CN118126119A - Tretinoin polypeptide derivative and preparation method and application thereof - Google Patents

Tretinoin polypeptide derivative and preparation method and application thereof Download PDF

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CN118126119A
CN118126119A CN202410571809.3A CN202410571809A CN118126119A CN 118126119 A CN118126119 A CN 118126119A CN 202410571809 A CN202410571809 A CN 202410571809A CN 118126119 A CN118126119 A CN 118126119A
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tretinoin
polypeptide
polypeptide derivative
compound
derivative
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张伟
杜立波
徐国金
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Hepburn Shixin Beijing Biotechnology Co ltd
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Hepburn Shixin Beijing Biotechnology Co ltd
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Abstract

The invention relates to a tretinoin polypeptide derivative, a preparation method and application thereof. The tretinoin polypeptide derivative is a condensation product of a compound A and a polypeptide, wherein the compound A is an effective component with carboxyl; the polypeptide is a condensation product of 2-6 amino acids; and the amino acids include glycine, histidine and lysine. The invention can reduce the irritation of tretinoin by modifying the polypeptide on tretinoin, and is mainly used in the field of skin aging resistance and can delay the speed of skin aging.

Description

Tretinoin polypeptide derivative and preparation method and application thereof
Technical Field
The invention relates to a tretinoin polypeptide derivative, a preparation method and application thereof.
Background
Tretinoin is a metabolic intermediate of vitamin A in vivo, can affect proliferation and differentiation of epithelial cells, can inhibit secretion of sebum, and is commonly used for treating psoriasis, acne, etc. In addition, retinoic acid and its derivatives (retinol, all-trans retinoic acid, isotretinoin, abamectin acid, etc.) can exert an anti-aging effect by promoting collagen synthesis and inhibiting collagen degradation; can improve skin surface wrinkles by enhancing proliferation and differentiation of skin epidermal cells; inhibiting the activity of the neuraminidase and improving rough skin and rough pores.
However, tretinoin has strong acidity and strong irritation to skin, so that the application of tretinoin in the field of skin care products is limited.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provides a tretinoin polypeptide derivative, a preparation method and application thereof.
In a first aspect, the present invention provides a tretinoin polypeptide derivative which is a condensation product of a compound a and a polypeptide, wherein compound a is an active ingredient having a carboxyl group; the polypeptide is a condensation product of 2-6 amino acids; and the amino acids include glycine, histidine and lysine.
Polypeptides have been widely used in skin care products, which can exert a variety of effects such as carriers, signals, neurotransmitters, and the like. For example, palmitoyl pentapeptide-4 can stimulate the production of collagen I, III, VI, and reduce the production of wrinkles. ARGIRELINE (acetyl hexapeptide-8) and SYN-AKE (dipeptide diamino Ding Xianbian-ylamide diacetate) can be used as neurotransmitter inhibitor, and can inhibit rapid wrinkle generation. Based on the above consideration, the invention provides the retinoic acid polypeptide derivative which can remarkably reduce the irritation of retinoic acid and fully exert the functions of resisting aging and removing wrinkles.
In some embodiments, compound a is selected from tretinoin or a derivative thereof.
In some embodiments, compound a is one or more of tretinoin, isotretinoin, or abamectin.
In some embodiments, the compound a is tretinoin.
In some embodiments, the polypeptide is a condensation product of glycine, histidine, and lysine.
In some embodiments, the tretinoin polypeptide derivatives include compounds having the structure of formula I and/or formula II:
I
II。
In some embodiments, the tretinoin polypeptide derivative has an average molecular weight of 496-623, e.g., 500, 520, 540, 560, 580, 600, 620, or any value therebetween.
In some embodiments, the polypeptide has an average molecular weight of 132-370, e.g., 135, 155, 175, 195, 215, 235, 255, 300, 325, 345, or any value therebetween.
In some embodiments, the polypeptide has an average molecular weight of 212-368.
In some embodiments, the polypeptide has an average molecular weight of 368.
In a second aspect, the present invention provides a method for preparing a tretinoin polypeptide derivative according to the first aspect of the present invention, comprising subjecting a polypeptide to a condensation reaction with a compound a to produce the tretinoin polypeptide derivative.
In some embodiments, the molar ratio of the polypeptide to the compound a is 1-2, e.g., 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, or any value therebetween.
In some embodiments, the condensation reaction employs EDC and NHS as the condensing reagents.
In some embodiments, the molar ratio of compound a to EDC is 1: (0.5 to 1.5); for example, 1:0.5, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, or any value therebetween.
In some embodiments, the molar ratio of compound a to NHS is 1: (0.5 to 1.5); for example, 1:0.5, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, or any value therebetween.
