A high-content, high-stability hydroxypinazone retinate composition and its application

Abstract

This invention relates to a high-content, high-stability hydroxypinazone retinate composition, comprising retinyl palmitate, hydroxypinazone retinate, and diisopropyl adipate; the components are mixed, heated and stirred until homogeneous, and then cooled to obtain the final product. This invention successfully solves the problems of poor stability and low active ingredient content in hydroxypinazone retinate compositions, improving the bioavailability of hydroxypinazone retinate in the prepared microemulsions, and can be applied in the preparation of cosmetics.

Description

Technical Field

[0001] This invention belongs to the field of cosmetic technology, specifically relating to a high-content, high-stability hydroxypinazone retinate composition and its application. Background Technology

[0002] Retinol, also known as Vitamin A, is a widely recognized active ingredient in the cosmetics industry, known for its antioxidant, anti-wrinkle, whitening, and acne-fighting effects, making it popular among consumers. However, retinol is sensitive to light and heat and easily oxidizes to retinoic acid, which is significantly irritating and is listed as a prohibited ingredient in cosmetics. For the sake of formula stability, formulators generally use retinol derivatives or encapsulations.

[0003] The catalogue of retinol ingredients already in use (2021 edition) includes retinyl palmitate, retinyl propionate, retinyl acetate, retinyl retinate, retinyl linoleate, retinaldehyde, and hydroxypinazone retinate. Retinol derivatives generally need to be converted to retinoic acid before binding to retinoic acid receptors to exert their effects; therefore, retinyl esters are generally milder than retinol and retinoic acid. However, due to its unique structure, hydroxypinazone retinate can directly bind to retinoic acid receptors to exert its effects without conversion to retinoic acid. Therefore, using retinyl esters and hydroxypinazone retinate together can achieve a synergistic effect.

[0004] Hydroxypinazone retinate is a powder with a high melting point. It is typically dissolved in isosorbide dimethyl ether (IME) to prepare a 10% solution for sale or use. However, IME has a logP value of -0.95 (calculated by ChemDraw; Log P: the logarithm of the partition coefficient between an organic phase (e.g., octanol) and an aqueous phase (e.g., buffer solution) under neutral pH conditions where all molecules of a compound exist in a neutral state. Log P = Log([organic phase of compound] / [aqueous phase of compound])). This means that IME is highly hydrophilic and more easily remains in the aqueous phase. When formulators add hydroxypinazone retinate (dissolved in IME) to the formulation system, IME migrates into the aqueous phase, causing hydroxypinazone retinate to gradually precipitate until visible needle-like crystals appear. Therefore, hydroxypinazone retinate can often only be added in small amounts, and the formulation requires high suspension performance.

[0005] Furthermore, because hydroxypinazone retinate exists in a suspended state within the system, it is difficult for it to penetrate the stratum corneum and enter the epidermis and dermis, resulting in very low bioavailability. Therefore, raw material suppliers often use encapsulation technology to create corresponding encapsulated forms of hydroxypinazone retinate, commonly using equipment such as high-pressure homogenizers and microfluidic equipment.

[0006] A search using "hydroxypinazone retinate" as the search term (October 31, 2023) yielded 45 published records, including 14 authorized patents. Patent analysis revealed that most of the patent applications were composition patents.

[0007] The patent application number 202211112258.1, entitled "A Highly Stable Hydroxypinazone Retinyl Ester Composition and Its Application", mentions a composition of hydroxypinazone retinyl ester, squalane, and dimethylmethoxybenzodihydropyranol, which has good stability. The content of HPR in this composition does not decrease during storage, and the content of retinoic acid does not increase. This overcomes the problems of poor stability and excessive retinoic acid content in commercially available hydroxypinazone retinyl ester raw materials and related cosmetics or skin care products containing hydroxypinazone retinyl ester. However, the mass ratio of hydroxypinazone retinyl ester to squalane in the patent is 0.01:99.99 to 2:98, and the proportion of hydroxypinazone retinyl ester in the composition is less than 2%, which limits its application in cosmetics and makes it almost unusable for preparing encapsulations.

