A hydroxypinacolone retinoate composition and its use in skin care

Abstract

The present invention relates to a composition comprising sustained release particles of hydroxy pinnacyl retinoate in which the ratio of hydroxy pinnacyl retinoate : methyl methacrylate / ethylene glycol dimethacrylate crosspolymer : ascorbyl tetraisopalmitate or tocopherol is from 0.05 to 3 : 0.1 to 10 : 0.05 to 1 and the use thereof in skin care.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of skin care raw materials and formulations, in particular to a sustained-release particle composed of hydroxypinacoloneretinoate, methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer and ascorbyl tetraisopalmitate (or tocopherol), wherein hydroxypinacoloneretinoate is a raw material with the functions of acne removal and anti-aging, methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer is a sustained-release skeleton, and ascorbyl tetraisopalmitate (or tocopherol) is an antioxidant. The present application discloses a method for preparing sustained-release microspheres containing hydroxypinacoloneretinoate, methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer and ascorbyl tetraisopalmitate (or tocopherol), and the use of the sustained-release microspheres in skin care products for anti-wrinkle effect. BACKGROUND

[0002] Hydroxypinacoloneretinoate is a new retinol derivative that can directly bind to retinoic acid receptors (RARs) and has functions such as regulating epidermal metabolism, and shows effects such as anti-wrinkle, prevention and treatment of acne, and skin whitening and spot lightening in skin care products.

[0003] Hydroxypinacoloneretinoate is oil-soluble when applied in skin care products, and is not soluble in water. The commercially available product Granactive Retinoid is a solution of hydroxypinacoloneretinoate dissolved in dimethyl isosorbide (DMI), which is added to skin care products. However, long-term storage often causes photodegradation and oxidative degradation, resulting in a decrease in the content of hydroxypinacoloneretinoate, a decrease in the skin care effect, and quality problems such as discoloration of the product.

[0004] In addition, the technical data of Granactive Retinoid shows that hydroxypinacoloneretinoate at a concentration of 0.5% has good skin irritation in human patch tests. However, in actual use, some consumers still experience skin allergies, redness, itching and other symptoms at a concentration of 0.2% of hydroxypinacoloneretinoate. The analysis shows that this may be related to the use of dimethyl isosorbide (DMI), a solvent with penetration-enhancing effect, which increases the skin penetration rate of hydroxypinacoloneretinoate and causes adverse reactions.

[0005] Common antioxidants in skin care products include fat-soluble vitamins such as tocopherol and ascorbyl tetraisopalmitate. There is no report on an antioxidant composition composed of hydroxypinacoloneretinoate, tocopherol and ascorbyl tetraisopalmitate.

[0006] In order to improve the stability of hydroxyl pinacolyl retinoate in skin care products, ensure product quality, and reduce the incidence of adverse reactions, a new improved carrier containing hydroxyl pinacolyl retinoate is urgently needed for anti-wrinkle products in skin care products. SUMMARY

[0007] The present application provides a sustained-release composition containing hydroxyl pinacolyl retinoate, which is composed of hydroxyl pinacolyl retinoate, methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer, and ascorbic acid tetraisopalmitate or tocopherol, and the content ratio of hydroxyl pinacolyl retinoate:methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer:ascorbic acid tetraisopalmitate or tocopherol in the composition is 0.05-3:0.1-10:0.05-1.

[0008] Preferably, the content ratio of hydroxyl pinacolyl retinoate:methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer:ascorbic acid tetraisopalmitate or tocopherol in the composition is 1-3:2-10:0.05-0.5.

[0009] The present application further provides a preparation method of the sustained-release composition, characterized in that the method steps are as follows: dissolve hydroxyl pinacolyl retinoate and ascorbic acid tetraisopalmitate (or tocopherol) in an appropriate amount of volatile solvent such as acetonitrile or tetrahydrofuran, add to methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer, mix uniformly at high speed, remove the volatile solvent by low-temperature vacuum drying, add 1-3 times the volume of water for leaching, and then remove the residual solvent by low-temperature vacuum drying to obtain the sustained-release composition containing hydroxyl pinacolyl retinoate.