In some embodiments, the time of the condensation reaction is 0.1 to 24 hours, for example, 1 hour, 1.5 h, 2 h, 3h, 3.5 h, 4h, 6h, 8h, 10 h, 15h, 20 h, or any value therebetween.
In some embodiments, the condensation reaction time is 0.1 to 4 hours.
In some embodiments, the condensation reaction is carried out at a temperature of 0 to 80 ℃, for example, 0 ℃,5 ℃, 10 ℃, 20 ℃,30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, or any value therebetween.
In some embodiments, a cleavage reagent is used in the condensation reaction, including TFA, phenyl sulfide, ethylene dithiol, phenol, and water.
In some embodiments, the volume ratio of TFA, phenyl sulfide, ethylene dithiol, phenol, and water is 80:1:1:0.5:0.5 to 90:10:10:8:2.
In some embodiments, the volume ratio of TFA, phenyl sulfide, ethylene dithiol, phenol, and water is 85:5:5:4:1.
In some embodiments, the polypeptide is prepared using solid phase synthesis.
In some embodiments, the method of producing a polypeptide comprises: amino acids are attached to insoluble resins, then the amino acids are attached by coupling and deprotection reactions, and finally the polypeptide molecule is cleaved from the resin.
In some embodiments, the insoluble resin is wang resin.
In some embodiments, the amino acids include glycine, histidine, and lysine.
In some embodiments, the polypeptide is a condensation product of glycine, histidine, and lysine.
In a third aspect, the present invention provides the use of the tretinoin polypeptide derivative of the first aspect or the tretinoin polypeptide derivative prepared by the preparation method of the second aspect in the field of skin care products.
In a fourth aspect, the present invention provides a skin care product comprising an active ingredient and a tretinoin polypeptide derivative as described in the first aspect or a tretinoin polypeptide derivative prepared by the method of preparation as described in the second aspect.
In some embodiments, the functional ingredient is a functional ingredient for skin, such as a whitening, acne removing ingredient, etc., including but not limited to: tranexamic acid (tranexamic acid), nicotinic acid, nicotinamide, salicylic acid, and the like.
In some embodiments, the skin care product may be water, milk, cream, facial mask, and the like.
In some embodiments, the tretinoin polypeptide derivative is present in the skin care product in an amount of 0.05-1%, such as 0.05%, 0.06%, 0.07%, 0.08%, 0.09%, 1%, or any value therebetween.
The invention can reduce the irritation of tretinoin and can be used in the field of skin aging resistance and delay the skin aging speed by modifying specific polypeptide molecules on tretinoin. Further, the invention can realize different functions of tretinoin by selecting different polypeptides and tretinoin derivatives.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of a tretinoin polypeptide derivative prepared in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance spectrum of a tretinoin polypeptide derivative prepared in example 1 of the present invention;
FIG. 3 is an infrared spectrum of a tretinoin polypeptide derivative prepared in example 1 of the present invention;
FIG. 4 shows the effect of different concentrations of blue copper peptide, retinoic acid, vitamin E and retinoic acid polypeptide derivatives prepared in example 2 on H 2O2 -induced HaCaT cell viability in accordance with the present invention;
FIG. 5 shows the effect of different concentrations of blue copper peptide, retinoic acid, vitamin E and retinoic acid polypeptide derivatives prepared in example 2 on H 2O2 -induced MDA levels in HaCaT cells according to application example 1 of the present invention;
Reference numerals:
1. Blank; 2. h 2O2（50μM）;3、H2O2 (50. Mu.M) +blue copper peptide (5. Mu.g/mL); 4. h 2O2 (50. Mu.M) +tretinoin (5. Mu.g/mL); 5. h 2O2 (50. Mu.M) +blue copper peptide (5. Mu.g/mL) +tretinoin (5. Mu.g/mL); 6. h 2O2 (50. Mu.M) +tretinoin polypeptide derivative of example 2 (5. Mu.g/mL/5. Mu.g/mL); 7. h 2O2 (50. Mu.M) +vitamin E (1. Mu.g/mL).
Detailed Description
The present invention will be further described in detail with reference to the following examples and the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way.
Unless defined otherwise, technical terms used in the following examples have the same meaning as commonly understood by one of ordinary skill in the art to which the present invention pertains. The reagents used in the following examples, unless otherwise specified, are all conventional biochemical reagents; the raw materials, instruments, equipment, etc. used in the following examples are all commercially available or available by existing methods; the reagent dosage is the reagent dosage in the conventional experimental operation if no special description exists; the experimental methods are conventional methods unless otherwise specified.
Example 1
Preparation of a tretinoin polypeptide derivative according to the following reaction scheme
(1) Preparation of the polypeptide
Preparation of Fmoc-Lys-Wang resin:
5g of Wang resin with substitution of 0.85mM/g was weighed, added to a solid phase reaction column, washed twice with 10mL of N, N-Dimethylformamide (DMF), and swollen for 30min with 35mL of DMF. The filtrate was collected by suction filtration, 2.53g of Fmoc-Lys-OH and 1.38g of 1-hydroxybenzotriazole (HOBt) were dissolved in 30 mL DMF, and 1.58mL of N, N' -Diisopropylcarbodiimide (DIC) was added to the solution in an ice bath, and the solution was allowed to stand and activate for 5 minutes in a dark place. The solution is added into a solid phase reaction column which is fully swelled with resin, 0.11g of Dimethylaminopyridine (DMAP) is added, the reaction is stirred for 3 hours under the protection of nitrogen, and the completion of the reaction is monitored by an ninhydrin color development method. The solvent was removed and washed 3 times with DMF, dichloromethane (DCM) and 50mL of blocking solution (acetic anhydride-pyridine, volume ratio 7:3) was added and blocked for 6h. The liquid was removed, washed 4 times with DCM, contracted with methanol (MeOH) and dried in vacuo to give 6.08g Fmoc-Lys-Wang resin with a degree of substitution of 0.32 mM/g, resin weight gain of 1.07g and yield of 90.42%.