[0008] The patent application number 202210270727.6, entitled "High-oil permeation enhancer of hydroxypinazone retinyl ester, preparation method and application thereof", mentions a method for preparing an encapsulation, wherein the content of hydroxypinazone retinyl ester is 1.9-2.1%, which is relatively low. Patent application number 202110175444.9, entitled "A Multi-Effect Hydroxypinazone Retinyl Ester Nanocomposition and Its Preparation Method and Application," mentions a composition consisting of hydroxypinazone retinyl ester, nicotinamide, glycyrrhetinic acid, emulsifier, co-emulsifier, and polyol, wherein the proportion of hydroxypinazone retinyl ester is only 0.1-10%. Patent application number 202211560665.9, entitled "A Preparation Method and Application of a Hydroxypinazone Retinyl Ester Supramolecular Liposome Formulation," mentions a supramolecular liposome formulation containing 5-20% hydroxypinazone retinyl ester, 10-50% isosorbide dimethyl ether, and polysorbate-60. 20-60%, poloxamer 5-20%, sucrose laurate 5-15%, modified ceramide 2-14%; due to the large amount of isosorbide dimethyl ether in the formulation, hydroxypinazone retinate is prone to precipitation when the system encounters a large amount of water.

[0009] In summary, the content of hydroxypinazone retinyl ester in the current compositions is mostly very low and unstable, which limits its application in the cosmetics field. Summary of the Invention

[0010] To address the problems of low content and low stability of traditional hydroxypinazone retinate, this invention provides a high-content, high-stability hydroxypinazone retinate composition and its applications. This invention combines diisopropyl adipate, retinyl palmitate, and hydroxypinazone retinate to prepare a high-content, high-stability hydroxypinazone retinate composition, successfully solving the problems of poor stability (especially low-temperature stability) and low active ingredient content in hydroxypinazone retinate compositions.

[0011] The objective of this invention can be achieved through the following methods:

[0012] This invention provides a high-content, high-stability hydroxypinazone retinate composition, comprising the following components by mass fraction:

[0013] Retinyl palmitate 30-50%,

[0014] Hydroxypinazone retinyl ester 10-25%,

[0015] Diisopropyl adipic acid 30-50%.

[0016] In one embodiment of the present invention, the hydroxypinazone retinate has a mass fraction of 10-20%.

[0017] The present invention provides a method for preparing the hydroxypinazone retinate composition, comprising the following steps: mixing retinyl palmitate, hydroxypinazone retinate, and diisopropyl adipate, heating and stirring until uniform, and cooling to obtain the hydroxypinazone retinate composition.

[0018] In one embodiment of the present invention, the heating temperature is 60-80°C.

[0019] The present invention also provides the application of a hydroxypinazone retinyl ester composition in the preparation of cosmetics.

[0020] As one embodiment of the present invention, the application is as follows: using a hydroxypinazone retinate composition as the oil phase, a microemulsion is prepared by a low-temperature emulsification process.

[0021] Compared with the prior art, the present invention has the following beneficial effects:

[0022] (1) A composition of diisopropyl adipate, retinyl palmitate and hydroxypinazone retinate was constructed, which successfully solved the problems of poor stability and low content of active ingredients in the hydroxypinazone retinate composition;

[0023] (2) The microemulsion prepared by the composition effectively solves the problem of low bioavailability of hydroxypinazone retinate. Attached Figure Description

[0024] Other features, objects, and advantages of the present invention will become more apparent from the following detailed description of non-limiting embodiments with reference to the accompanying drawings:

[0025] Figure 1 This is a particle size distribution diagram for Example 2. Detailed Implementation

[0026] The present invention will now be described in detail with reference to the accompanying drawings and specific embodiments. The following examples are implemented under the premise of the technical solution of the present invention, providing detailed implementation methods and specific operating procedures, which will help those skilled in the art to further understand the present invention. It should be noted that the scope of protection of the present invention is not limited to the following embodiments; any adjustments and improvements made under the concept of the present invention are all within the scope of protection of the present invention.

[0027] Example 1

[0028] Weigh 7g of retinyl palmitate, 2g of hydroxypinazone retinate (13.3%), and 6g of diisopropyl adipate into a 100g beaker, heat and stir at 65°C until homogeneous; then cool to room temperature and stand at 3°C ​​for 36h without precipitation.

