Preparation method and application of retinol composite freeze-drying functional core sphere steady-state delivery system

Abstract

The invention discloses a preparation method and application of a retinol composite freeze-dried functional core sphere steady-state delivery system, and belongs to the field of cosmetics. The invention creatively develops a microemulsion freeze-drying functional core sphere steady-state delivery system of retinol, skin-care grease, an emulsifier, an oil-soluble micromolecular antioxidant active component and a natural or fermented macromolecular protein active component, and provides a preparation method of the freeze-drying functional core sphere steady-state delivery system. In the functional core ball, retinol, skin-care grease, an emulsifier, an oil-soluble micromolecular antioxidant active component and a natural or fermented macromolecular protein active component form an ordered stable nano-assembly steady-state structural system through intermolecular multiple interaction; the retinol has excellent spherical appearance, smooth spherical surface, good mechanical strength and excellent dissolution dispersibility, and solves the problems of stability, compatibility, absorptivity and the like of retinol.

Description

Technical Field

[0001] The invention relates to a preparation method and application of a retinol composite freeze-dried functional core ball steady-state delivery system, belonging to the field of cosmetics. Background Art

[0002] Functional ingredients are gradually being widely used in the cosmetics and food sectors, and are also sought after by the market and consumers. However, many ingredients with good efficacy have problems such as poor water solubility, poor stability, and easy isomerization when exposed to light, making them difficult to be compatible with cosmetic formulas, which greatly limits their application in cosmetics and food. Therefore, the application of such functional ingredients through advanced stabilized delivery technology and innovative product design has become a research hotspot. Steady-state delivery technology can greatly improve the water solubility and stability of such substances, while increasing their transdermal absorption capacity; innovative product design improves the compatibility and application scenarios of such substances in the cosmetics and food sectors, greatly expanding the application of functional ingredients.

[0003] Vitamin A1, also known as retinol or vitamin A, is not only an essential substance for the human body but also a popular anti-aging active ingredient in the market and among consumers. Retinol promotes the proliferation of keratinocytes in the basal layer of the epidermis and stimulates the synthesis of type I and type II procollagen in fibroblasts. It also inhibits the over-excitation of matrix metalloproteinases 1 and 9 by ultraviolet light, thereby reducing collagen fiber damage, preventing photoaging, and improving skin sagging and fine lines. Retinol also regulates the shedding rate of keratinocytes, unclogging excess cuticles that clog pores, smoothing and firming the stratum corneum. It can be used as an auxiliary ingredient in acne-removing products. Furthermore, retinol addresses melanin deposition by accelerating the shedding of already formed melanin and inhibiting its formation, achieving a whitening and brightening effect.

[0004] In cosmetic applications, while retinol possesses beneficial skin benefits such as wrinkle reduction, photoaging resistance, and acne treatment, it also has significant limitations. Retinol's poor water solubility and stability make it difficult to incorporate into cosmetic formulations. Furthermore, retinol can easily cause cosmetic materials to turn yellow under light exposure, and its degradation rate increases significantly under high temperatures. These effects significantly limit the widespread use of retinol in cosmetics. Summary of the Invention

[0005] The present invention uses retinol as a representative of fat-soluble active raw materials to develop a retinol composite freeze-dried functional core ball steady-state delivery system, which successfully solves the pain points of retinol application. First, a type of "retinol + skin care oil + emulsifier + oil-soluble small molecule antioxidant active ingredient + natural or fermented macromolecular protein active ingredient" microemulsion freeze-dried functional core ball steady-state delivery system was innovatively developed. Retinol, skin care oil, emulsifier, oil-soluble small molecule antioxidant active ingredient and natural or fermented macromolecular protein active ingredient form an orderly and stable nano-assembly stabilized structure system through multiple intermolecular interactions. The specific excellent spherical appearance, smooth spherical surface, good mechanical strength and excellent solubility and dispersibility solve the problems of retinol stability, compatibility, absorbability and so on.

[0006] The present invention provides a preparation method and application of a freeze-dried functional core ball steady-state delivery system based on retinol microemulsion, and innovatively develops a type of composite freeze-dried functional core ball steady-state delivery system of "retinol + skin care oil component + emulsifier component + natural or fermented macromolecular protein active ingredient + oil-soluble small molecule antioxidant active ingredient". The system has excellent spherical appearance, smooth spherical surface, good mechanical strength and outstanding solubility and dispersibility, which solves the pain points of retinol such as stability, compatibility and absorbability.