Extension of peptide chain:
5.0g Fmoc-Lys-Wang resin was weighed, added to a solid phase reaction column, washed twice with 10mL DMF, the solvent removed, and swollen for 30min with 35: 35 mL DMF. Washing with DMF twice, adding piperidine-DMF mixed solution (volume ratio 1:3) and stirring for 15min, and monitoring the reaction completion by ninhydrin color development. 2.06g of Fmoc-His (trt) -OH and 0.52g of HOBt were dissolved in DMF by washing 5 times with DMF and DCM, added under ice-bath conditions with 0.59 mL DIC, stirred for 5min in the absence of light, then added to the above solvent-removed solid phase reaction column, added with 0.04g of DMAP, stirred under nitrogen for 3h, and monitored for completion by ninhydrin color development. The solvent was removed and washed 5 times with DMF to give Fmoc-His-Lys-Wang resin. According to the coupling method, corresponding Fmoc protected amino acid is added in sequence to the peptide, and the peptide chain is extended by condensation coupling in sequence. After the end of the last coupling reaction, the resin was washed 4 times with DCM, DMF, meOH and dried under vacuum to constant weight to give 6.23g of fully protected polypeptide fragment X-Wang resin, which increased 1.23g and gave a yield of 76.32%.
The steps are repeated to obtain Gly-His-Lys-Wang resin, the weight of the resin is increased by 1.2g, and the yield is 75.1%.
(2) Condensation of tretinoin with polypeptide
0.3G of tretinoin was weighed out and dissolved in 15ml of LDMF, 0.22g of EDC and 016g of NHS were added thereto under ice bath, and after stirring for 2 hours, 1.0g of Gly-His-Lys-Wang resin prepared as described above was added thereto, and the reaction was continued overnight. After removal of DMF by suction filtration, the resin was washed with DMF for 5 more times to give VA-Lys-His-Gly.
The VA-Lys-His-Gly resin prepared above was transferred to a 500mL three-necked flask and freshly prepared 250mL cleavage reagent TFA was added: benzenethiol (PhSMe) Ethanedithiol (EDT): phenol (PhOH): h 2 O (volume ratio 85:5:5:4:1) was reacted at 25℃for 3H. The filtrate was filtered, poured into 1L of glacial diethyl ether, and allowed to stand overnight in a refrigerator at 0 ℃. Suction filtration, washing filter cake with glacial ethyl ether (30 ml x 5) and ethyl acetate (30 ml x 5), freeze drying to obtain tretinoin polypeptide derivative shown in formula I, the total yield of crude peptide is 35.6%, and the purity of crude peptide is 52.35% detected by analytical HPLC.
The structural characterization of the tretinoin polypeptide derivative prepared in the embodiment is shown in figures 1-3, and the tretinoin polypeptide molecule is successfully modified in the invention.
I
Example 2
The tretinoin polypeptide derivatives of formula II were prepared by the procedure shown in example 1:
II
(1) Preparation of the polypeptide
Preparation of Fmoc-Lys-Wang resin:
5g of Wang resin with substitution of 0.85mM/g was weighed, added to a solid phase reaction column, washed twice with 10mL of N, N-Dimethylformamide (DMF), and swollen for 30min with 35mL of DMF. The filtrate was collected by suction filtration, 2.53g of Fmoc-Lys-OH and 1.38g of 1-hydroxybenzotriazole (HOBt) were dissolved in 30 mL DMF, and 1.58mL of N, N' -Diisopropylcarbodiimide (DIC) was added to the solution in an ice bath, and the solution was allowed to stand and activate for 5 minutes in a dark place. The solution is added into a solid phase reaction column which is fully swelled with resin, 0.11g of Dimethylaminopyridine (DMAP) is added, the reaction is stirred for 3 hours under the protection of nitrogen, and the completion of the reaction is monitored by an ninhydrin color development method. The solvent was removed and washed 3 times with DMF, dichloromethane (DCM) and 50mL of blocking solution (acetic anhydride-pyridine, volume ratio 7:3) was added and blocked for 6h. The liquid was removed, washed 4 times with DCM, contracted with MeOH and dried in vacuo to give 5.98g of Fmoc-Lys-Wang resin with a degree of substitution of 0.29 mM/g, resin weight gain of 0.97g and yield 88.42%.
Extension of peptide chain:
5.0g Fmoc-Lys-Wang resin was weighed, added to a solid phase reaction column, washed twice with 10mL DMF, the solvent removed, and swollen for 30min with 35: 35 mL DMF. Washing with DMF twice, adding piperidine-DMF mixed solution (volume ratio 1:3) and stirring for 15min, and monitoring the reaction completion by ninhydrin color development. 2.06g of Fmoc-His (trt) -OH and 0.52g of HOBt were dissolved in DMF by washing 5 times with DMF and DCM, added under ice-bath conditions with 0.59 mL DIC, stirred for 5min in the absence of light, then added to the above solvent-removed solid phase reaction column, added with 0.04g of DMAP, stirred under nitrogen for 3h, and monitored for completion by ninhydrin color development. The solvent was removed and washed 5 times with DMF to give Fmoc-His-Lys-Wang resin. According to the coupling method, corresponding Fmoc protected amino acid is added in sequence to the peptide, and the peptide chain is extended by condensation coupling in sequence. After the end of the last coupling reaction, the resin was washed 4 times with DCM, DMF, meOH and dried under vacuum to constant weight to give 5.64g of the fully protected polypeptide fragment X-Wang resin, which had a weight gain of 0.93g and a yield of 86.34%.