[0010] Preferably, the preparation method of the sustained-release composition is characterized in that the method steps are as follows: dissolve 1.5 g of hydroxyl pinacolyl retinoate and 0.1 g of ascorbic acid tetraisopalmitate in 10 ml of acetonitrile, add to 8.4 g of methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer, mix uniformly at high speed, remove the volatile solvent by low-temperature vacuum drying, add 10 ml of water for leaching, remove the residual solvent by low-temperature vacuum drying at 60°C, and obtain 10 g of sustained-release particles containing hydroxyl pinacolyl retinoate.

[0011] Preferably, the preparation method of the sustained-release composition is characterized in that the method steps are as follows: take an appropriate amount of 1.5 g of hydroxyl pinacolyl retinoate and 0.5 g of ascorbic acid tetraisopalmitate, dissolve in 8 ml of tetrahydrofuran, add 8 g of methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer with a pore size of 50 microns, mix uniformly at high speed, remove the tetrahydrofuran by vacuum drying at 55°C, add 20 ml of water for leaching, and then remove the residual solvent by vacuum drying at 45°C to obtain 10 g of sustained-release particles containing hydroxyl pinacolyl retinoate.

[0012] Another preferred, the preparation method of the sustained release composition of the present application, characterized in that, the method steps are as follows: take the right amount of hydroxyl pinakonretinol 1.5 g, tocopherol 0.5 g, dissolved in tetrahydrofuran 8 ml, add the pore size of 50 microns of methyl methacrylate / ethylene glycol dimethacrylate crosslinked polymer 8 g, high speed mixing uniform, 55 ℃ vacuum drying to remove tetrahydrofuran, after washing with 30 ml of water, 45 ℃ vacuum drying to remove residual solvent, namely the weight of the sustained release particles containing hydroxyl pinakonretinol is 10 g.

[0013] The present application further includes the use of the composition of the present application in anti-wrinkle skin care products.

[0014] The present application further includes a skin care product containing the sustained release composition of the present application, wherein the weight percentage of the sustained release composition in the skin care product is 0.1-3%.

[0015] The purpose of the present application is to solve the stability problem of hydroxyl pinakonretinol during long-term storage and reduce the incidence of adverse reactions during use in anti-wrinkle efficacy skin care products. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 The in vitro skin cumulative penetration curve of hydroxyl pinakonretinol in the control group and the sample group. DETAILED DESCRIPTION

[0017] The following will be described more specifically with reference to the examples. However, these examples are only for illustration of the present application, and the scope of the present application is not limited to these examples.

[0018] Example 1 Preparation method of sustained release particles containing hydroxyl pinakonretinol

[0019] Hydroxyl pinakonretinol (provided by the Institute of Applied Technology Research and Industrialization Center of Chinese Academy of Sciences, chromatographic purity 99.71%) 1.5 g, ascorbic acid tetraisopalmitate 0.1 g (trade name VC-IP, provided by MITSUBISHI CHEMICAL CORPORATION, chromatographic purity ≥ 99.5%) were dissolved in acetonitrile 8 ml, added to methyl methacrylate / ethylene glycol dimethacrylate crosslinked polymer 8.4 g (trade name Luxomatte MT128, provided by Shanghai Saifu Chemical Development Co., Ltd.), high speed mixing uniform, low temperature vacuum drying to remove volatile solvents, adding 20 ml of water washing, 60 ℃ low temperature vacuum drying for 4-10 hours to remove residual solvents, to obtain the weight of the sustained release particles containing hydroxyl pinakonretinol is 10 g, the residual amount of acetonitrile solvent is <0.001%, and the moisture content is <0.5%.

[0020] Example 2 Preparation of sustained release granules containing hydroxypinacolone retinoate

[0021] Hydroxypinacolone retinoate 4 g, ascorbyl tetraisopalmitate 1 g was dissolved in tetrahydrofuran 5 ml, added to methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer 5 g, mixed well at high speed, dried at low temperature under vacuum to remove volatile solvent, washed with water 10 ml, dried at low temperature under vacuum at 45 °C to remove residual solvent, to obtain sustained release granules containing hydroxypinacolone retinoate 10 g in weight, tetrahydrofuran solvent residue less than 0.001 %, water content <0.5 %.

[0022] Example 3 Preparation of sustained release granules containing hydroxypinacolone retinoate but without antioxidant ascorbyl tetraisopalmitate

[0023] Hydroxypinacolone retinoate 1.5 g was dissolved in tetrahydrofuran 2 ml, added to methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer 8.5 g, mixed well at high speed, dried at low temperature under vacuum to remove volatile solvent, washed with water 30 ml, dried at low temperature under vacuum at 45 °C to remove residual solvent, to obtain sustained release granules containing hydroxypinacolone retinoate 10 g in weight, tetrahydrofuran solvent residue less than 0.001 %, water content <0.5 %.