[0029] Example 2

[0030] Weigh 7g of retinyl palmitate, 3g of hydroxypinazone retinate (18.7%), and 6g of diisopropyl adipate into a 100g beaker, heat and stir at 65°C until homogeneous; then cool to room temperature and stand at 3°C ​​for 36 hours without precipitation.

[0031] Example 3

[0032] 7g of retinyl palmitate, 4g of hydroxypinazone retinate (23.5%), and 6g of diisopropyl adipate were weighed into a 100g beaker and heated and stirred at 65°C until homogeneous. After cooling to room temperature, 0.81g of solid precipitated out after standing at 3°C ​​for 36 hours. The precipitated solid was identified by analysis as hydroxypinazone retinate.

[0033] Example 4

[0034] Weigh 5g of retinyl palmitate, 3g of hydroxypinazone retinate (21.4%), and 6g of diisopropyl adipate into a 100g beaker. Heat and stir at 65°C until homogeneous, then cool to room temperature. After standing at 3°C ​​for 36 hours, 0.63g of solid precipitates out. The precipitated solid is hydroxypinazone retinate.

[0035] Example 5

[0036] Weigh 9g of retinyl palmitate, 3g of hydroxypinazone retinate (16.7%), and 6g of diisopropyl adipate into a 100g beaker, heat and stir at 65°C until homogeneous, then cool to room temperature and stand at 3°C ​​for 36 hours without precipitation.

[0037] Example 6

[0038] Weigh 7g of retinyl palmitate, 3g of hydroxypinazone retinate (21.4%), and 4g of diisopropyl adipate into a 100g beaker. Heat and stir at 65°C until homogeneous, then cool to room temperature. After standing at 3°C ​​for 36 hours, 0.75g of solid precipitates out. The precipitated solid is hydroxypinazone retinate.

[0039] Example 7

[0040] Weigh 7g of retinyl palmitate, 3g of hydroxypinazone retinate (16.7%), and 8g of diisopropyl adipate into a 100g beaker, heat and stir at 65°C until homogeneous, then cool to room temperature and stand at 3°C ​​for 36 hours without precipitation.

[0041] Application Example 1

[0042] Referring to the low-temperature emulsification production process of the patent "A Microemulsion and its Preparation Method" (application number 202211695584.X), a microemulsion was prepared from the composition of Example 2, as detailed below:

[0043] The microemulsion was prepared entirely at 65°C: 7g of retinyl palmitate, 3g of hydroxypinazone retinate, and 6g of diisopropyl adipate were weighed into a 100g beaker and heated and stirred at 65°C until homogeneous, designated as the oil phase; 20g of PPG-13-decyltetradecyl alcohol polyether-24 and 20g of glycerol were weighed into a 150mL beaker and heated and stirred until homogeneous, designated as the alcohol phase; 44g of water was weighed into a 100mL beaker and heated and stirred until homogeneous, designated as the aqueous phase; the oil phase was then added to the alcohol phase in batches and heated and stirred until homogeneous at 65°C; finally, the aqueous phase was added to the oil-alcohol mixture in batches, stirred until homogeneous, and cooled to room temperature to obtain the retinyl palmitate microemulsion containing hydroxypinazone retinate. The microemulsion was then diluted with water to prepare a 1% solution, and its stability at 3°C ​​was observed. The particle size was determined using a Bettersize 3000 particle size analyzer, and the transdermal absorption efficiency was determined using the Franz diffusion cell method.

[0044] The particle size distribution of Application Example 1 is as follows Figure 1 As shown in Table 1, the transdermal absorption results are as follows.

[0045] Table 1. Transdermal absorption results in Application Example 1

[0046] project Example 2 24-hour penetration rate, % 0.085 24-hour intradermal retention rate, % 2.648 24-hour skin residue rate, % 50.32

[0047] By analyzing the appendix Figure 1 Table 1 shows that the retinyl palmitate microemulsion containing hydroxypinazone retinate prepared using Example 1 is clear and transparent in appearance, and no precipitation occurred in the diluted solution after storage at 3°C ​​for 36 hours. In addition, particle size analysis results show that the microemulsion has a relatively uniform particle size, with an average particle size of less than 200 nm. Transdermal absorption results show that the microemulsion prepared using Example 1 can achieve a transdermal rate of 0.085% and an intradermal retention rate of 2.648%. Since the intradermal retention rate needs to be measured by crushing pig skin to extract hydroxypinazone retinate, the actual intradermal retention rate should be higher than 2.648%.

