution was filtered, the filtrate was concentrated and extracted with dichloromethane, and the extract was freeze-dried to obtain the retinol derivative.

[0044] Example 3

[0045] This embodiment provides a method for preparing a retinol derivative, comprising the following steps:

[0046] 1) 100 g of hydroxyethyl cellulose powder, 300 g of water, 12 g of 40% sulfuric acid and 120 g of potassium permanganate were mixed and reacted at 170° C. for 5 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with deionized water until the washing water was colorless and dried to obtain oxidized cellulose.

[0047] 2) 100 g of retinol powder and 210 g of hydroxy silicone oil (molecular weight of 500) were mixed and stirred at a stirring rate of 200 rpm for 1.5 h. After the stirring was completed, the mixture was filtered to obtain retinol coated with hydroxy silicone oil;

[0048] 3) 120 g of oxidized cellulose, 100 g of hydroxy silicone oil-coated retinol, 15 g of potassium carbonate and 300 g of acetone were mixed, and heated at 50° C. for reaction for 2 h. After the reaction, the reaction solution was subjected to ultrasonic treatment at an ultrasonic power of 300 W and an ultrasonic time of 1.0 h. After the ultrasonic treatment, the solution was filtered, the filtrate was concentrated and extracted with dichloromethane, and the extract was freeze-dried to obtain the retinol derivative.

[0049] Example 4

[0050] This embodiment provides a method for preparing a retinol derivative, comprising the following steps:

[0051] 1) 100 g of hydroxyethyl cellulose powder, 350 g of water, 12 g of 40% sulfuric acid and 120 g of potassium permanganate were mixed and reacted at 180° C. for 5 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with deionized water until the washing water was colorless and dried to obtain oxidized cellulose.

[0052] 2) 100 g of retinol powder and 220 g of hydroxy silicone oil (molecular weight 450) were mixed and stirred at a stirring rate of 200 rpm for 1.5 h. After the stirring was completed, the mixture was filtered to obtain retinol coated with hydroxy silicone oil;

[0053] 3) 95 g of oxidized cellulose, 100 g of hydroxy silicone oil-coated retinol, 15 g of potassium carbonate and 300 g of acetone were mixed, and heated at 50° C. for reaction for 2.5 h. After the reaction, the reaction solution was subjected to ultrasonic treatment at a power of 300 W and a time of 1.0 h. After the ultrasonic treatment, the solution was filtered, the filtrate was concentrated and extracted with dichloromethane, and the extract was freeze-dried to obtain the retinol derivative.

[0054] Example 5

[0055] This embodiment provides a method for preparing a retinol derivative, comprising the following steps:

[0056] 1) 100 g of hydroxyethyl cellulose powder, 350 g of water, 15 g of 40% sulfuric acid and 120 g of potassium permanganate were mixed and reacted at 180° C. for 6 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filter cake was washed with deionized water until the washing water was colorless and dried to obtain oxidized cellulose;

[0057] 2) 100 g of retinol powder and 200 g of hydroxy silicone oil (molecular weight of 500) were mixed and stirred at a stirring rate of 200 rpm for 1.5 h. After the stirring was completed, the mixture was filtered to obtain retinol coated with hydroxy silicone oil;

[0058] 3) 88 g of oxidized cellulose, 100 g of hydroxy silicone oil-coated retinol, 15 g of potassium carbonate and 300 g of acetone were mixed, and heated at 50° C. for reaction for 3 h. After the reaction, the reaction solution was subjected to ultrasonic treatment at a power of 300 W and a time of 2.0 h. After the ultrasonic treatment, the solution was filtered, the filtrate was concentrated and extracted with dichloromethane, and the extract was freeze-dried to obtain the retinol derivative.

[0059] Comparative Example 1

[0060] This comparative example provides a method for preparing a retinol derivative, which differs from Example 1 in that in step 3): 100 g of oxidized cellulose, 100 g of retinol coated with hydroxy silicone oil and 300 g of acetone are mixed and stirred for 1.0 h, and then ultrasonically treated with an ultrasonic power of 300 W and an ultrasonic time of 1.0 h. After the ultrasonic treatment, the mixture is filtered, the filtrate is concentrated and extracted with dichloromethane, and the extract is freeze-dried to obtain the retinol derivative.

[0061] Comparative Example 2

[0062] This comparative example provides a method for preparing a retinol derivative, which differs from Example 1 in that in step 3): 100 g of oxidized cellulose, 65.5 g of retinol powder, 10 g of potassium carbonate and 300 g of acetone are mixed, and heated at 50° C. for reaction for 1.0 h. After the reaction, the reaction solution is subjected to ultrasonic treatment with an ultrasonic power of 300 W and an ultrasonic time of 1.0 h. After the ultrasonic treatment, the solution is filtered, the filtrate is concentrated and extracted with dichloromethane, and the extract is freeze-dried to obtain the retinol derivative.