The steps are repeated to obtain Gly-His-Lys-Wang resin, the weight of the resin is increased by 0.95g, and the yield is 87.65%.
(2) Condensation of tretinoin with polypeptide
0.3G of tretinoin was weighed out and dissolved in 15ml of LDMF, 0.22g of EDC and 016g of NHS were added thereto under ice bath, and after stirring for 2 hours, 1.0g of Gly-His-Lys-Wang resin prepared as described above was added thereto, and the reaction was continued overnight. After removal of DMF by suction filtration, the resin VA-Gly-His-Lys-Wang was obtained by washing with DMF for 5 times.
The VA-Gly-His-Lys-Wang resin prepared above was transferred to a 500mL three-necked flask and freshly prepared 250mL cleavage reagent TFA was added: benzenethiol (PhSMe) Ethanedithiol (EDT): phenol (PhOH): h 2 O (volume ratio 85:5:5:4:1) was reacted at 25℃for 3H. The filtrate was filtered, poured into 1L of glacial diethyl ether, and allowed to stand overnight in a refrigerator at 0 ℃. Suction filtration, washing filter cake with glacial ethyl ether (30 mL. Times.5), ethyl acetate (30 mL. Times.5), and freeze drying to obtain tretinoin polypeptide derivative shown in formula II.
Application example 1 protection of tretinoin polypeptide derivatives of example 2 in HaCaT oxidative damage model
(1) HaCat cell culture
HaCat cells are respectively cultured in a high-sugar DMEM culture medium containing 10% of peptide bovine serum and 1% of antibiotics, placed in a cell culture box with 5% of CO 2 and 37 ℃ for culture, the old cell culture medium is replaced by a fresh cell culture medium every 2-3 days according to the growth condition of the cells, when the cells reach 80-90% of fusion degree, digestion and passage are carried out by using 0.25% of trypsin, and then the cells in the logarithmic phase are taken for experiment.
(2) Determination of H 2O2 injury model
The HaCaT cells in logarithmic growth phase are selected to prepare cell suspension of 1X 10 5 cells/mL, each cell is inoculated into a 96-well plate with 100 mu L of each well, 6 compound wells are arranged in each group, the cells are cultured in a cell culture box with 5% CO 2 and 37 ℃, after 24 hours, H 2O2 with the final concentration of 0.1, 0.2, 0.3, 0.4, 0.5, 0.6 and 0.7mM/L is respectively added to the cells after the cell state is stable, and the incubation is continued for 24 hours. Cell viability was measured using CCK-8 kit (Shanghai Biyun technology Co., ltd.) and H 2O2 concentration with cell viability close to 50% was selected as optimal effect concentration. Cell viability (%) = (drug a-blank)/(control a-blank) ×100%, where drug a is the experimental group absorbance value and blank a is the blank group absorbance value; control a is the absorbance value of the control group.
The optimum action concentration was determined to be 50 μm by the experiment to determine H 2O2 injury.
(3) Cell protection by drugs
Cells were seeded in 6-well plates with 2mL of each well, and a blank, H 2O2 -injured, and drug-treated group were established. After the treatment, the original culture medium was removed, rinsed gently with PBS for 2 times, scraped gently with a cell scraper, centrifuged and the supernatant was poured off, 200. Mu.L of double distilled water was added, the cells were broken by repeated freeze thawing, and after centrifugation, the supernatant was taken and measured with reference to the kit (Nanjing's Biotechnology) instructions for SOD and MDA.
The concentrations of the blue copper peptide, tretinoin, vitamin E and tretinoin polypeptide derivatives prepared in example 2 were determined by cytotoxicity experiments. The effect of varying concentrations of blue copper peptide, tretinoin, vitamin E and tretinoin polypeptide derivatives prepared in example 2 on H 2O2 -induced HaCaT cell viability is shown in FIG. 4. The effect of varying concentrations of blue copper peptide, tretinoin, vitamin E and tretinoin polypeptide derivatives prepared in example 2 on H 2O2 -induced MDA levels in HaCaT cells is shown in FIG. 5.
1 In fig. 4 and 5 represents a blank; 2. h 2O2（50μM）;3、H2O2 (50. Mu.M) +blue copper peptide (5. Mu.g/mL); 4. h 2O2 (50. Mu.M) +tretinoin (5. Mu.g/mL); 5. h 2O2 (50. Mu.M) +blue copper peptide (5. Mu.g/mL) +tretinoin (5. Mu.g/mL); 6. h 2O2 (50. Mu.M) +tretinoin polypeptide derivative of example 2 (5. Mu.g/mL/5. Mu.g/mL); 7. h 2O2 (50. Mu.M) +vitamin E (1. Mu.g/mL). As can be seen from fig. 4, the tretinoin polypeptide derivative of example 2 of the present invention exhibits a protective effect on H 2O2 -induced HaCaT cell viability. As can be seen from fig. 5, the tretinoin polypeptide derivative of example 2 of the present invention can reduce the amount of MDA released.
The preferred embodiments of the present invention have been described in detail above, but the present invention is not limited thereto. Within the scope of the technical idea of the invention, a number of simple variants of the technical solution of the invention are possible, including combinations of the individual technical features in any other suitable way, which simple variants and combinations should likewise be regarded as being disclosed by the invention, all falling within the scope of protection of the invention.

