Azelaic acid micro-nanocrystal suspension targeting acne and application thereof

Abstract

The present application relates to the field of cosmetic technology, in particular to a kind of azelaic acid micro-nano crystal suspension for targeting acne and its application. The scheme adopts the method of high pressure homogenization to prepare azelaic acid micro-nano crystal suspension, and the average particle size of azelaic acid micro-nano crystal is 0.45-3 μm. The specific preparation method is as follows: the stabilizer is stirred and dissolved into distilled water, azelaic acid is added, uniformly dispersed, high-speed shearing is formed into a coarse suspension, high pressure homogenization is carried out, and azelaic acid micro-nano crystal suspension is obtained. The present application selects nanocrystal preparation technology, realizes that active ingredients target to reach the inflammatory site of hair follicle acne, and reduces the irritation to the surrounding normal skin. On this basis, it is matched with physical penetration technology, realizes that active ingredients are deeply delivered from hair follicle opening to hair follicle interior to achieve the goal of acne-removing effect, realizes that acne-removing active ingredients efficiently and safely play a role, and the actual application effect is excellent.

Description

TECHNICAL FIELD

[0001] The present application relates to the cosmetic technology field, and in particular to a azelaic acid micro-nano crystal suspension for targeted acne removal and application thereof. BACKGROUND

[0002] Acne is a chronic inflammatory skin disease of hair follicles and sebaceous glands, also known as acne, acne, and dark spots. The clinical symptoms are whitehead, blackhead, inflammatory papules, pustules, and nodules. The four recognized acne pathogenic factors are excessive sebum secretion, excessive keratinization of hair follicles, inflammatory reaction, and propionibacterium acnes.

[0003] At present, the common acid acne-removing products on the market mainly use acid such as salicylic acid and fruit acid. Although azelaic acid has good acne-removing effect and low side effects, its physicochemical properties make it relatively difficult to produce acne-removing preparations, so there are few azelaic acid acne-removing products on the market, and all of them are ordinary preparations, which cannot achieve targeted acne removal and have great irritation to the surrounding normal skin.

[0004] Therefore, based on the above situation, the present application discloses a azelaic acid micro-nano crystal suspension for targeted acne removal and application thereof, which realizes the targeted delivery of active ingredients to the acne inflammatory site of hair follicles, reduces the irritation to the surrounding normal skin, and makes the acne-removing active ingredients work efficiently and safely. SUMMARY

[0005] The present application aims to provide a azelaic acid micro-nano crystal suspension for targeted acne removal and a freeze-dried powder prepared therefrom, to solve the problems in the background art.

[0006] Therefore, in order to solve the above technical problems, the present application provides the following technical scheme:

[0007] A azelaic acid micro-nano crystal suspension for targeted acne removal is prepared by high-pressure homogenization method, and the average particle size of the azelaic acid micro-nano crystal is 0.45-3 μm.

[0008] In a preferred embodiment, the average particle size of the azelaic acid micro-nano crystal is 0.5 μm.

[0009] In a preferred embodiment, the preparation method is as follows: the stabilizer is dissolved in distilled water by stirring, azelaic acid is added and uniformly dispersed, high-speed shearing is performed to form a coarse suspension, and high-pressure homogenization is performed to obtain the azelaic acid micro-nano crystal suspension.

[0010] The present application uses high-pressure homogenization method (HPH) to prepare azelaic acid micro-nano crystal suspension to obtain particles with uniform particle size and good stability. According to the existing literature and data research, the relationship between particle size and targeting is as follows:

[0011] ①Particles larger than 10 μm do not enter either the follicle or the stratum corneum.

[0012] ②Particles between 3 and 10 μm target the follicle and accumulate in the follicle duct.

[0013] ③Particles smaller than 3 μm partially enter the stratum corneum as well as accumulating in the follicle duct.

[0014] ④Particles as small as 0.45 μm are uniformly distributed in the follicle and the stratum corneum, having lost their follicle targeting.