[0007] The retinol composite freeze-dried functional core ball steady-state delivery system of the present invention comprises retinol and skin care oil.

[0008] The skin care oils include, but are not limited to, caprylic / capric triglyceride GTCC, squalane, squalene, sunflower seed oil, jojoba oil, shea butter, rapeseed oil, and combinations thereof.

[0009] The retinol content of the retinol composite freeze-dried functional core ball steady-state delivery system is 0.01-20% by weight, more preferably 0.05-10%, and even more preferably 0.1-5%.

[0010] The retinol composite freeze-dried functional core ball steady-state delivery system has a skin care oil content of 0.05-50% by weight, more preferably 0.5-30%, and even more preferably 1-10%.

[0011] Furthermore, in the above technical solution, the retinol composite freeze-dried functional core ball stable delivery system also includes a macromolecular protein active ingredient. This macromolecular protein active ingredient primarily refers to naturally derived macromolecular proteins and fermented macromolecular proteins. Proteins have certain emulsifying properties and can emulsify and stabilize retinol microemulsions, promoting transdermal absorption of retinol. They also serve as an important component of the freeze-dried core ball.

[0012] The natural macromolecular protein active ingredients mentioned above mainly refer to water-soluble macromolecular active raw materials used in cosmetic products, including collagen, hydrolyzed collagen, casein, whey protein, fibroin, and sericin.

[0013] The fermented macromolecular protein active ingredients mainly include recombinant collagen, recombinant type III collagen, recombinant fibronectin, and yeast protein.

[0014] The molecular weight of the macromolecular protein is in the range of 1,000-2,000,000, more preferably in the range of 3,000-1,200,000, and even more preferably in the range of 10,000-800,000.

[0015] The retinol composite freeze-dried functional core ball steady-state delivery system has a macromolecular protein content of 0.01-30% by weight, more preferably 0.1-20%, and even more preferably 1-10%.

[0016] Furthermore, in the above technical solution, the retinol composite freeze-dried functional core ball stable delivery system further includes an emulsifier. The emulsifier can further improve the stability and transdermal absorption of the retinol microemulsion.

[0017] The emulsifiers mentioned above mainly refer to those commonly used in cosmetics or foods, including one or more active ingredients such as Tween 80, Span 80, Beheneth-25, PEG-7 Glyceryl Cocoate, Vitamin E Polyethylene Glycol Succinate, Oleth-20, Polyoxyethylene Fatty Alcohol Ether, and Rhamnolipid.

[0018] The retinol composite freeze-dried functional core ball steady-state delivery system has an emulsifier content of 0.005-10% by weight, more preferably 0.05-5%, and even more preferably 0.1-1% by weight;

[0019] The preparation process of the retinol microemulsion includes but is not limited to homogenization, high-pressure homogenization, high-pressure microfluidization, ultrasonic dispersion, extrusion, mechanical stirring, etc.

[0020] Furthermore, in the above technical solution, the retinol composite freeze-dried functional core ball stable delivery system also includes an oil-soluble small molecule antioxidant active ingredient. This oil-soluble small molecule antioxidant active ingredient reduces or minimizes the oxidation of retinol, further improving the stability of retinol.

[0021] The oil-soluble small molecule antioxidant active ingredients mentioned above mainly refer to small molecule antioxidants commonly used in cosmetics or foods, including one or more active ingredients such as vitamin E (tocopherol), coenzyme Q10 (ubiquinone), ascorbyl palmitate, resveratrol, phloretin, and lutein.

[0022] The oil-soluble small molecule antioxidant active ingredient has a weight content of 0.005-10% in the efficacy core ball, more preferably 0.05%-5%, and even more preferably 0.1-2%.

[0023] Under optimal conditions, the retinol composite freeze-dried functional core ball steady-state delivery system of the present invention includes: retinol, skin care oil, emulsifier, oil-soluble small molecule antioxidant active ingredients, and natural or fermented macromolecular protein active ingredients.

[0024] Furthermore, under optimal conditions, the weight ratio of each component of retinol, skin care oil, emulsifier, oil-soluble small molecule antioxidant active ingredient and natural or fermented large molecule protein active ingredient is 1:0.1-100:0.01-10:0.1-50:0.01-10; the more preferred ratio is 1:0.5-20:0.05-5:0.5-10:0.05-5; the more preferred ratio is 1:1-5:0.1-1:1-5:0.1-1.