[0024] Example 4 Preparation of sustained release granules containing hydroxypinacolone retinoate but with antioxidant as tocopherol

[0025] Hydroxypinacolone retinoate 1.5 g, tocopherol 0.5 g was dissolved in tetrahydrofuran 5 ml, added to methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer 8 g, mixed well at high speed, dried at low temperature under vacuum to remove volatile solvent, washed with water 10 ml, dried at low temperature under vacuum at 45 °C to remove residual solvent, to obtain sustained release granules containing hydroxypinacolone retinoate 10 g in weight, tetrahydrofuran solvent residue less than 0.001 %, water content <0.5 %.

[0026] Example 5 Antioxidant stability experiment of sustained release granules containing hydroxypinacolone retinoate

[0027] Sustained release granules prepared according to Examples 1-4 were taken for comparison with commercially available sorbitan dimethyl ether (DMI) solution containing 10 % hydroxypinacolone retinoate to investigate their antioxidant properties.

[0028] Test method: 1.5 ml of 10% hydroxypinacolone retinoate sorbitan dimethyl ether (DMI) solution was placed in a 100 ml beaker, and allowed to contact with air in the beaker, sealed, and the sample was numbered as HPR01. 1.5 g of each of the prepared samples of Examples 1-4 was placed on the bottom of a 100 ml beaker, and allowed to contact with air in the beaker, sealed; and the samples were numbered as MS01-MS04. The content of hydroxypinacolone retinoate was detected on day 0, day 30, day 60, day 90 and day 180, respectively.

[0029] Content detection method of hydroxypinacolone retinoate: The content of hydroxypinacolone retinoate was determined by high performance liquid chromatography (Chinese Pharmacopoeia General 0512): the chromatographic conditions and system suitability test were as follows: octadecylsilane-bonded silica gel as the filler (5 μm, 250*4.6 mm), methanol as the mobile phase, isocratic elution, flow rate of 1.0 ml per minute, wavelength of 365 nm. About 100 mg of sample was taken, and a sample solution with a concentration of 50 μg / ml was prepared with methanol as the solvent. 20 μl of the prepared solution and the control sample solution was injected into the liquid chromatograph, respectively. The main peak area and purity of hydroxypinacolone retinoate were calculated by area normalization method. The control sample was purchased (hydroxypinacolone retinoate with a chromatographic purity of >99.5% provided by Aldrin Reagent Company). The content of hydroxypinacolone retinoate in the sample was calculated according to the external standard method.

[0030] The content of hydroxypinacolone retinoate at different time nodes was as follows

[0031]

[0032]

[0033] From the above data, it can be seen that the sample of 10% hydroxypinacolone retinoate sorbitan dimethyl ether (DMI) solution (sample number HPR01) contacted with a large amount of air for a long time, and the content decreased significantly within 180 days.

[0034] The sample MS03 of Example 3 was a prepared solid that wrapped hydroxypinacolone retinoate and did not contain the antioxidant ascorbic acid tetraisopalmitate, and a similar situation of a significant decrease in content within 180 days occurred as the 10% hydroxypinacolone retinoate sorbitan dimethyl ether (DMI) solution.

[0035] The sample MS01 of Example 1 is a solid preparation encapsulating hydroxypinacolone retinoate and containing a low content of antioxidant ascorbyl tetraisopalmitate. The content of hydroxypinacolone retinoate shows a small decrease within 180 days, which proves that adding antioxidant ascorbyl tetraisopalmitate to the prepared sustained-release granules helps to improve the stability of hydroxypinacolone retinoate.

[0036] The sample MS02 of Example 2 is a solid preparation encapsulating hydroxypinacolone retinoate and containing a high content of antioxidant ascorbyl tetraisopalmitate. The content of hydroxypinacolone retinoate shows almost no decrease within 180 days, which proves that adding sufficient antioxidant ascorbyl tetraisopalmitate to the prepared sustained-release granules can better prevent the oxidative degradation of hydroxypinacolone retinoate and improve the stability of hydroxypinacolone retinoate in the sustained-release granules.