[0015] To ensure that the active ingredient reaches the target site, which is the clogged acne follicle, the active ingredient, azelaic acid, is made to enter the stratum corneum at the clogged follicle site, so as to use its keratolytic property to unblock the pores. Therefore, the average particle size of the azelaic acid micro-nanocrystals is designed to be 0.45-3 μm, so as to ensure that the active ingredient, azelaic acid, targets the acne inflammatory site in the follicle, and the acne-removing effect is more excellent.

[0016] In a more preferred embodiment, the mass concentration of the drug in the azelaic acid micro-nanocrystal suspension is 0.2-5%. In a more preferred embodiment, the mass concentration of the drug is 5%.

[0017] In a more preferred embodiment, the high-pressure homogenization parameters are: the pressure is 800-1500 bar, and the homogenization time is 5-25 min.

[0018] In a more preferred embodiment, the high-speed dispersion parameters are: the stirring speed is 20,000-25,000 rpm, and the stirring time is 9-18 min.

[0019] In a more preferred embodiment, the stabilizer is any one or a combination of Tween 80, PVP-K30 (polyvinylpyrrolidone), HA (hyaluronic acid), and YJ (sodium lauroyl methyl amino acid).

[0020] In a more preferred embodiment, the mass concentration of the stabilizer is 0.1-1%.

[0021] In a more preferred embodiment, a lyophilized powder prepared from the azelaic acid micro-nanocrystal suspension according to any one of the above embodiments.

[0022] In a more preferred embodiment, the lyophilization step is: uniformly mixing the azelaic acid micro-nanocrystal suspension with a lyophilization protective agent, pre-freezing at -80°C for 24-36 h, film-sealing and punching, and lyophilizing in a lyophilizer for 48-72 h.

[0023] In a more preferred embodiment, the lyophilization protective agent is any one or a combination of trehalose, mannitol, and glucose.

[0024] The optimized scheme is that the freeze-dried powder is mixed with an active solution to obtain the acne-removing composition; the active solution contains the following components: 0.05-1wt% of sodium hyaluronate, 0.25-1wt% of glycyrrhizin, 0-2wt% of baicalin, 2-2.5wt% of slow-release salicylic acid, 0-3wt% of extract of green flower Ennan tomato bark, and 0.1-0.15wt% of arginine, with the balance being water. The ratio of the freeze-dried powder to the active solution is 0.2g:0.5mL.

[0025] The freeze-dried powder is mixed with an active solution to obtain the acne-removing composition, wherein sodium hyaluronate (HA-Na) is a natural polysaccharide and widely exists in nature. Sodium hyaluronate can help the skin absorb water from the body and the skin surface layer, and can also enhance the long-term water retention capacity of the skin, so that the skin looks full, plump, and elastic. When used in cosmetics, it can play a unique role in protecting the skin, keeping the skin smooth, delicate, tender, and elastic, and has the effects of preventing and resisting wrinkles, beautifying and health care, and restoring the physiological function of the skin. Therefore, the addition amount of sodium hyaluronate is limited to 0.05-1wt%.

[0026] The dipotassium glycyrrhizinate in glycyrrhizin can penetrate into the skin and maintain high activity, whiten, and efficiently antioxidant. It can effectively inhibit the activity of various enzymes in the melanin production process, especially the activity of tyrosine enzyme; at the same time, it can also prevent the skin from becoming rough. Dipotassium glycyrrhizinate has the effects of anti-inflammatory and anti-allergic, and has no irritation, toxicity, and side effects to the skin, and is effective with a small amount. It has wide compatibility in cosmetics and can be used for skin inflammation, dry skin, itching, anti-allergy, and sebum regulation, so the addition amount of glycyrrhizin is limited to 0.25-1wt%.