[0025] Furthermore, in the above technical solution, in order to enhance the stability of the retinol compound freeze-dried functional core ball stable delivery system and improve the mechanical strength and toughness of the freeze-dried functional core ball stable delivery system, the retinol compound freeze-dried functional core ball stable delivery system preferably also includes other water-soluble macromolecular active ingredients.

[0026] The water-soluble macromolecular active substances include one or more active ingredients such as polyglutamic acid, sodium hyaluronate, sodium DNA, aloe polysaccharide, and tremella polysaccharide.

[0027] The water-soluble macromolecular active substance has a weight content of 0.1-50% in the functional core ball.

[0028] A more suitable content range is 1-30%, and an even more suitable content range is 5-20%.

[0029] Furthermore, in the above technical solution, in order to enhance other skin care effects of the retinol composite freeze-dried functional core ball steady-state delivery system, the retinol composite freeze-dried functional core ball steady-state delivery system further includes other water-soluble small molecule active substances.

[0030] The water-soluble small molecule active substance includes one or more active ingredients such as verbascoside anhydride, ergothioneine, allantoin, L-lactic acid, ferulic acid, theanine, ectoine, dipotassium glycyrrhizate, arginine, asiatically acid, and betaine.

[0031] The water-soluble small molecule active substance has a weight content of 0.1-50% in the efficacy core ball.

[0032] A more suitable content range is 1-30%, and an even more suitable content range is 5-20%.

[0033] Furthermore, in the above technical solution, the retinol composite freeze-dried efficacy core ball steady-state delivery system of the present invention has a particle size range of 0.1-15 mm, more preferably 0.5-8 mm; and even more preferably 1-5 mm.

[0034] The present invention also provides a processing technology for the aforementioned retinol composite freeze-dried efficacy core ball steady-state delivery system, comprising the following steps:

[0035] A. Weigh retinol and an oil-soluble small molecule antioxidant active ingredient separately, and disperse and dissolve them in skin care oil to obtain an oil phase solution;

[0036] B. Weigh the macromolecular protein and emulsifier separately, and disperse and dissolve them in deionized water to obtain aqueous phase I;

[0037] C. During homogenization or mechanical stirring, the retinol oil phase solution is added to the aqueous phase I and homogenized to obtain a retinol microemulsion;

[0038] D. dissolving other macromolecular active substances and / or small molecular active substances in deionized water to obtain aqueous phase II;

[0039] E. Then, the retinol microemulsion is mixed with the aqueous phase II and stirred evenly to obtain the target dispersion;

[0040] F. Add the target dispersion dropwise into the insulated liquid nitrogen bucket;

[0041] G. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry to obtain a retinol composite freeze-dried efficacy core ball steady-state delivery system.

[0042] Under further preferred conditions, the dropping device includes but is not limited to a peristaltic pump, a syringe pump, a flow pump, and the like, which can control the speed and droplet size.

[0043] Under further preferred conditions, the retinol composite freeze-dried efficacy core ball steady-state delivery system can be packaged into different packaging containers as needed, including but not limited to vials, plastic bottles, glass bottles and various customized packaging materials.

[0044] Advantageous Effects of the Invention

[0045] The present invention proposes for the first time a method for preparing a retinol composite freeze-dried functional core ball steady-state delivery system, namely, a freeze-dried functional core ball steady-state delivery system with the functional combination of "retinol + skin care oil + emulsifier + oil-soluble small molecule antioxidant active ingredient + large molecule protein active ingredient". The system has an excellent spherical appearance, a smooth spherical surface, good mechanical strength and outstanding solubility and dispersibility, which solves the stability and compatibility problems of retinol.

[0046] This invention is the first to introduce retinol microemulsion into the freeze-dried functional core ball steady-state delivery system, which not only solves the stability and compatibility problems of retinol, but also improves the transdermal absorption rate of retinol. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] Figure 1 This is a physical picture of the retinol composite freeze-dried efficacy core ball steady-state delivery system; B1, B2, B3 and B4 are samples of the retinol composite freeze-dried efficacy core ball steady-state delivery system of Examples 1-4, respectively.

[0048] Figure 2 This is a physical picture of the retinol composite freeze-dried efficacy core ball steady-state delivery system; B6, B7, B8 and B9 are samples of the retinol composite freeze-dried efficacy core ball steady-state delivery system of Examples 6-9, respectively.

[0049] Figure 3 : is a scanning electron micrograph of a cross section of a retinol composite freeze-dried functional core ball steady-state delivery system; B4, B8 and B10 are samples of the composite freeze-dried functional core ball steady-state delivery system of Examples 4, 8 and 10, respectively.

