KR101620577B1 - Acne therapeutics and sebum secernent inhibitor containing chlorin derivatives, and kits for photodynamic therapy including the same - Google Patents

Abstract

The present invention relates to novel uses as an agent for treating acne of chlorin derivatives and a sebum secretion inhibitor. More specifically, the present invention relates to: a photosensitizer for photodynamic therapy (PDT), containing chlorin derivatives having activation properties due to rays; a kit for PDT, comprising the same; and a composition for PDT. In addition, the present invention relates to novel uses as an agent for treating acne and a sebum secretion inhibitor.

Description

FIELD OF THE INVENTION The present invention relates to an acne remedy and an anti-sebum secretion inhibitor, and a photodynamic therapy kit containing the same,

The present invention relates to a novel therapeutic use of chlorin derivatives as acne remedy and sebum secretion inhibitor. More particularly, the present invention relates to a photosensitizer for photodynamic therapy (PDT) containing a choline derivative having a property to be activated by light, a photodynamic therapy kit comprising the same and a composition for photodynamic therapy And relates to a novel use as an acne remedy and sebum secretion inhibitor.

Photodynamic therapy (PDT) is one of the most promising treatments in recent cancer treatments. The principle of photodynamic therapy is the singlet oxygen, which is derived from a comprehensive chemical reaction between oxygen and light (photons) supplied externally and photosensitizer (photosensitizer) Or free radicals destroy various lesions or cancer cells to treat cancer.

The advantage of this photodynamic therapy is that it is easy to remove only diseased cells while preserving normal cells, thereby eliminating the risk of general anesthesia and allowing easy operation with local anesthesia alone . Therefore, photodynamic therapy is not only superior in cancer cell specific elimination effect, but also has a good socioeconomic effect by improving the quality of life of the patient by shortening the hospitalization period and facilitating the return of social activities .

Photodynamic therapy has been studied in earnest since the 1980s. Since the 1990s, when clinical procedures were approved in Canada, Germany, and Japan, the US FDA approved the treatment of esophageal cancer in January 1996, And approved for lung cancer treatment. By early 1996, about 3,000 photodynamic therapies were performed in about 32 countries.

However, current photodynamic therapy has the problem that light is not able to penetrate the entire tumor in bulky tumors, which limits its use. Most of the photosensitizers, such as porphyrin, are expensive, There is a problem in that the effect of photodynamic therapy can not be sufficiently observed because the metabolism is slow and side effects of phototoxicity occur and the concentration of the photosensitizer in the tumor is low.

Photofrin ^™, a light sensitizer used in photodynamic therapy, was approved by the US FDA in 1996 and has good therapeutic efficacy and stability. However, cumulative accumulation in the body for 5 to 6 weeks after dosing can cause side effects, and pure Photofrin ^™ is difficult to produce and due to absorption at 630 nm, which is less than 650-850 nm, known to be the optimal condition for photodynamic therapy, (Chemistry & Industry, Sep 21, 1998, 739-743: Chemical & Engineering News, Nov 2, 1998, 22-27). Thus, there is a disadvantage in that relatively few therapeutic effects are required , There is an urgent need to develop a new photosensitizer that overcomes these problems.

Among the compounds known as the next-generation photosensitizers are porphyrins, chlorines, bacteriochlrins, and porphycenes (J Org. Chem., 63, 1998, 1646 -1656). Of these, pheophytins, which remove metal ions from chlorophylls, which are widely distributed in plants, are more susceptible to long-wavelength absorption than Photofrin ^TM , a hematoporphyrin derivative, As a result, many studies have been focused on the next generation of photosensitizers, but they have not yet achieved remarkable results.

In recent years, attempts have been made to use these photodynamic therapies for the treatment of acne and psoriasis. Aminolevulinic acid (ALA) is mainly used as a photosensitizer for acne treatment. It should be avoided for a long period of time like the photosensitizer mentioned above. The disadvantage is that the side effects are severe.

As described above, until now, various researches and efforts have been made on the photosensitizing substance, and some of them have been developed as a therapeutic agent for acne, but the patient has inconvenience in daily life and serious side effects. It has been urgently required to develop new photosensitizers for easy and safe application to the human body.

On the other hand, the inventors of the present invention have found that chlorin derivatives of Korean Laid-Open Publication No. 2009-0027470 filed on September 12, 2007 exhibit excellent anti-acne and phyto-secretory effects, The present invention has been completed.

