KR100389670B1 - A novel retinol derivative as an anti-aging agent and process for preparing thereof - Google Patents

Abstract

The present invention relates to a retinol derivative prepared by combining PEO-PPO-PEO triblock polymer or PEO-PPO diblock polymer having biocompatibility with tretinoin having a function of preventing skin aging due to ultraviolet rays, and a method of manufacturing the same. The retinol derivatives of the present invention reduce the side effects and toxicity of tretinoin, dissolve in water, improve skin permeability and stability, and exhibit excellent effects in preventing skin aging due to ultraviolet rays.

Description

A novel retinol derivative as an anti-aging agent and process for preparing

The present invention relates to a retinol derivative for preventing skin aging caused by ultraviolet rays and a method for producing the same.

The aging of the skin is caused by intrinsic skin aging, which is atrophy with structural and functional decline of the skin, and by extrinsic skin aging, which is mainly caused by hypertrophy such as inflammation under the influence of ultraviolet rays. , photoaging). In particular, ultraviolet rays denature the structure and function of the epidermis and dermis, and have a decisive effect on aging with immunological degeneration and tumor formation.

To treat this aging, tretinoin, sunscreen, alpha-hydroxy acids, antioxidants, chemical peels, skin abrasions or dermabrasion, transplantation and surgery have been studied.

Retinol has a hydroxyl group as a trimethylated cyclohexaene ring, a conjugated tetraene side chain and a polar carbon-oxygen functional group. In contrast, tretinoin refers to a case where a polar carbon-oxygen functional group is changed to a carboxyl group. When retinol penetrates into the skin, it is converted into tretinoin (retinoic acid) by a biological process. These tretinoin is recognized by the receptors present in the nucleus of the cell and is expressed in genes to have the effect of preventing aging.

In the 1960s, research was conducted on the function of preventing the disorder of epidermal differentiation of tretinoin. In 1983, for the first time in humans, a double-blind method of aging by tretinoin / ultraviolet (Cordero A Jr, Actual Ter Dermatol. 6, 49 (1983)) was conducted. Wrinkles were removed and skin roughness was reduced.

In 1986, a study of the effects of 0.05% tretinoin cream in people with oily, acne-prone skin (Kligman Am, Grove GL, Hirose R, Leyden JJ, J Am Acad Dermatol. 15, 836 (1986)) Was.

In 1991, there was a study using tretinoin as an emollient cream to treat aging caused by ultraviolet light on dry skin. From this study (Weinstein GD, Nigra TP, Pochi PE, Savin RC, Allan A, Benik K, Jeffes E, Lufrano L, Thorne EG, Arch Dermatol, 127, 659 (1991)) Results were observed to be affected by the degree. In other words, tretinoin has a more even distribution of melanin, has a particularly good effect on stained hyperpigmentation and sunspots, normalizes epidermal atypical formation and forms new collagen in the dermis, and also in the epidermis of keratinocytes. It has been known to be effective in treating thin wrinkles by stimulating proliferation and increasing exfoliation of keratinocytes, and in treating redness due to angiogenesis.

Recently, studies on the mechanism of aging by ultraviolet light and the action of tretinoin on it have been made.

Other treatments include sunscreen, a topical product that protects the skin from UV-induced erythema. This reduces skin cancer and wrinkle formation caused by UV-B. Recent studies have shown that having a high-performance sun-protection factor (SPF) reduces pre-cancerous keratosis (Glichrest BA, N Engl J Med, 329, 1193 (1993)). However, in terms of effectiveness, there was a slight difference compared to the control.

Alpha-hydroxy acids, such as glycolic or lactic acids, are present mainly in sugar cane, wild milk, and citrus fruits. They have an effect on normalizing Hyperkeratiniaztion (Van Scott EJ, Yu RJ, J Geriatr Dermatol, 3 (Suppl. A), 19 (1995)) and increase epidermal thickness and dermal glycosaminoglycane. Effect (Bernstein EF, Uitto J, J Geriatr Dermatol, 3 (Suppl. A), 7 (1995)). They act primarily as skin moisturizers and exfoliants, but the exact mechanisms have not yet been identified and their effectiveness has not yet been demonstrated in controlled clinical trials.