[0050] Figure 4 This is a flow chart of the preparation process of the retinol composite freeze-dried efficacy core ball steady-state delivery system. DETAILED DESCRIPTION

[0051] Example 1 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. 1

[0052] A. Weigh 1.00g of retinol and 3.00g of sunflower seed oil separately, add them to a beaker, heat and stir evenly;

[0053] B. Weigh 2.20g of silk fibroin, 0.50g of fibronectin, and 0.10g of recombinant collagen III separately, add 40.00g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0054] C. Weigh 0.50 g of ectoine, 1.00 g of theanine, and 0.70 g of asiaticoside, respectively, add 51.00 g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0055] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0056] E. Use a peristaltic pump to add the above dispersion dropwise into a liquid nitrogen bucket. The droplet size is about 40 mg. Quickly freeze to obtain small ice balls.

[0057] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B1. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0058] G. The freeze-dried functional core ball steady-state delivery system is packaged into plastic bottles, which can then be packaged into various packaging containers such as vials and glass bottles as needed.

[0059] Example 2 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. II

[0060] A. Weigh 1.00g of retinol and 3.00g of sunflower seed oil separately, add them to a beaker, heat and stir evenly;

[0061] B. Weigh 2.20 g of silk fibroin, 0.50 g of fibronectin, 0.10 g of recombinant collagen III, and 0.80 g of Tween 80, add 40.00 g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0062] C. Weigh 0.50g of ectoine, 1.00g of theanine, and 0.70g of asiaticoside respectively, add 50.20g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0063] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0064] E. Use a peristaltic pump to add the above dispersion dropwise into a liquid nitrogen bucket. The droplet size is about 40 mg. Quickly freeze to obtain small ice balls.

[0065] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B2. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0066] G. The freeze-dried functional core ball steady-state delivery system is packaged into plastic bottles, which can then be packaged into various packaging containers such as vials and glass bottles as needed.

[0067] Example 3 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. III

[0068] A. Weigh 1.00g of retinol, 3.00g of sunflower seed oil, and 0.50g of vitamin E separately, add them to a beaker, heat, and stir evenly.

[0069] B. Weigh 2.20 g of silk fibroin, 0.50 g of fibronectin, 0.10 g of recombinant collagen III, and 0.80 g of Tween 80, add 40.00 g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0070] C. Weigh 0.10 g of ectoine, 0.90 g of theanine, and 0.20 g of asiaticoside, add 50.70 g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0071] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0072] E. Use a peristaltic pump to add the above dispersion dropwise into a liquid nitrogen bucket. The droplet size is about 40 mg. Quickly freeze to obtain small ice balls.

[0073] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B3. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0074] G. The freeze-dried functional core ball steady-state delivery system is packaged into plastic bottles, which can then be packaged into various packaging containers such as vials and glass bottles as needed.

[0075] Example 4 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. IV

[0076] A. Weigh 1.00g of retinol, 3.00g of sunflower seed oil, and 0.50g of vitamin E into a beaker, heat, and stir until evenly combined.

[0077] B. Weigh 2.20 g of silk fibroin, 0.50 g of fibronectin, 0.10 g of recombinant collagen III, and 0.80 g of Tween 80, add 40.00 g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0078] C. Weigh 0.10g of ectoine, 0.9g of theanine, 0.20g of asiaticoside, and 1.00g of sodium DNA respectively, add 49.70g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0079] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0080] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0081] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B4. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0082] G. The freeze-dried functional core ball steady-state delivery system is packaged into plastic bottles, which can then be packaged into various packaging containers such as vials and glass bottles as needed.

[0083] Example 5 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. V

[0084] A. Weigh 1.50g retinol, 3.50g shea butter, and 0.50g coenzyme Q10 separately, add them to a beaker, heat and stir evenly;

[0085] B. Weigh 1.00g collagen, 2.50g casein, 0.50g sericin, and 1.00g beheneth-25 separately, add 50.00g purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0086] C. Weigh 0.30g of verbascosa anhydrous sugar, 0.50g of allantoin, 0.60g of L-lactic acid, and 1.00g of sodium hyaluronate, add 37.10g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0087] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0088] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0089] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B5. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0090] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0091] Example 6 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. VI

[0092] A. Weigh 1.50g retinol, 3.50g caprylic capric triglyceride, and 0.5g ascorbyl palmitate separately, add them to a beaker, heat, and stir evenly.