Claims (10)

1. A tretinoin polypeptide derivative which is a condensation product of a compound a and a polypeptide, wherein the compound a is an effective component having a carboxyl group; the polypeptide is a condensation product of 2-6 amino acids; and the amino acids include glycine, histidine and lysine.
2. The tretinoin polypeptide derivative according to claim 1, characterized in that compound a is selected from tretinoin or its derivatives, and/or
The polypeptide is a condensation product of glycine, histidine and lysine.
3. The tretinoin polypeptide derivative according to claim 1, wherein said compound a is one or more of tretinoin, isotretinoin or abamectin, and/or
The tretinoin polypeptide derivatives comprise compounds with structures shown in formula I and/or formula II:
I
II。
4. A tretinoin polypeptide derivative according to any one of claims 1-3, characterized in that said tretinoin polypeptide derivative has an average molecular weight of 496-623; and/or
The average molecular weight of the polypeptide is 132-370.
5. A process for the preparation of a tretinoin polypeptide derivative as claimed in any one of claims 1 to 4 comprising subjecting a polypeptide to a condensation reaction with compound a to produce the tretinoin polypeptide derivative.
6. The method for producing a tretinoin polypeptide derivative according to claim 5, wherein the molar ratio of said polypeptide to said compound A is 1 to 2.
7. The method for producing a tretinoin polypeptide derivative according to claim 5, wherein EDC and NHS are used as condensing agents for the condensation reaction; and/or the molar ratio of the compound a to the EDC is 1: (0.5 to 1.5); and/or the molar ratio of the compound a to the NHS is 1: (0.5 to 1.5); and/or
The time of the condensation reaction is 0.1-24 h, and/or the temperature of the condensation reaction is 0-80 ℃, and/or
The condensation reaction uses a cutting reagent, wherein the cutting reagent comprises TFA, phenyl sulfide, ethanedithiol, phenol and water, and/or the volume ratio of the TFA, the phenyl sulfide, the ethanedithiol, the phenol and the water is 80:1:1:0.5:0.5-90:10:10:8:2.
8. The method for producing a tretinoin polypeptide derivative as claimed in claim 5, wherein said polypeptide is produced by solid phase synthesis.
9. Use of a tretinoin polypeptide derivative as claimed in any one of claims 1 to 4 or prepared by a method as claimed in any one of claims 5 to 8 in the field of skin care products.
10. A skin care product comprising an active ingredient and the tretinoin polypeptide derivative as claimed in any one of claims 1 to 4 or the tretinoin polypeptide derivative prepared by the method of any one of claims 5 to 8.
CN202410571809.3A 2024-05-10 2024-05-10 Tretinoin polypeptide derivative and preparation method and application thereof Pending CN118126119A (en)