[0063] Comparative Example 3

[0064] This comparative example provides a method for preparing a retinol derivative, which differs from Example 1 in that in step 3): 100 g of oxidized cellulose, 65.5 g of retinol powder, 34.5 g of hydroxy silicone oil, 10 g of potassium carbonate and 300 g of acetone are mixed, and heated at 50° C. for reaction for 1.0 h. After the reaction, the reaction solution is subjected to ultrasonic treatment with an ultrasonic power of 300 W and an ultrasonic time of 1.0 h. After the ultrasonic treatment, the solution is filtered, the filtrate is concentrated and extracted with dichloromethane, and the extract is freeze-dried to obtain the retinol derivative.

[0065] The amount of retinol powder and hydroxy silicone oil added in Comparative Examples 2 and 3 of the present invention is determined based on the mass ratio of hydroxy silicone oil to retinol in the hydroxy silicone oil-coated retinol in step 2) of Example 1. Specifically, (the mass of hydroxy silicone oil-coated retinol obtained in (step 2) - 100) / the mass of hydroxy silicone oil-coated retinol obtained in step 2) × 100%, that is, the mass content of hydroxy silicone oil in the hydroxy silicone oil-coated retinol is 34.5%.

[0066] Test Case

[0067] The retinol derivatives prepared in the above examples and comparative examples were subjected to stability tests. Sample preparation: 1 g of the retinol derivative, 50 g of methanol and 10 g of deionized water were mixed to prepare a solution sample.

[0068] High temperature stability test:

[0069] The solution samples were placed in a constant temperature box at 50° C. for 7 days, and then the retinol content in the samples was detected. The retinol retention rate was calculated according to the retinol content of the test sample after 7 days / the initial retinol content of the test sample×100%. The test results are shown in Table 1.

[0070] Light stability test:

[0071] The solution samples were placed under natural light for 7 days, and then the retinol content in the samples was detected. The retinol retention rate was calculated according to the retinol content of the test sample after 7 days / the initial retinol content of the test sample×100%. The test results are shown in Table 1.

[0072] Table 1

[0073]

[0074] Obviously, for ordinary technicians in the field, other modifications can be made based on the above embodiments, and the obvious modifications brought about by these modifications are still within the protection scope of the present invention.

Claims

1. A method for preparing a retinol derivative, characterized in that: The steps include: 1) Mix hydroxyethyl cellulose powder, water, inorganic acid and oxidant, heat to react, cool after the reaction, filter, wash and dry to obtain oxidized cellulose; 2) mixing retinol powder and hydroxy silicone oil, and filtering after the stirring to obtain retinol coated with hydroxy silicone oil; 3) mixing the oxidized cellulose, the hydroxy silicone oil-coated retinol, the catalyst and the first organic solvent, heating for reaction, subjecting the reaction solution to ultrasonic treatment after the reaction, filtering the solution after the ultrasonic treatment, concentrating the filtrate, extracting the solution with the second organic solvent, and drying the extract to obtain the retinol derivative; The mass ratio of the hydroxyethyl cellulose powder, water, inorganic acid and oxidant is 100: (200-400): (5-20): (100-140); The mass ratio of the retinol powder to the hydroxy silicone oil is 100:(150-250); The mass ratio of the oxidized cellulose, the hydroxy silicone oil-coated retinol, the catalyst and the first organic solvent is (80-120): (80-120): (8-15): (200-400).

2. The preparation method according to claim 1, characterized in that: The inorganic acid is selected from a sulfuric acid solution, and the mass fraction of the sulfuric acid solution is 30-45%; The oxidizing agent is selected from potassium permanganate.

3. The preparation method according to claim 1, characterized in that: Step 1) The heating reaction temperature is 160-220°C and the heating reaction time is 1-5h.

4. The preparation method according to claim 1, characterized in that: Step 1) After the reaction is completed, the temperature is lowered to room temperature, filtered, and the filter cake is washed with deionized water until the washing water is colorless, and dried to obtain oxidized cellulose.

5. The preparation method according to claim 1, characterized in that In step 2), the stirring rate is 150-300 rpm and the stirring time is 0.5-3 h.

6. The preparation method according to claim 1, characterized in that: Step 3) the heating reaction temperature is 45-60°C and the heating reaction time is 1-5h; During the ultrasonic treatment, the ultrasonic power is 100-500W, and the ultrasonic time is 0.5-3h.

7. The preparation method according to claim 1, characterized in that: The catalyst is selected from at least one of potassium carbonate and sodium carbonate; The first organic solvent is selected from at least one of acetone, carbon tetrachloride, and tetrahydrofuran; The second organic solvent is selected from at least one of acetone and dichloromethane.

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