[0027] Baicalin can be used for medicine and cosmetics, and is a good functional cosmetic raw material. Baicalin extract has an inhibitory effect on Propionibacterium acnes (gram-positive bacteria). It is often added to whitening cosmetics, acne treatment products, anti-allergy products, and sunscreen products in a certain proportion, and in combination with its free radical scavenging effect, the extract shows the effects of increasing skin metabolism, increasing skin elasticity, and anti-wrinkle, and can be used for anti-aging cosmetics. In addition, baicalin extract can also be used as an anti-inflammatory agent, a sebum secretion inhibitor, and a moisturizing agent. The addition amount of baicalin is limited to 0-2wt%.

[0028] Salicylic acid has the effects of sterilization, anti-inflammation, preventing pores from being blocked, etc. Salicylic acid is an important ingredient in many skin care products. As a keratolytic drug, salicylic acid can remove the accumulated and old keratin on the skin surface, inhibit the secretion of skin oil, prevent pores from being blocked, shrink pores, tighten skin, and has the effects of sterilization and anti-inflammation. The amount of salicylic acid is limited to 2-2.5 wt%; green flower ennan tomato bark extract can effectively control oil, reduce the intercellular space, improve the skin texture, significantly shrink pores, make the skin tight and smooth, and rich in luster. In the field of personal care, it is often used as a skin conditioner, and the amount of green flower ennan tomato bark extract is limited to 0-3 wt%. Arginine is used as a pH regulator to adjust the pH of the system to about 7.0.

[0029] Compared with the prior art, the beneficial effects achieved by the present application are:

[0030] The present application selects corresponding effective active ingredients to synergistically combat acne symptoms based on the deep research on the physiological characteristics of acne skin, uses nanocrystal preparation technology to realize the target of active ingredients reaching the inflammatory site of the hair follicle acne, and reduces the irritation to the surrounding normal skin. On this basis, the physical penetration technology is matched to realize the goal of delivering the active ingredients from the hair follicle opening to the inside of the hair follicle to play the role of acne removal, and the active ingredients of acne removal can efficiently and safely play the role, and the practical application effect is excellent. BRIEF DESCRIPTION OF DRAWINGS

[0031] The accompanying drawings are included to provide a further understanding of the application, and constitute a part of the specification, which together with the embodiments of the application, is used to explain the application, and does not constitute a limitation to the application. In the drawings:

[0032] Figure 1 is a schematic diagram of the particle size comparison of the azelaic acid micro-nanocrystal suspension prepared by the experimental groups 1-3 of the present application.

[0033] Figure 2 is a schematic diagram of the particle size comparison before freeze-drying and after freeze-drying and re-dissolving of the experimental groups 1-3 of the present application.

[0034] Figure 3 is a schematic diagram of the freeze-dried powder and the re-dissolved solution prepared by the experimental groups 1-3 of the present application (the left figure is the freeze-dried powder, and the right figure is the re-dissolved solution).

[0035] Figure 4 is a schematic diagram of the follicle targeting value of each group in the detection experiment 1 of the present application.

[0036] Figure 5 is a schematic diagram of the azelaic acid concentration of each group in the detection experiment 2 of the present application.

[0037] Figure 6is a clinical indication change chart of sample 1 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0038] Figure 7 is an epidermis change chart of sample 1 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0039] Figure 8 is a dermis change chart of sample 1 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0040] Figure 9 is a porphyrin value change chart of sample 1 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0041] Figure 10 is a clinical indication change chart of sample 6 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0042] Figure 11 is an epidermis change chart of sample 6 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0043] Figure 12 is a dermis change chart of sample 6 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0044] Figure 13 is a porphyrin value change chart of sample 6 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0045] Figure 14 is a clinical indication change chart of sample 9 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0046] Figure 15 is an epidermis change chart of sample 9 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0047] Figure 16 is a dermis change chart of sample 9 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing).

[0048] Figure 17 is a porphyrin value change chart of sample 9 in the detection experiment 3 of the present application (the left chart is before testing, and the right chart is after testing). DETAILED DESCRIPTION

[0049] With reference to the accompanying drawings, the technical solutions in the embodiments of the present application will be clearly and completely described in the present application. Obviously, the described embodiments are only part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those of ordinary skill in the art without creative work fall within the scope of the present application.