Antioxidants contain vitamin E or beta-carotene as substances that block free radicals. They have a positive effect on aging, but previous studies have not yet produced standards or ideal models (Werninghaus KI, "In Photodamage" (Gilchrest BA, ed) pp 249-58, Cambridge, MA: Blackwell science (1995).

Chemical peels are being studied to reduce wrinkles and uneven pigmentation. Skin abrasion and ablation are used to remove photochemical keratosis, that is, to treat deep wrinkles (Nelson BR, Majmudar G, Griffiths CEM, Gillard MO, Dixon AE, Tavakkol A, Hamilton TA, Woodbury RA, Voorhees JJ, JohnsonTM, Arch Dermatol, 130, 1136 (1994). However, double-blind, controlled studies have not yet been performed in clinical conditions or the results are inadequate.

Transplantation is used to enhance deep wrinkles that require too much to be treated by pharmacological agents. Collagen, silicone, lipids (Burke KE, Postgrad Med, 88, 207 (1990)) are used. Silicone injection is a technique that requires attention, and it is prohibited to use it for eyes or infra-orbital creases. There is also a method of autografting from the abdomen or thighs to the face or hands by fat cells, but it is not clear how long the fat cells can survive and replace them with fibrous tissue at the site of transplantation.

Major surgical treatments include blepharoplasty and wrinkle resection (Fuleihan NS, Webster RC, Smith RC, J Dermatol Surg Oncol, 16, 975 (1990)). Although it can be said that the improvement is made in physical shape, it has a disadvantage that it cannot be changed in terms of skin quality.

Although tretinoin is currently being studied most actively and has been shown to be effective compared to other methods, it has been reported to have side effects such as retinoid dermatitis (Weiss JS, Ellis CN, Headington JT, Tincoff T, Hamilton TA, Voorhess JJ, JAMA , 259, 527 (1988). The tretinoin affects a variety of biological processes such as cell growth, visual reproduction, epithelial cell proliferation, and cell differentiation and is involved in keratin synthesis, adipose secretion and the construction of extracellular matrix (ECM). In the epidermis, it shows fibroblast proliferation, metabolism of collagen, immunological control effect, and cancer prevention effect. When the amount is excessive, it is toxic, irritating the skin or inducing high malformation rate, hypervitaminosis, nausea, vomiting, It can also cause side effects that can cause headaches. It also has the disadvantage of being unstable against light, oxygen, temperature and water, and having poor skin permeability.

Therefore, the present inventors continue to study the novel polymer composition having utility as an anti-aging agent by reducing the toxicity and side effects of tretinoin, dissolving in water, and improving skin permeability and stability, thereby preparing the retinol derivative of the present invention. It became.

That is, an object of the present invention is clinically toxic by combining PEO-PPO-PEO triblock polymer or PEO-PPO diblock polymer with tretinoin, which enhances skin permeability of affinity molecules and prevents the degeneration of tretinoin by oxidation. It is to provide a novel retinol derivative having the role of this less effective anti-aging agent.

Another object of the present invention is to provide a method for preparing the retinol derivative.

1 is a UV analysis graph of the retinol derivative of the present invention.

The present invention relates to a retinol derivative having a structure of the formula (1) and having a molecular weight of 442 to 20,000.

Provided that x, y and z are integers of 1 or more and x and z are the same or z and 0 are x and y are integers of 1 or more.

In addition, the present invention is a molecular weight produced by combining the tretinoin of the formula (2) and the ethylenediamine PEO-PPO-PEO triblock polymer or the ethylenediamine PEO-PPO diblock polymer of the formula (3) using a coupling agent 442 to 20,000 and a method for producing a retinol derivative having the structure of formula (1).