[0093] B. Weigh 1.00 g of hydrolyzed collagen, 3.00 g of whey protein, and 1.00 g of vitamin E polyethylene glycol succinate, add 50.00 g of purified water, place in a beaker, and stir until the active ingredients are completely dissolved;

[0094] C. Weigh 0.10 g of ferulic acid, 0.7 g of dipotassium glycyrrhizate, 1.20 g of ergothioneine, and 1.50 g of sodium polyglutamate, respectively, and add 36.00 g of purified water, stirring until the active ingredients are evenly dispersed and dissolved;

[0095] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0096] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0097] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B6. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is controlled at approximately 30°C.

[0098] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0099] Example 7 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. VII

[0100] A. Weigh 1.50g retinol, 3.50g squalane, and 0.5g lutein separately, add them to a beaker, heat, and stir evenly;

[0101] B. Weigh 2.00g of whey protein, 1.50g of fibroin, 0.80g of collagen, and 0.9g of PEG-7 glyceryl cocoate separately, add 50.00g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0102] C. Weigh 0.10g betaine, 0.40g theanine, 1.00g arginine, and 1.50g aloe polysaccharide, add 36.30g purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0103] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0104] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0105] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated B7. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0106] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0107] Example 8 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. VIII

[0108] A. Weigh 2.00g retinol, 3.00g jojoba oil, 0.50g resveratrol, and 0.5g vitamin E separately, add them to a beaker, heat, and stir evenly.

[0109] B. Weigh 2.00g casein, 0.50g fibroin, 0.20g hydrolyzed collagen, and 0.90g oleth-20 separately, add 50.00g purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0110] C. Weigh 0.30 g of ergothioneine, 0.70 g of theanine, and 1.50 g of sodium hyaluronate, respectively, add 37.90 g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0111] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0112] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0113] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated B8. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0114] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0115] Example 9 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. IX

[0116] A. Weigh 3.00 g of retinol, 3.00 g of shea butter, 0.10 g of phloretin, and 0.90 g of vitamin E separately, add them to a beaker, heat, and stir evenly;

[0117] B. Weigh 3.00g casein, 0.30g whey protein, 0.20g hydrolyzed collagen, and 0.70g rhamnolipid separately, add 50.00g purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0118] C. Separately weigh 0.30 g of asiaticoside, 0.60 g of sodium polyglutamate, and 1.50 g of sodium hyaluronate, add 36.4 g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0119] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0120] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0121] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B9. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is controlled at approximately 30°C.

[0122] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0123] Example 10 Preparation of Retinaldehyde Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. X

[0124] A. Weigh 1.50g retinal, 3.00g caprylic capric triglyceride, 0.5g ascorbyl palmitate, and 0.5g vitamin E, add them to a beaker, heat, and stir evenly.

[0125] B. Weigh 1.00 g of silk fibroin, 3.00 g of whey protein, and 0.80 g of fatty alcohol polyoxyethylene ether, add 50.00 g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0126] C. Weigh 0.10g of ectoine, 0.90g of theanine, 0.20g of asiaticoside, and 1.50g of sodium DNA respectively, add 37.00g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0127] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0128] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0129] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B10. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0130] G. The freeze-dried functional core ball steady-state delivery system is packaged into plastic bottles, which can then be packaged into various packaging containers such as vials and glass bottles as needed.

[0131] Example 11 Preparation of Retinaldehyde Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. XI

[0132] A. Weigh 1.00 g retinal, 3.00 g shea butter, 0.10 g phloretin, and 0.60 g coenzyme Q10 separately, add them to a beaker, heat, and stir evenly;

[0133] B. Weigh 2.50g of silk fibroin, 0.30g of fibronectin, 0.10g of collagen, and 0.70g of Tween 80 separately, add 40.00g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0134] C. Weigh 0.10g of ectoine, 0.70g of dipotassium glycyrrhizate, and 0.20g of asiaticoside separately, add 50.70g of purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0135] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0136] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0137] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B11. The freeze dryer's cold trap temperature is controlled at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0138] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0139] Example 12 Preparation of Retinol Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System No. XII

[0140] A. Weigh 1.50g of retinol, 1.50g of retinal, 3.00g of rapeseed oil, and vitamin E separately, add them to a beaker, heat, and stir evenly;

[0141] B. Weigh 0.30g of fibroin, 2.50g of whey protein, 0.30g of hydrolyzed collagen, and 0.70g of rhamnolipid, add 50.00g of purified water into a beaker, and stir until the active ingredients are completely dissolved;