[0050] The product purchase channel is: azelaic acid, provided by Belilie Company, model is Brillian-MB220;

[0051] Tween-80, provided by Guangdong Runhua Chemical Co., Ltd.;

[0052] Trehalose, provided by Kosher International Trade (Guangzhou) Co., Ltd., model is TREHALOSE 100;

[0053] Arginine, provided by Guangzhou Qisheng Company, model is L-Arginine;

[0054] Sustained-release salicylic acid, provided by Belilie Company, model is Brillian-QD83;

[0055] Glycyrrhizin, provided by Elion Biological Technology Co., Ltd., model is: Elion-G941;

[0056] Baicalin, provided by Belilie Company, model is Brillian-SBG755;

[0057] Green flower ennan tomato extract, provided by Aoyuan Company, model is EVERMAT TM ;

[0058] Hydrolyzed sodium hyaluronate (6060 Da), provided by Shandong Zhongshan Biological Technology Co., Ltd., model is HHA01210201_06.

[0059] (1) Example 1:

[0060] A kind of azelaic acid micro-nano crystal suspension targeting acne, the specific preparation method is: dissolving stabilizer into distilled water by stirring, adding azelaic acid, uniformly dispersing, high-speed shearing to form coarse suspension, high-pressure homogenization, to obtain azelaic acid micro-nano crystal suspension. The average particle size of azelaic acid micro-nano crystal is 0.45-3 μm.

[0061] The azelaic acid micro-nanocrystal suspension has a drug mass concentration of 0.2-5%. The high-pressure homogenization parameters are: pressure of 800-1500 bar, and homogenization time of 5-25 min. The high-speed dispersion parameters are: stirring speed of 20000-25000 rpm, and stirring time of 9-18 min. The stabilizer is any one or a plurality of combinations of Tween 80, PVP-K30, HA and YJ. The stabilizer has a mass concentration of 0.1-1%.

[0062] According to the method disclosed in Embodiment 1 above, adjusting each experimental parameter, the experimental groups described in Table 1 below are obtained; and the particle size comparison diagram of experimental groups 1-3 is shown in Figure 1

[0063] Table 1

[0064]

[0065]

[0066] (2) Embodiment 2:

[0067] A lyophilized powder prepared by using azelaic acid micro-nanocrystal suspension, the lyophilization step is: mixing 20 mL of azelaic acid micro-nanocrystal suspension with 5% of pharmaceutical trehalose, pre-freezing at -80℃ for 36 h, film sealing and punching, and lyophilizing in a freeze dryer for 72 h to obtain the lyophilized powder.

[0068] The azelaic acid micro-nanocrystal suspension prepared in experimental groups 1-3 is lyophilized according to the lyophilization method described above, and then the lyophilized powder and distilled water are mixed to reconstitute the reconstituted solution; the particle size comparison of the azelaic acid micro-nanocrystal before lyophilization and after reconstitution is observed, which can be seen in Figure 2 . At the same time, the product schematic diagram of the lyophilized powder and the reconstituted solution can be seen in Figure 3 .

[0069] After comparison, it is found that the particle size of the product before and after lyophilization and reconstitution has no significant change, and the stability is good.

[0070] (3) Embodiment 3:

[0071] The lyophilized powder experimental group: 0.2 g of lyophilized powder and 0.5 mL of active solution are mixed uniformly to obtain an acne-removing composition; the active solution specifically comprises: 0.2 wt% of sodium hyaluronate, 1 wt% of glycyrrhizin, 1 wt% of baicalin, 2.5 wt% of sustained-release salicylic acid, 3 wt% of green flower ennan tomato bark extract, and 0.15 wt% of arginine, and the balance is water.