[0048] Comparative Example 1

[0049] Weigh 7g of retinyl palmitate, 3g of hydroxypinazone retinate, and 6g of ethylhexylglycerin into a 100g beaker, heat and stir at 65°C until homogeneous; then cool to room temperature, and let stand at 3°C ​​for 36 hours to precipitate 1.05g of solid, which is hydroxypinazone retinate; compared with Example 2, it can be seen that diisopropyl adipate is more suitable for dissolving hydroxypinazone retinate than ethylhexylglycerin; therefore, diisopropyl adipate in the composition is necessary to help dissolve hydroxypinazone retinate.

[0050] Application Example 2

[0051] Referring to the low-temperature emulsification production process of the patent "A Microemulsion and its Preparation Method" (application number 202211695584.X), a microemulsion was prepared from the composition of Comparative Example 1, as detailed below:

[0052] The microemulsion was prepared entirely at 65°C: 7g of retinyl palmitate, 3g of hydroxypinazone retinate, and 6g of ethylhexylglycerin were weighed into a 100g beaker and heated and stirred at 65°C until homogeneous, which was recorded as the oil phase; 20g of PPG-13-decyltetradecyl alcohol polyether-24 and 20g of glycerin were weighed into a 150mL beaker and heated and stirred until homogeneous, which was recorded as the alcohol phase; 44g of water were weighed into a 100mL beaker and heated and stirred until homogeneous, which was recorded as the aqueous phase; the oil phase was then added to the alcohol phase in batches and heated and stirred until homogeneous at 65°C; finally, the aqueous phase was added to the oil-alcohol mixture in batches, stirred until homogeneous, and cooled to room temperature to obtain the retinyl palmitate microemulsion containing hydroxypinazone retinate. The solution was then diluted with water to prepare a 1% microemulsion. The solution was clear and transparent, but a large number of needle-like crystals precipitated after being placed at 3°C ​​for 36 hours. This indicates that the prepared microemulsion is a metastable system and precipitation will occur after prolonged storage, making it unsuitable for use in the cosmetics field.

[0053] Comparative Example 2

[0054] Weigh 3g of hydroxypinazone retinate and 6g of diisopropyl adipate into a 100g beaker, heat and stir at 65°C until homogeneous; then cool to room temperature, and let stand at 3°C ​​for 36h to precipitate 1.96g of solid, which is hydroxypinazone retinate; compared with Example 2, it can be seen that retinyl palmitate is necessary in the composition, which helps to dissolve hydroxypinazone retinate.

[0055] Comparative Example 3

[0056] 3g of hydroxypinazone retinate and 13g of diisopropyl adipate were weighed into a 100g beaker and heated and stirred at 65°C until homogeneous. After cooling to room temperature, the mixture was allowed to stand at 3°C ​​for 36 hours, resulting in the precipitation of 0.94g of solid, which was hydroxypinazone retinate. Comparison with Example 2 and Comparative Example 2 shows that even if all retinyl palmitate in the composition is replaced with diisopropyl adipate, the system remains unstable. This indirectly indicates a synergistic effect between retinyl palmitate and diisopropyl adipate, which aids in the dissolution of hydroxypinazone retinate.

[0057] Comparative Example 4

[0058] 7g of camellia seed oil, 3g of hydroxypinazone retinate, and 6g of diisopropyl adipate were weighed into a 100g beaker and heated and stirred at 65°C until homogeneous. After cooling to room temperature, 2.35g of solid precipitated out after standing at 3°C ​​for 36 hours. The precipitated solid was hydroxypinazone retinate. Compared with Example 2, it can be seen that the system is also unstable after replacing retinyl palmitate in the composition with camellia seed oil.