[0142] C. Weigh 0.60g Tremella polysaccharide, 1.20g sodium polyglutamate, and 1.00g asiaticaoside separately, add 36.90g purified water, and stir until the active ingredients are evenly dispersed and dissolved;

[0143] D. Add the oil phase dropwise to the aqueous phase in B while homogenizing with a homogenizer at 5000 rpm for 20 min, then add the solution in C and stir until the solution is uniform to obtain the target dispersion;

[0144] E. Using a peristaltic pump, add the above solution dropwise into a container of insulated liquid nitrogen. During the addition, introduce nitrogen gas into the target dispersion to prevent oxidation and loss of retinol. The droplet size is approximately 40 mg, and small ice balls are obtained by rapid freezing.

[0145] F. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry for 24-48 hours to obtain a retinol-compound freeze-dried functional core ball steady-state delivery system, designated as B12. The freeze dryer's cold trap temperature is maintained at approximately -70°C, and the final drying chamber temperature is maintained at approximately 30°C.

[0146] G. Pack the freeze-dried functional core balls into plastic bottles, which can then be packed into various packaging containers such as vials and glass bottles as needed.

[0147] Detection and analysis examples

[0148] Test Example 1: Photo of a sample of a retinol compound freeze-dried efficacy core ball steady-state delivery system, sample set 1

[0149] A camera was used to take pictures and characterize the appearance and morphology of the retinol composite freeze-dried efficacy core ball steady-state delivery system, and a comparative analysis was performed.

[0150] Samples B1, B2, B3 and B4 are from Examples 1-4, respectively. Figure 1 As can be seen, after freeze-drying, B1, B2, B3, and B4 all exhibited pale yellow retinol freeze-dried microemulsions for a stable delivery system. Except for B1, the microemulsions were all perfectly spherical and uniform in size. Sample B1 exhibited uneven yellow distribution and size, primarily due to the lack of an emulsifier in B1, resulting in poor emulsification and unstable, easily separated emulsions. Samples B2, B3, and B4 all incorporated an emulsifier, allowing the retinol microemulsion to be evenly dispersed throughout the liquid, resulting in a more uniform color for the microemulsions.

[0151] Test Example 2: Photograph of a sample of a retinol composite freeze-dried efficacy core ball steady-state delivery system, sample set 2

[0152] Samples B6, B7, B8, and B9, from Examples 6-9, respectively, are all pale yellow retinol freeze-dried functional core sphere steady-state delivery systems. The spheres are well-rounded and uniform in size. Samples 6 and 7 use 1.5% retinol, Sample 8 uses 2% retinol, and Sample 9 uses 3% retinol. The retinol content of Samples 6, 7, and 8 is similar, so the color difference is not noticeable. Sample 9 has the highest retinol content. Therefore, the color of the retinol-combined freeze-dried functional core sphere steady-state delivery system in Sample 9 is noticeably darker.

[0153] Scanning electron microscope photo of the sample of the steady-state delivery system of retinol composite freeze-dried efficacy core ball in test example 3

[0154] Gently break the functional core ball apart and then observe it with a scanning electron microscope. Figure 3As can be seen in the figure, the interior of the pellets is a uniform layered structure, with evenly distributed micron-sized channels between the layers. Small particles, representing microemulsion droplets, are present throughout the sample. During rapid freezing with liquid nitrogen, the active ingredient dissolved in water rapidly precipitates, forming tiny crystals. Then, during freeze-drying, as the ice crystals sublime, water vapor forms micron-sized channels, connecting the tiny active ingredient crystals together to form a layered structure. Because liquid nitrogen freezes so quickly, the microstructure of the entire pellet is remarkably uniform. The active ingredient layer is extremely thin, typically less than 1 micron, ensuring rapid dissolution when water is added.

[0155] Test Example 4: Content of Retinol or Retinaldehyde in a Sample of a Composite Freeze-Dried Efficacy Core Ball Steady-State Delivery System

[0156] The table below lists the retinol content and retinol retention rates of various retinol-compound freeze-dried functional core ball steady-state delivery systems. Samples B1, B2, B3, and B4 all contain 1% retinol. However, sample B1 has a retinol retention rate of approximately 91.90%, while B2 has a retention rate of 94.90%, B3 has a retention rate of 97.02%, and B4 has a retention rate of 98.66%.