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Citations (6)

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Publication number Priority date Publication date Assignee Title
CN101048375A (en) * 2004-07-09 2007-10-03 帝斯曼知识产权资产管理有限公司 Amino, amino acid or peptide conjugates of retinoic acid
CN101182299A (en) * 2006-07-31 2008-05-21 赛德玛公司 Mydrial derivates,preparation method of mydrial derivates and cosmetics or skin medicinal composition
CN109311939A (en) * 2016-06-14 2019-02-05 赛德玛公司 Peptide, composition comprising the peptide and application thereof, especially cosmetic use
CN110612125A (en) * 2017-05-11 2019-12-24 凯尔格恩有限公司 Conjugates of isotretinoin and peptides
WO2022226209A1 (en) * 2021-04-22 2022-10-27 Glo Pharma, Inc. Skin peel compositions
WO2024012400A1 (en) * 2022-07-11 2024-01-18 南京毓浠医药技术有限公司 Tretinoin alcohol-amine compound, preparation method therefor and use thereof

Patent Citations (7)

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Publication number Priority date Publication date Assignee Title
CN101048375A (en) * 2004-07-09 2007-10-03 帝斯曼知识产权资产管理有限公司 Amino, amino acid or peptide conjugates of retinoic acid
CN101182299A (en) * 2006-07-31 2008-05-21 赛德玛公司 Mydrial derivates,preparation method of mydrial derivates and cosmetics or skin medicinal composition
CN109311939A (en) * 2016-06-14 2019-02-05 赛德玛公司 Peptide, composition comprising the peptide and application thereof, especially cosmetic use
CN110612125A (en) * 2017-05-11 2019-12-24 凯尔格恩有限公司 Conjugates of isotretinoin and peptides
US20200246473A1 (en) * 2017-05-11 2020-08-06 Caregen Co., Ltd. Conjugate of isotretinoin and peptide
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WO2024012400A1 (en) * 2022-07-11 2024-01-18 南京毓浠医药技术有限公司 Tretinoin alcohol-amine compound, preparation method therefor and use thereof

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