Specifically, the amino group is introduced into the PEO-PPO-PEO triblock polymer (trade name: pluronic or poloxamer) or the PEO-PPO diblock polymer which is a synthetic polymer having the structure of Formula (4) The ethylenediamine PEO-PPO-PEO triblock polymer or ethylenediamine PEO-PPO diblock polymer of the following is prepared by combining with tretinoin of formula (2) using a coupling agent, the formula (1) It relates to a retinol derivative of the) and a method for preparing the same.

Provided that x, y and z are integers of 1 or more and x and z are the same or z and 0 are x and y are integers of 1 or more.

In the present invention, the ethylenediamine PEO-PPO-PEO triblock polymer or the ethylenediamine PEO-PPO diblock polymer of the formula (3) is a PEO-PPO-PEO triblock polymer or PEO having the structure of formula (4) It is preferred to make from -PPO diblock polymers.

Provided that x, y and z are integers of 1 or more and x and z are the same or z and 0 are x and y are integers of 1 or more.

PEO-PPO-PEO triblock polymer is a triblock copolymer composed of polyethylene oxide (PEO) -polypropylene oxide (PPO) -polyethylene oxide (PEO) of the formula (4), trade name pluronic or floc Sold as a poloxamer. In addition, the PEO-PPO diblock polymer is a diblock copolymer composed of polyethylene oxide (PEO) -polypropylene oxide (PPO).

Tretinoin used in the present invention is a retinoid (Retinoids) represented by the formula (2).

Hereinafter, the method for preparing a derivative of the present invention will be described in more detail by dividing the reaction into two steps.

1. Preparation of ethylenediamine PEO-PPO-PEO triblock polymer or ethylenediamine PEO-PPO diblock polymer

The reaction of introducing an amino group into a PEO-PPO-PEO triblock polymer or a PEO-PPO diblock polymer and activating the reaction is shown in Scheme (1) below.

As shown in Scheme (1), first dissolve the PEO-PPO-PEO triblock polymer or the PEO-PPO diblock polymer of the formula (4) in a suitable solvent (for example methylene chloride), and then 4-nitrophenyl Chloroformate is added to react in the presence of a neutralizing agent (eg triethylamine). At this time, to attach the amino group to only one end of the PEO-PPO-PEO triblock polymer or PEO-PPO diblock polymer, PEO-PPO-PEO triblock polymer or PEO-PPO diblock polymer: 4-nitrophenyl chloroformate: tri The molar ratio of ethylamine is preferably 1: 1: 1 to 1: 2: 2, more preferably 4: 5: 5. The reaction is carried out at room temperature, and the reaction time is preferably 3 to 5 hours.

The reaction product is then reacted with ethylenediamine to produce a PEO-PPO-PEO triblock polymer or a PEO-PPO diblock polymer substituted with an amino group of formula (3). At this time, the molar ratio between the reactants is preferably 1: 2 to 1: 4, more preferably 1: 3 to 1: 4, and reacted at room temperature for 12 to 15 hours.

2. Preparation of the derivative of the present invention by polymerization of ethylenediamine PEO-PPO-PEO triblock polymer or ethylenediamine PEO-PPO diblock polymer with tretinoin.

As shown in Scheme (2), after reacting tretinoin of Formula (2) with dicyclohexylcarbodiimide, it is a PEO-PPO-PEO triblock polymer substituted with an amino group as a dry product of Scheme (1) or The binder of the present invention is prepared by reacting with a PEO-PPO diblock polymer. At this time, the reaction time is preferably 2 to 5 days, more preferably about 3 to 4 days.

Hereinafter, the present invention will be described by specific examples, but the present invention is not limited by the following examples.