[0157]

[0158] This is mainly because no emulsifier is added to B1. The emulsifier helps stabilize the system and thus protects retinol from oxidation during the preparation process. In addition to the emulsifier, B3 also adds an oil-soluble antioxidant, so the degree of protection of retinol is better, and the measured retinol content is also higher. B4 adds macromolecular active substances on the basis of B3 to help enhance the stability of the emulsion. Samples B5-B12 are all added with emulsifiers, oil-soluble antioxidants and macromolecular active substances, so the retention rate of retinol or retinal in B5-B12 reaches more than 98%. This shows that the embedding of the microemulsion and the addition of oil-soluble antioxidants and macromolecular active substances can significantly reduce the oxidation of retinol or retinal and improve its stability.

[0159] Test Example 5: Stability

[0160] Retinol is susceptible to oxidation and deterioration. Referring to cosmetic stability evaluation, the stability of retinol-compounded functional core beads was evaluated through a 45°C accelerated test and compared with a retinol control dispersion (see Application Examples). Accelerated testing was first conducted on the retinol-compounded freeze-dried functional core bead steady-state delivery system, and then solutions of varying concentrations were analyzed. Using an initial retinol concentration of 100%, the percentage of retinol retained relative to the initial concentration was measured at different aging times.

[0161]

[0162] As can be seen from the table above, the retinol content of the retinol control dispersion drops rapidly (control sample 1), dropping by about 13% after 1 hour, by about 21% after 5 hours, by about 64% after 48 hours, and only 1% after 120 hours. Sample B2, a retinol composite freeze-dried efficacy core ball steady-state delivery system, is based on retinol encapsulated in a microemulsion. No antioxidant active ingredients are added, and the retinol has good stability. After 10 days (240 hours), the retinol retention rate is about 93%, and after 60 days (60 days), the retention rate is still about 87%. The addition of the antioxidant active ingredient B3 further improves the stability of retinol. After 10 days, the retinol retention rate reaches more than 98%, and after 60 days (60 days), the retention rate is still 96.32%. For other samples with added antioxidant active ingredients, the retinol content in the retinol-compounded freeze-dried functional core ball steady-state delivery system did not change much after 240 hours (10 days), with a retention rate of around 98%. After 60 days (60 days), the retention rate was generally above 96%, and some even exceeded 97%. This is mainly because the microemulsion coating can reduce the oxidative degradation rate of retinol. The addition of antioxidant active ingredients further enhances the stability of retinol, and retinol is more stable in a dry state. The results of the analytical evaluation experiments show that the stability of retinol in the freeze-dried functional core ball steady-state delivery system is significantly higher than that of retinol or essence, and the content remains stable.

[0163] Test Example 6 Transdermal Absorption

[0164] A systematic transdermal efficacy evaluation and comparison was conducted for the application cases. The evaluation method was based on the "In Vitro Test Method for Skin Absorption of Chemicals". The evaluation results are shown in the table below.

[0165] First, for comparison purposes, a retinol control dispersion, retinol compound freeze-dried functional core essence-I, retinol compound freeze-dried functional core essence-II, and retinol compound freeze-dried functional core essence-III were diluted with saline to a retinol concentration of approximately 0.05%, and then subjected to transdermal testing. Transdermal data were analyzed over 1 and 8 hours to minimize the impact of retinol instability on the test. As shown in the table below, the retinol transdermal absorption of the retinol compound freeze-dried functional core essence was significantly higher than the 8-hour transdermal absorption of the retinol control dispersion. These results demonstrate that the retinol microemulsion and the nano-assembly structure of the functional core essence not only enhance retinol stability but also improve its transdermal absorption rate.

[0166]

[0167] Application Examples

[0168] Application Example 1 Retinol Control Dispersion

[0169] (1) Weigh 2.0 g of Tween 80 and dissolve it in 95.0 g of saline to obtain a Tween 80-saline solution. Then weigh 3.0 g of retinol. During the dispersion process using a shear homogenizer, add 3.0 g of retinol dropwise to the Tween 80-saline solution. After complete addition, homogenize for 20 minutes to obtain a retinol control dispersion. This will be used for subsequent evaluation.

[0170] Application Example 2 Retinol Compound Freeze-Dried Effective Core Ball Essence-I

[0171] (1) Take 500 mg of the functional core ball sample B4 from Example 4 and place it in a vial;

[0172] (2) Prepare a quantity of 0.9% saline solution and add 10 mL of saline solution to the vial using a pipette;

[0173] (3) Pour 10 mL of normal saline into the functional core ball vial and shake gently to dissolve evenly to obtain the retinol compound freeze-dried functional core ball essence-I.