[0037] The sample MS04 of Example 4 is a solid preparation encapsulating hydroxypinacolone retinoate and containing a high content of antioxidant tocopherol. The content of hydroxypinacolone retinoate also shows a small decrease within 180 days, which has a certain antioxidant effect, but the decrease is greater than that of the sample MS02 of Example 2 prepared by adding the same dose of antioxidant ascorbyl tetraisopalmitate, which shows that ascorbyl tetraisopalmitate is better than tocopherol as an antioxidant in stabilizing hydroxypinacolone retinoate.

[0038] Example 6: Skin irritation comparison test

[0039] (1) Sample preparation:

[0040] The control sample is 10% hydroxypinacolone retinoate isosorbide dimethyl ether solution (trade name Granactive Retinoid, provided by Guangzhou Bideyuan Trade Co., Ltd.) 5 ml (containing 0.5% hydroxypinacolone retinoate), and the hydroxypinacolone retinoate control emulsion is prepared according to Formula 1; the experimental sample is 1.25 g of hydroxypinacolone retinoate sustained-release microspheres (containing 0.5% hydroxypinacolone retinoate) prepared in Example 2, and the hydroxypinacolone retinoate sustained-release microsphere-containing emulsion is prepared according to Formula 2. The blank matrix emulsion is prepared according to Formula 3.

[0041] Formula 1:

[0042]

[0043] The preparation method is as follows:

[0044] Step one, clean and disinfect the emulsification equipment, and prepare the materials.

[0045] Step two, A phase (No. 1-7 raw materials) into the oil phase cylinder, start heating, temperature to 80-85 ℃, keep stirring until the material is completely dissolved, ready for use;

[0046] Step three, B phase (No. 9, 10, 11 raw materials) in advance dispersed into a vacuum emulsifying pot, add the remaining raw materials of B phase (No. 8, 12-16) into the vacuum emulsifying pot, start stirring, start heating, until completely dissolved at 85-90 ℃, stop stirring, open high-speed homogenization, and then A phase is pumped into the vacuum emulsifying pot, homogenized for 10 minutes. Stop homogenization, start stirring, keep warm for 10 minutes, and vacuumize while keeping warm until there are no bubbles, and then start cooling;

[0047] Step four, when the temperature is reduced to 70 ℃, add C phase (No. 17 raw material) into the emulsifying pot, homogenize for 8-10 minutes to stir evenly, and continue to cool.

[0048] Step five, when the temperature is reduced to 60-50 ℃, add D phase (No. 18 raw material) into the emulsifying pot, stir evenly, and continue to cool.

[0049] Step six, when the temperature is reduced to 45-40 ℃, add E phase (19, 20 phase is pre-stirred and dissolved until transparent and no particles) into the pot, stir and disperse evenly.

[0050] Step seven, continue to stir until the temperature is about 38 ℃, filter out the pot, and then fill after standing.

[0051] Formula 2:

[0052]

[0053] The preparation method is:

[0054] Step one, clean and disinfect the emulsifying equipment, and prepare the materials.

[0055] Step two, A phase (No. 1-7 raw materials) into the oil phase cylinder, start heating, temperature to 80-85 ℃, keep stirring until the material is completely dissolved, ready for use;

[0056] Step three, B phase (No. 9, 10, 11 raw materials) in advance dispersed into a vacuum emulsifying pot, add the remaining raw materials of B phase (No. 8, 12-16) into the vacuum emulsifying pot, start stirring, start heating, until completely dissolved at 85-90 ℃, stop stirring, open high-speed homogenization, and then A phase is pumped into the vacuum emulsifying pot, homogenized for 10 minutes. Stop homogenization, start stirring, keep warm for 10 minutes, and vacuumize while keeping warm until there are no bubbles, and then start cooling;

[0057] Step four, when the temperature is reduced to 70 ℃, add C phase (No. 17 raw material) into the emulsifying pot, homogenize for 8-10 minutes to stir evenly, and continue to cool.

[0058] Step five, when the temperature is reduced to 60-50℃, add D phase (raw material No. 18) into the emulsifying pot, stir evenly, and continue to reduce the temperature.

[0059] Step six, when the temperature is reduced to 45-40℃, add E phase (raw materials No. 19, 20, 21) into the pot in sequence, stir and disperse evenly.

[0060] Step seven, continue to stir until the temperature is about 38℃, filter out the pot, and then fill after standing.

[0061] Formulation 3

[0062]

[0063] Preparation method:

[0064] Step one, clean and disinfect the emulsifying equipment, and prepare the materials.