Example 1 Preparation of Ethylenediamine PEO-PPO-PEO Triblock Polymer

3 g (about 2.381 x 10 ^-4 mol) of Pluronic F127 (Ploxamer 407, X = 100, Y = 65, molecular weight about 12,600) were dissolved in 30 ml of methylene chloride as a solvent. 42 μl (about 2.965 × 10 ⁻⁴ mol) of triethylamine as a neutralizing agent was added thereto. Finally, 0.06 g (about 2.9761 x 10 ^-4 mol) of 4-nitrophenyl chloromate was added thereto. After reacting at room temperature for 4 hours, the mixture was precipitated in a poor solvent petroleum ether, filtered, and dried in a vacuum oven.

2.9 g (about 2.272 × 10 ⁻⁴ mol) of the dried product was dissolved in 29 ml of methylene chloride, and 46 μl of ethylenediamine (about 6.816 × 10 ⁻⁴ mol) was added thereto to adjust the molar ratio of 1: 3. After reacting for about 12 hours at room temperature, precipitation, filtration, and drying were performed. To remove the aromatic rings of the salt and 4-nitrophenyl chloropromate in the product was dialyzed for 3 days using a dialysis membrane with a cut-off of about 3,500. After dialysis, lyophilization yielded 1.753 g (ethylenediamine PEO-PPO-PEO triblock polymer) substituted with an amino group (yield 60%).

Example 2. Preparation of Retinol Derivatives

First, 11.9 mg of tretinoin was added to 3 ml of methanol. Then, 9.1 mg of N-hydroxysuccinimide (NHS: Mw = 115.09) was added thereto, followed by 40.9 mg of dicyclohexylcarbodiimide (DCC: Mw = 206.33), and after about 15 minutes, Example 1 50 mg of product was added and allowed to react at room temperature for 3 days. In other words, Pluronic F127: tretinoin: DCC: NHS = 1: 1: 50: 20 was reacted.

After the reaction, the dialysis membrane with cut-off of 300 or more was first dialyzed in methanol at 4 ° C. for about one day, then dialyzed in distilled water for two days, and lyophilized to obtain 20 mg of a product (yield 40%).

UV analysis of the product is shown in FIG. Referring to FIG. 1, when methanol was used as a solvent in a mixture of tretinoin alone and pluronic, it was found that λmax appeared at 340 nm. On the contrary, the conjugate (formula 1) was able to confirm that λmax was shifted to 358 nm. This indicates that the bond occurs between the two substances and the movement changes as the environment changes. Tretinoin was quantified using the λmax absorbance regression line for each concentration. As a result, it was confirmed that about 7 mg of tretinoin per 1 mg of the conjugate. The molecular weight of the conjugate varied from 518 to 20,000.

After dissolving the binder in distilled water, it was confirmed that more than 10wt% was dissolved.

Retinol derivatives of the present invention, due to the binding to the PEO-PPO-PEO triblock polymer or PEO-PPO diblock polymer, the fat-compatible material, tretinoin is dissolved in water, improves skin permeability and stability, and also has tretinoin Toxic effects and side effects are reduced, so it shows a better effect as a skin anti-aging agent by ultraviolet rays.

Claims (3)

The retinol derivative which has a structure of following General formula (1), and whose molecular weight is 442-20,000. Formula 1 Provided that x, y and z are integers of 1 or more and x and z are the same or z and 0 are x and y are integers of 1 or more. A method for preparing a retinol derivative by combining a polymer compound of formula (3), ethylenediamine PEO-PPO-PEO triblock polymer or ethylenediamine PEO-PPO diblock polymer, and tretinoin of formula (2) using a coupling agent. Formula 2 Formula 3 3. The PEO-PPO-PEO triblock polymer according to claim 2, wherein the ethylenediamine PEO-PPO-PEO triblock polymer of Formula (3) or the ethylenediamine PEO-PPO diblock polymer is a polymer compound of Formula (4) A method for producing PEO-PPO diblock polymer, characterized in that the prepared by reacting ethylenediamine. Formula 4 Provided that x, y and z are integers of 1 or more and x and z are the same or z and 0 are x and y are integers of 1 or more.