[0174] Application Example 3 Retinol Compound Freeze-dried Effective Core Ball Essence-Ⅱ

[0175] (1) Take 500 mg of the functional core ball sample B8 from Example 8 and place it in a vial;

[0176] (2) Prepare a quantity of 0.9% saline solution and add 10 mL of saline solution to the vial using a pipette;

[0177] (3) Pour 10 mL of normal saline into the functional core ball vial and shake gently to dissolve evenly to obtain the retinol compound freeze-dried functional core ball essence-II.

[0178] Application Example 4 Retinol Compound Freeze-dried Efficacy Core Ball Steady-state Delivery System Essence-Ⅲ

[0179] (1) Take 500 mg of the functional core ball sample B9 from Example 9 and place it in a vial;

[0180] (2) Prepare a quantity of 0.9% saline solution and add 10 mL of saline solution to the vial using a pipette;

[0181] (3) Pour 10 mL of normal saline into the functional core ball vial and shake gently to dissolve evenly to obtain the retinol compound freeze-dried functional core ball essence-III.

[0182] The above description is only a preferred specific embodiment of the present invention, but the scope of protection of the present invention is not limited thereto. Any technician familiar with the technical field, within the technical scope disclosed by the present invention, who makes equivalent replacements or changes based on the technical solution and inventive concept of the present invention, should be covered by the scope of protection of the present invention.

Claims

1. Retinol composite freeze-dried efficacy core ball steady-state delivery system, characterized by: include: Retinol, skin care oil, large molecule protein active ingredients, emulsifier, oil-soluble small molecule antioxidant active ingredients.

2. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 1, characterized in that: The skin care oil is selected from the group consisting of caprylic capric triglyceride GTCC, squalane, squalene, sunflower seed oil, jojoba oil, shea butter, rapeseed oil and combinations thereof.

3. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 1, characterized in that: The macromolecular protein active ingredient is selected from natural macromolecular protein or fermented macromolecular protein active ingredient.

4. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 3, characterized in that: The natural macromolecular protein active ingredients include collagen, hydrolyzed collagen, casein, whey protein, fibroin, and sericin; the fermented macromolecular protein active ingredients include recombinant collagen, recombinant type III collagen, recombinant fibronectin, and yeast protein.

5. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 1, characterized in that: The emulsifier is selected from one or more of Tween 80, Span 80, Beheneth-25, PEG-7 glyceryl cocoate, vitamin E polyethylene glycol succinate, oleth-20, fatty alcohol polyoxyethylene ether, and rhamnolipid active ingredients; the oil-soluble small molecule antioxidant active ingredients include one or more of vitamin E, coenzyme Q10, ascorbyl palmitate, resveratrol, phloretin, and lutein active ingredients.

6. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 1, characterized in that: The weight ratio of retinol, skin care oil, emulsifier, oil-soluble small molecule antioxidant active ingredient and large molecule protein active ingredient is 1:0.1-100:0.01-10:0.1-50:0.01-10.

7. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 1, characterized in that: It also includes other water-soluble macromolecular active substances and / or other water-soluble small molecule active substances.

8. The retinol composite freeze-dried functional core ball steady-state delivery system according to claim 1, characterized in that: The particle size range of the steady-state delivery system is 0.1-15 mm.

9. The processing technology of the retinol composite freeze-dried functional core ball steady-state delivery system according to claim 7, characterized in that: The steps include: A. Weigh retinol and an oil-soluble small molecule antioxidant active ingredient separately, and disperse and dissolve them in skin care oil to obtain an oil phase solution; B. Weigh the macromolecular protein and emulsifier separately, and disperse and dissolve them in deionized water to obtain aqueous phase I; C. During homogenization or mechanical stirring, the retinol oil phase solution is added to the aqueous phase I and homogenized to obtain a retinol microemulsion; D. dissolving other macromolecular active substances and / or small molecular active substances in deionized water to obtain aqueous phase II; E. Mixing the retinol microemulsion with the aqueous phase II and stirring evenly to obtain the target dispersion; F. Add the target dispersion dropwise into the insulated liquid nitrogen bucket; G. Transfer the small ice balls formed by freezing with liquid nitrogen to a freeze dryer and freeze-dry to obtain a retinol composite freeze-dried efficacy core ball steady-state delivery system.

Images