[0065] Step two, add A phase (raw materials No. 1-7) into the oil phase cylinder, start heating, and raise the temperature to 80-85℃, and keep stirring until the material is completely dissolved, and then standby;

[0066] Step three, add B phase (raw materials No. 9, 10, 11) into the vacuum emulsifying pot in advance, and then add the remaining raw materials of B phase (raw materials No. 8, 12-16) into the vacuum emulsifying pot, start stirring, and start heating until the temperature is 85-90℃, then stop stirring, open the high-speed homogenizer, and then add A phase into the vacuum emulsifying pot, and homogenize for 10 minutes. Stop homogenizing, start stirring, keep the temperature for 10 minutes, and then vacuum until there is no bubble, and then start reducing the temperature.

[0067] Step four, when the temperature is reduced to 70℃, add C phase (raw material No. 17) into the emulsifying pot, homogenize for 8-10 minutes, stir evenly, and continue to reduce the temperature.

[0068] Step five, when the temperature is reduced to 60-50℃, add D phase (raw material No. 18) into the emulsifying pot, stir evenly, and continue to reduce the temperature.

[0069] Step six, when the temperature is reduced to 45-40℃, add E phase (raw material No. 19) into the pot in sequence, stir and disperse evenly.

[0070] Step seven, continue to stir until the temperature is about 38℃, filter out the pot, and then fill after standing.

[0071] (2) Multiple administration of skin irritation test

[0072] Take 12 healthy SD rats, half male and half female, and randomly divide them into a control sample group (emulsion prepared according to Formula 1) and a sample group (emulsion prepared according to Formula 2), with 4 rats in each group, and a blank group as a matrix emulsion group (without hydroxyl pinacolyl retinoate, i.e., emulsion prepared according to Formula 3). Before the test, the abdominal hair of the two groups of rats is removed without damaging the epidermis, and the hair removal area is 3 cm x 3 cm on the left and right. The next day, 0.5 g of the control sample (emulsion prepared according to Formula 1), the sample (emulsion prepared according to Formula 2), and the blank sample (emulsion prepared according to Formula 3) are respectively applied to the normal skin of the three groups of rats, with an application area of 2.5 cm x 2.5 cm. This is done once a day for 7 consecutive days, and 24 h after the last administration, the skin is washed with sterilized warm water. The erythema, edema, and other conditions of the administration site are observed at 1 h, 2 h, 48 h, and 72 h after the administration is stopped, and the observations are recorded and scored according to the standard Table 1.

[0073] Table 1: Skin irritation reaction score and intensity evaluation standard

[0074]

[0075] The test results show that the blank group (without hydroxyl pinacolyl retinoate) has no erythema (score 0) and no edema (score 0), and the skin irritation intensity score is no irritation (score 0.5); the control sample group (containing 0.5% hydroxyl pinacolyl retinoate emulsion) has obvious visible erythema (score 2) and visible edema (score 2), and the skin irritation intensity score is moderate irritation (score 4.0); the sample group (containing 0.5% hydroxyl pinacolyl retinoate sustained-release microsphere emulsion) has no erythema (score 0) and no edema (score 0), and the skin irritation intensity score is no irritation (score 0.5).

[0076] As can be seen, under the same concentration of hydroxyl pinacolyl retinoate, the sustained-release particles of hydroxyl pinacolyl retinoate and ascorbic acid tetraisopalmitate wrapped by methyl methacrylate / ethylene glycol dimethacrylate crosslinked polymer have much less skin irritation than the commercially available hydroxyl pinacolyl retinoate dissolved in dimethyl isosorbide (DMI) solution.

[0077] Example 7: In vitro skin cumulative penetration test of emulsion containing hydroxyl pinacolyl retinoate sustained-release particles

[0078] It is known that hydroxypinacolone retinoate can directly bind to cellular retinoic acid receptors (RARs), exerting similar effects to tretinoin, but also causing adverse reactions such as skin redness, itching, and peeling. By slow-releasing hydroxypinacolone retinoate, the skin penetration rate of hydroxypinacolone retinoate is reduced, which is an effective means to reduce the probability of adverse reactions. Through in vitro skin cumulative penetration test, we confirmed that the slow-release particles of hydroxypinacolone retinoate and ascorbyl tetraisopalmitate wrapped by methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer are an effective carrier that can slowly release hydroxypinacolone retinoate within 24 hours.