[0072] Detection experiment:

[0073] ​Detection Experiment 1: To investigate the targeting ability of nanocrystals with different particle sizes to hair follicles, an in vitro experiment was conducted using a rabbit ear skin model. 5% azelaic acid coarse suspension (coarse suspension obtained according to the parameters of Experiment Group 1), 200 nm lyophilized redissolution solution (Experiment Group 4 lyophilized powder redissolution), 500 nm lyophilized redissolution solution (Experiment Group 3 lyophilized powder redissolution), 1000 nm lyophilized redissolution solution (Experiment Group 2 lyophilized powder redissolution), and 1500 nm lyophilized redissolution solution (Experiment Group 1 lyophilized powder redissolution) were used for in vitro release experiments. The skin model was placed in a Franz diffusion cell, and after 1 h of operation at 37°C and 400 rpm, hair follicles were extracted.

[0074] The tape was peeled off to obtain the stratum corneum sample and the hair follicle sample. A specific amount of ethanol solvent was added for ultrasonic extraction of azelaic acid. The azelaic acid in the sample was derivatized, and then gas chromatography was used for quantitative detection of the sample concentration, with the average value ± SD. The ratio of the concentration of azelaic acid in the hair follicle sample to the concentration of azelaic acid in the stratum corneum was calculated as the hair follicle targeting value to evaluate the hair follicle targeting effect of the preparation. The larger the hair follicle targeting value, the better the hair follicle targeting effect and the higher the safety of the drug.

[0075] The sample site azelaic acid concentration detection results are shown in Table 2; the hair follicle targeting value is shown in Figure 4

[0076] Table 2

[0077]

[0078] Conclusion: From Table 2 and Figure 4 it can be seen that compared with the coarse suspension group, azelaic acid nanocrystals with a particle size of 500 nm can significantly increase the concentration of the drug in the hair follicle, and each micro-nano crystal group can reduce the concentration of azelaic acid in the stratum corneum, i.e., reduce skin irritation, and the hair follicle targeting value is significantly increased, i.e., hair follicle targeting is achieved.

[0079] Detection Experiment 2: A number of New Zealand rabbits were taken, and 300 μL of 500 nm micro-nano crystal lyophilized redissolution solution (Experiment Group 3 lyophilized powder redissolution) was applied to the stratum corneum of the donor pool skin at 37°C in water, and the skin was kept in the open state for 45 min. After normal transdermal penetration for 45 min, the skin surface sample solution was sucked out of the diffusion cell, and the test solution was added when using the probe to avoid physical operation on the dry skin. The ultrasonic probe (intensity 1.15 w / cm 2 ​), and a radio frequency probe (intensity of 5 bars, device model DHL01-2) was placed on the surface of the skin for 15 min. The stratum corneum and hair follicle samples were obtained by peeling off the tape. A specific amount of ethanol solvent was used for the ultrasonic extraction of azelaic acid. The azelaic acid in the sample was derivatized, and then the sample concentration was quantitatively detected by gas chromatography.

[0080] Conclusion: The specific test results are shown in Table 1. Figure 5 Compared with the preparation group, the two groups using physical penetration operations had increased azelaic acid concentrations in the stratum corneum. At the same time, ultrasonic operation made the targeting ability of azelaic acid the strongest, increasing the targeted delivery of azelaic acid to the hair follicle.

[0081] Test Experiment 3: Healthy volunteers aged 18-45 years old were selected, who had mild or moderate facial length errors and no other skin diseases. On the test day, the subjects did not use any cosmetics on the test site, and after cleaning the face with water, they sat quietly in a constant temperature and humidity environment (temperature 20-22℃, relative humidity 40-60% RH) for at least 30 min. During the test period, the subjects could not drink water and beverages, the test site was exposed, and they were kept relaxed and avoided touching the test site. The test area was measured 3 times using a skin oil test probe, and the test area was measured 3 times using a moisture loss test probe, and the initial data was collected by taking a picture with a skin detector. The subjects used the test product according to the product usage requirements, and during the test period, they could not use cosmetics similar in function to the test sample. The subjects were retested for skin data collection 4 weeks after using the product.

[0082] The sample was a freeze-dried powder during the test, which was then applied to the acne site and then treated with an ultrasonic probe for 15 min (intensity of 1.15 w / cm 2 ). Each subject was tested on multiple sites.