[0059] Comparative Example 5

[0060] 7g of caprylic / capric triglyceride, 3g of hydroxypinazone retinate, and 6g of diisopropyl adipate were weighed into a 100g beaker and heated and stirred at 65°C until homogeneous. After cooling to room temperature, the mixture was allowed to stand at 3°C ​​for 36 hours, resulting in the precipitation of 2.05g of solid, which was hydroxypinazone retinate. Comparison with Example 2 shows that replacing retinyl palmitate with caprylic / capric triglyceride in the composition also resulted in instability. Based on Examples 2, 4, and 5, retinyl palmitate is essential to the composition. This may be because retinyl palmitate and hydroxypinazone retinate are both derivatives of retinol and have structural similarities. According to the principle of "like dissolves like," this facilitates the dissolution of hydroxypinazone retinate.

[0061] Comparative Example 6

[0062] Weigh 3g of caprylic / capric triglyceride and 3g of hydroxypinazone retinate into a 100g beaker, heat and stir at 65℃ until homogeneous; then cool to room temperature and let stand at 3℃ for 36h to precipitate 2.83g of solid, which is hydroxypinazone retinate.

[0063] Referring to the low-temperature emulsification production process of the patent "A Microemulsion and its Preparation Method" (application number 202211695584.X), the following experiments were repeated:

[0064] The microemulsion was prepared at 65°C throughout the process: 5g of PPG-13-decyltetradecyl alcohol polyether-24 and 10g of glycerol were weighed and added to a 150mL beaker. Mechanical stirring was started and the mixture was stirred at 300rpm for 10min until homogeneous. Then, 1.25g of caprylic / capric triglyceride and 1.25g of hydroxypinazone retinate were mixed evenly and added to the beaker in three batches. The mixture was stirred for 30min until homogeneous to obtain the microemulsion premix. The microemulsion premix was then added to 100g of water, and the resulting gel block was stirred evenly to obtain the microemulsion loaded with hydroxypinazone retinate. The microemulsion was clear and transparent and showed no precipitation after centrifugation at 9000rpm for 10min.

[0065] This microemulsion precipitated in large quantities after standing at 3°C ​​for 36 hours. The precipitated solid was hydroxypinazone retinate, which indicates that this system is metastable and will precipitate when placed at low temperature.

[0066] Comparative Example 7

[0067] Weigh 13g of retinyl palmitate and 3g of hydroxypinazone retinate into a 100g beaker, heat and stir at 65℃ until homogeneous; then cool to room temperature and let stand at 3℃ for 36h to precipitate 0.43g of solid, which is hydroxypinazone retinate.

[0068] Comparative Example 8

[0069] Weigh 7g of retinyl palmitate, 2g of hydroxypinazone retinate, and 6g of ethylhexylglycerin into a 100g beaker, heat and stir at 65°C until homogeneous; then cool to room temperature, and let stand at 3°C ​​for 36 hours to precipitate 0.13g of solid, which is hydroxypinazone retinate; compared with Example 2, it can be seen that diisopropyl adipate is more suitable for dissolving hydroxypinazone retinate than ethylhexylglycerin; therefore, diisopropyl adipate in the composition is necessary to help dissolve hydroxypinazone retinate.

[0070] The specific embodiments of the present invention have been described above. It should be understood that the present invention is not limited to the specific embodiments described above, and those skilled in the art can make various modifications or variations within the scope of the claims, which do not affect the essence of the present invention.

Claims

1. A hydroxypinazone retinyl ester composition, characterized in that, It consists of the following components by mass fraction: Retinyl palmitate 30-50%, Hydroxypinazone retinyl ester 10-20%, Diisopropyl adipic acid 30-50%.

2. A method for preparing the hydroxypinazone retinate composition as described in claim 1, characterized in that, The process includes the following steps: mixing retinyl palmitate, hydroxypinazone retinate, and diisopropyl adipate, heating and stirring until homogeneous, and then cooling to obtain the hydroxypinazone retinate composition.

3. The preparation method according to claim 2, characterized in that, The heating temperature is 60-80℃.

4. The use of the hydroxypinazone retinyl ester composition as described in claim 1 in the preparation of cosmetics.

5. The application according to claim 4, characterized in that, The application is as follows: using a hydroxypinazone retinate composition as the oil phase, a microemulsion is prepared by a low-temperature emulsification process.

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