[0079] Take the emulsion formula containing 0.5% hydroxypinacolone retinoate prepared in Example 6 (Formula 1) and the emulsion formula containing 0.5% hydroxypinacolone retinoate slow-release microspheres (Formula 2) each in an appropriate amount, and carry out in vitro skin permeability test.

[0080] The test instrument is C1820 type vertical improved Franz diffusion cell (Shanghai Kai Kai Science and Technology Trade Co., Ltd.), TK-12D type transdermal instrument (Shanghai Kai Kai Science and Technology Trade Co., Ltd.).

[0081] Preparation of isolated pig skin: immediately after the Bama miniature pig was sacrificed, the abdominal skin was cut, the subcutaneous fat layer and connective tissue were carefully peeled off, and the skin was washed with physiological saline and then placed in physiological saline. The skin was stored in a refrigerator at a low temperature below-25℃ for standby use. Before the test, the skin was naturally thawed, soaked in physiological saline for 30 min, and then dried with filter paper for standby use. The exposed skin area in the diffusion cell was 3.14 cm2, and the receiving chamber volume was 19 mL. The prepared isolated skin was thawed at room temperature, fixed between the supply pool and the receiving pool, with the horny layer facing the supply pool, and placed in the receiving liquid [0.9% physiological saline-ethanol (4:1) mixture]. The bubbles in the receiving pool were exhausted to make the receiving liquid completely contact with the inner layer of the skin. The receiving pool was kept in a constant temperature water bath at 32±1℃, and the magnetic stirring speed in the pool was 400 r / min. After 15 min of equilibrium, the new receiving liquid was replaced.

[0082] The test method is as follows: 1 g of the emulsion of Formula 1 prepared in Example 6 is applied to the skin surface as a control group, and 1 g of the emulsion of Formula 2 prepared in Example 6 is applied to the skin surface as a sample group. The recording time is 0 h. The control group and the sample group are sampled at 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h, 10 h, 12 h, 24 h, and 36 h, respectively, as the test samples, and the same volume of fresh receiving liquid is added in time. Each test sample is detected according to the content detection method of hydroxypinacolone retinoate described in Example 5 to detect the concentration of hydroxypinacolone retinoate in the test sample.

[0083] Calculation of cumulative penetration of hydroxypinacolone retinoate in vitro: cumulative penetration was calculated according to Formula 1, wherein 19 is the volume of the receiving pool (ml), 0.2 is the sampling volume (ml), Cn is the concentration of hydroxypinacolone retinoate measured at the nth sampling point (μg / ml), Ci is the measured concentration of hydroxypinacolone retinoate at a certain time point before the nth sampling point (g / ml), and 3.14 is the transdermal diffusion area (cm2).

[0084] Formula 1:

[0085]

[0086] The results of the determination of the cumulative penetration of hydroxypinacolone retinoate in vitro of the control group and the sample group after sampling at different time points are shown in Table 2 below.

[0087] Table 2 Determination results of the cumulative penetration of hydroxypinacolone retinoate in vitro of the control group and the sample group

[0088] Time point (h) Control group (pg / ml) Sample group (pg / ml) 0 0.00 0.00 0.5 1.72 0.91 1 4.07 2.58 2 10.09 5.62 4 18.46 9.14 6 25.09 12.48 8 31.24 15.30 10 36.02 18.48 12 37.55 20.91 24 40.21 27.20 36 40.69 28.38

[0089] The penetration curve was plotted with the cumulative penetration of each component at each sampling point as the ordinate and time as the abscissa, as shown in Figure 1 The results show that after 36 h, the cumulative penetration of the sample group (emulsion of Formula 2 prepared in Example 6) was 28.38 μg / ml, while the cumulative penetration of the control group (emulsion of Formula 1 prepared in Example 6) was 40.69 μg / ml, and the cumulative penetration of the sample group was only 69.74% of that of the control group, achieving the purpose of sustained release.

[0090] Example 8 Comparison of Anti-wrinkle Efficacy and Adverse Reaction Incidence of Emulsion Containing Sustained-release Particles of Hydroxypinacolone Retinoate

[0091] Test samples: the control group used the emulsion of Formula 1 prepared in Example 6, the sample group used the emulsion of Formula 2 prepared in Example 6, and the blank group used the emulsion of Formula 3 prepared in Example 6.