[0083] The specific test results are shown in Table 3.

[0084]

[0085]

[0086] Conclusion: The changes in clinical indications, epidermis, dermis, and porphyrin values of each sample are shown in Table 4. After 28 days of preparation and ultrasonic treatment, the acne or acne mark conditions of 10 skin samples were improved to some extent, of which 8 samples were "strongly improved", and 2 samples were "weakly improved". (The improvement of clinical indications is judged as "strongly improved", and the improvement of other auxiliary indicators alone is judged as "weakly improved".) Figures 6 to 17

[0087] ​It is to be noted that, in the present text, relational terms such as first and second and the like can be used solely to distinguish one entity or action from another entity or action without necessarily requiring or implying any actual such relationship or order between such entities or actions. Moreover, the terms "comprises", "comprising", or any other variations thereof, are intended to cover a non-exclusive inclusion such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but can include other elements not expressly listed or inherent to such process, method, article, or apparatus.

[0088] Finally, it should be noted that the above-mentioned only constitutes the preferred embodiments of the present application and is not intended to limit the present application. Although the present application has been described in detail with reference to the foregoing embodiments, it will be apparent to those skilled in the art that modifications, equivalent replacements, and improvements of the technical solutions described in the foregoing embodiments can be made. Any modifications, equivalent replacements, and improvements made within the spirit and principle of the present application shall fall within the scope of the present application.

Claims

1. An application of a freeze-dried powder, characterized in that: The freeze-dried powder is used to prepare an anti-acne composition, which is prepared by the following process: mixing the freeze-dried powder with an active solution to obtain an anti-acne composition; The active solution specifically comprises: sodium hyaluronate 0.05-1wt%, glycyrrhizin 0.25-1wt%, baicalin 0-2wt%, sustained-release salicylic acid 2-2.5wt%, Enanthophyllum nobilis bark extract 0-3wt%, arginine 0.1-0.15wt%, and the balance is water; The freeze-dried powder is prepared from azelaic acid micro-nanocrystalline suspension; the azelaic acid micro-nanocrystalline suspension is prepared by the following process: dissolving a stabilizer in distilled water with stirring, adding azelaic acid, dispersing uniformly, shearing at high speed to form a coarse suspension, and homogenizing under high pressure to obtain azelaic acid micro-nanocrystalline suspension; the average particle size of the azelaic acid micro-nanocrystalline is 0.45 to 3 μm; The parameters of the high-pressure homogenization are: pressure of 800-1500 bar, homogenization time of 5-25 min; The dispersion parameters are: stirring speed of 20000-25000 rpm, stirring time of 9-18 min; The stabilizer is a compound of Tween80 and PVP-K30.

2. The use of a freeze-dried powder according to claim 1, characterized in that: The average particle size of azelaic acid micro-nano crystals is 0.5 μm.

3. The use of a freeze-dried powder according to claim 1, characterized in that: In the azelaic acid micro-nano crystal suspension, the mass concentration of azelaic acid is 0.2-5%.

4. The use of a freeze-dried powder according to claim 3, characterized in that: The mass concentration of azelaic acid is 5%.

5. The use of a freeze-dried powder according to claim 1, characterized in that: The mass concentration of the stabilizer is 0.1-1%.

6. The use of a freeze-dried powder according to claim 1, characterized in that: The freeze-drying steps of the freeze-dried powder are as follows: mixing the azelaic acid micro-nano crystal suspension with a freeze-drying protective agent, pre-freezing at -80°C for 24 to 36 hours, sealing the membrane and puncturing holes, and freeze-drying in a freeze dryer for 48 to 72 hours.

7. The use of a freeze-dried powder according to claim 6, characterized in that: The freeze-drying protective agent is any one or more of trehalose, mannitol and glucose.

8. The use of a freeze-dried powder according to claim 1, characterized in that: The usage ratio of the lyophilized powder and active solution is 0.2 g:0.5 mL.

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