[0092] Detection instrument: Cutometer@ dual MPA580 skin elasticity tester (Germany CK Company); Primos skin rapid three-dimensional imaging system (LMI Company, USA);

[0093] Inclusion criteria: 90 healthy volunteers were selected, who met the following conditions: ① aged 30-65 years (except pregnant or lactating women); ② had obvious dry lines or wrinkles on the eye; ③ had no serious systemic diseases, no immune deficiency or autoimmune diseases; ④ had no active allergic diseases; ⑤ had no highly sensitive constitution; ⑥ had not used hormone drugs and immunosuppressants in the past month; ⑦ had not participated in other clinical trials in the test site in the past three months. Termination and exclusion criteria: ① the volunteer required to terminate the test due to personal reasons; ② the volunteer had adverse reactions that could not continue the test; ③ the volunteer had poor compliance, such as using other skin care products that affected the test, etc. The test time was from September 2022 to November 2022, lasting for 8 weeks.

[0094] Test method:

[0095] 1. Product use and test method

[0096] 1) 90 volunteers were randomly allocated into 3 groups according to the random double-blind principle, one group of 30 people was used as the sample test group, using the emulsion of formula 2 prepared in example 6; the second group of 30 people was used as the control group, using the emulsion of formula 1 prepared in example 6; the third group of 30 people was used as the blank group, using the emulsion of formula 3 prepared in example 6.

[0097] 2) The volunteers used the corresponding samples once a day in the morning and evening for 8 consecutive weeks, and did not use other wrinkle-removing skin care products during the test period.

[0098] 3) Follow-up once at 0, 2, 4 and 8 weeks, a total of 4 times. Before each test, the subjects needed to clean the eye area with clean water, use a paper towel without fluorescent agent to dry the eye moisture, sit still for at least 20 min in a constant temperature and humidity environment (20-22℃, relative humidity 40%-60%), and be measured by the measurer.

[0099] 4) Instrument test method: the skin elasticity tester was used to measure the fixed area position around the left and right eyes of the volunteers, and the stratum corneum elasticity R2 value was recorded, each measurement area was measured 3 times to take the average value; the Primos skin rapid three-dimensional imaging system was used to measure the wrinkle skin position (representative parts) around the left and right eyes of the volunteers, and the roughness Sa value and wrinkle volume were recorded.

[0100] 5) Subjective evaluation of the subjects: 90 effective volunteers filled in the use log every day after using the product, and evaluated the adverse reactions of the skin according to the personal subjective feeling.

[0101] 2. Statistical method

[0102] SPSS19.0 statistical software was used for data analysis. T-test or rank-sum test was used to compare the values at 0, 2, 4 and 8 weeks, and significance analysis was performed. P<0.05 indicates that the difference is statistically significant, marked as "*"; P<0.01 and P<0.001 indicate that the difference is extremely statistically significant, marked as "**" and "***" respectively.

[0103] 3. Results and analysis

[0104] 1) Volunteer statistical data results: 90 volunteers who met the inclusion criteria were selected, and finally 90 volunteers completed the test, with an average age of 42 years old.

[0105] 2) Skin elasticity test results

[0106] The elasticity R2 value represents the ratio of the skin rebound amount without negative pressure to the maximum stretching amount with negative pressure. The closer the ratio is to 1, the better the skin elasticity. The elasticity R2 value of the volunteers was measured using the skin elasticity tester, and the results are shown in Table 3:

[0107] Table 3 Skin elasticity test results

[0108]

[0109] The elasticity R2 value of each test group at 0 weeks was the lowest. The sample group using the emulsion of Formula 2 prepared in Example 6 (containing hydroxyl pinakonretinoid sustained-release microspheres) and the control group using the emulsion of Formula 1 prepared in Example 6 (containing hydroxyl pinakonretinoid- isosorbide dimethyl ether solution) showed a gradual upward trend in skin elasticity scores after 2, 4 and 8 weeks, indicating that the skin elasticity was significantly improved. The elasticity R2 value of the sample group and the control group at 8 weeks was improved by 20.96% and 17.81% respectively compared with before the test (0 weeks), which had statistical significance (P<0.05). Compared with the blank group (using the emulsion of Formula 3 prepared in Example 6 without hydroxyl pinakonretinoid), the improvement rate of the elasticity R2 value of the sample group and the control group at 8 weeks was increased by 19.08% and 15.94% respectively. The improvement rate of the eye elasticity R2 value continued to rise after using the sample group and the control group, indicating that both the sample group and the control group had good efficacy in improving the skin elasticity of the eye. The improvement rate of the sample group was higher than that of the control group.

[0110] 3) Skin roughness improvement

[0111] The skin roughness Sa value represents the arithmetic mean of the height of each point within the test range. The lower the index value, the smaller the skin roughness, and the smoother the skin. The skin roughness Sa value of the volunteers was measured using the skin rapid three-dimensional imaging system, and the results are shown in Table 4:

[0112] Table 4 Skin roughness test results

[0113]

[0114] The sample group and the control group using the emulsion prepared by Example 6 of Formula 2 (containing hydroxyl pinakon retinoate sustained-release microspheres) and Formula 1 (containing hydroxyl pinakon retinoate-isosorbide dimethyl ether solution) showed a gradual downward trend in roughness Sa value after 2, 4 and 8 weeks. The sample group and the control group showed an improvement rate of 17.85% and 17.30% respectively in roughness Sa value at the 8th week compared with before the test (0 weeks), which was statistically significant (P < 0.05). Compared with the blank group, the sample group and the control group showed an improvement rate of 14.85% and 14.30% respectively in roughness Sa value at the 8th week. The improvement rate of the eye Sa value of the sample group and the control group continued to rise after 8 weeks, indicating that both the sample group and the control group had a strong effect on improving the roughness of the eye.

[0115] 4) Wrinkle volume test results

[0116] Wrinkle volume value represents the volume of wrinkles in the analysis area. The lower the index value, the smaller the wrinkle volume, and the fewer the wrinkles. The skin rapid three-dimensional imaging system was used to measure the wrinkle volume value of the volunteers, and the results are shown in Table 5.

[0117] Table 5: Wrinkle volume test results

[0118]

[0119]

[0120] The sample group and the control group using the emulsion prepared by Example 6 of Formula 2 (containing hydroxyl pinakon retinoate sustained-release microspheres) and Formula 1 (containing hydroxyl pinakon retinoate-isosorbide dimethyl ether solution) showed a gradual downward trend in roughness Sa value after 2, 4 and 8 weeks. The sample group and the control group showed an improvement rate of 17.85% and 17.30% respectively in roughness Sa value at the 8th week compared with before the test (0 weeks), which was statistically significant (P < 0.05). Compared with the blank group, the sample group and the control group showed an improvement rate of 14.85% and 14.30% respectively in roughness Sa value at the 8th week. The improvement rate of the eye Sa value of the sample group and the control group continued to rise after 8 weeks, indicating that both the sample group and the control group had a strong effect on improving the roughness of the eye.

[0121] 5) Incidence of adverse reactions

[0122] 90 effective volunteers filled in the use log after using the product every day, and evaluated the skin adverse reaction according to the personal subjective feeling. After using the sample for 8 weeks, the log was collected and the results were as follows:

[0123] The blank group and the sample group each had 30 people, and none of them had adverse reactions.

[0124] The control group had 30 people, 1 person had dry and peeling skin, 2 people had skin itching, 1 person had skin tingling, and a total of 4 people had adverse reactions, with an adverse reaction rate of 13.33%. No serious adverse reactions as stipulated in the "Cosmetic Adverse Reaction Monitoring Management Method" occurred.

[0125] It can be seen that the safety of the sample of the emulsion (containing hydroxyl pinakon retinoate sustained-release microspheres) prepared from the formula 2 of Example 6 used in the sample group is higher than that of the control group, which confirms that the technology of releasing hydroxyl pinakon retinoate can reduce the incidence of adverse reactions.

Claims

1. A sustained release composition comprising hydroxylpinacolone retinoate, characterized in that, The preparation method of the composition is as follows: Hydroxypinacolone retinoate 4g, ascorbyl tetraisopalmitate 1g is dissolved in tetrahydrofuran 5ml, added to methyl methacrylate / ethylene glycol dimethacrylate cross-linked polymer 5g, mixed uniformly at high speed, low-temperature vacuum drying to remove volatile solvent, 10ml water is added to rinse, low-temperature vacuum drying at 45℃ to remove residual solvent, to obtain the sustained-release granules containing hydroxypinacolone retinoate.

2. The use of the sustained-release composition of claim 1 in the preparation of anti-wrinkle skin care products, which belongs to the diagnosis and treatment of non-disease.

3. The skin care product containing the sustained-release composition of claim 1, wherein the weight percentage of the sustained-release composition in the skin care product is 0.1-3%.

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