The object of the present invention can be attained by identifying a novel pharmacological effect as a photosensitizer for the treatment of acne of a chlorin derivative or inhibition of sebum secretion.

It is another object of the present invention to provide a photodynamic agent for photodynamic therapy (PDT) containing a chlorine derivative which is activated by light rays for the treatment of acne or inhibition of sebum secretion, and a photodynamic therapy kit And a composition for photodynamic therapy.

According to one embodiment, the present invention discloses a photosensitizer containing a chlorine derivative of formula (I) or (II) for acne treatment or sebaceous gland control.

[Chemical Formula 1]

(2)

(In the above formula (1) or (2)

R is a hydrogen atom, a monovalent metal ion, a straight chain, a branched or cyclic alkyl group having 1 to 20 carbon atoms, a straight chain, a branched or cyclic heteroalkyl group having 2 to 20 carbon atoms including a hetero atom, and a carbohydrate group;

,

,

이며; R 1, R 2, R 3, R 4 and R 5 are the same or different and each represents a hydrogen atom, a straight chain, a branched or cyclic alkyl group having 1 to 20 carbon atoms, an alkylcarboxylate group having 2 to 20 carbon atoms,

,

,

;

A1 is a straight chain, branched or cyclic alkyl group having 1 to 20 carbon atoms, a straight chain, a branched or cyclic alkyl group having 2 to 20 carbon atoms containing an alkenyl group hetero atom, an alkenyl group, a straight chain having 2 to 20 carbon atoms containing a hetero atom, A branched or cyclic heteroalkyl or heteroalkenyl group;

A2, X, Y, Z and R6 are the same or different from each other and are a carbon atom or a hetero atom; A3 represents a halogen atom, a hetero atom, a straight chain, a branched or cyclic alkyl group of 1 to 20 carbon atoms, an alkenyl group of 2 to 20 carbon atoms, an allyl group of 2 to 20 carbon atoms, a heteroaryl group of 3 to 20 carbon atoms containing a hetero atom ≪ / RTI >

According to another embodiment, the present invention provides a photodynamic therapy composition comprising a therapeutically effective amount of a choline derivative having the structure of the above formula (1) or (2) having photoactivating properties as an active ingredient for acne treatment or sebum secretion regulation do.

According to another embodiment, the present invention provides a kit for photodynamic therapy comprising a chlorine derivative having the structure of Formula 1 or 2 and a light source for in vivo or in vitro irradiation.

The chlorine derivative having the structure of formula (1) or (2) according to the present invention is used as a new photosensitizer and exhibits acne treatment and suppression of sebum secretion. The chlorin derivative having the structure of formula (I) or (II) according to the present invention is expected to be commercially used in the pharmaceutical industry as a novel acne remedy or sebum secretion inhibitor.

1 is a photograph showing an acne improvement effect of a patient according to Experimental Example 1 of the present invention.

Hereinafter, the present invention will be described in more detail with reference to examples. However, these examples are for illustrative purposes only, and the scope of the present invention is not limited to these examples.

The present invention is to provide a photosensitizer containing a chlorine derivative for acne treatment or sebum secretion regulation.

As used herein, the term " chlorin " refers to a large heterocyclic aromatic ring consisting of pyrrole and pyrroline connected by four methine bonds at the center. Magnesium-containing chlorine is called chlorophyll, and it is a central light sensitizing dye in the chloroplast.

The term " chlorine derivative " as used herein means a compound having the above-mentioned chlorine as a basic skeleton structure. Chlorine and choline derivatives are effectively used as photosensitizers in photodynamic therapy because of their photosensitizing properties. In particular, chlorine and chlorine derivatives can be used more effectively in curing photosensitizers because they have good spectral characteristics and low toxicity on the one hand, and on the other hand have many reaction center points which enable various chemical conversions to be carried out have.

In the photosensitizer containing the chlorin derivative for acne treatment or sebum secretion regulation according to the present invention, the chlorin derivative is characterized by being represented by the following formula (1) or (2).

[Chemical Formula 1]

(2)

(In the above formula (1) or (2)

R is a hydrogen atom, a monovalent metal ion, a straight chain, a branched or cyclic alkyl group having 1 to 20 carbon atoms, a straight chain, a branched or cyclic heteroalkyl group having 2 to 20 carbon atoms including a hetero atom, and a carbohydrate group;

,

,

이며; R 1, R 2, R 3, R 4 and R 5 are the same or different and each represents a hydrogen atom, a straight chain, a branched or cyclic alkyl group having 1 to 20 carbon atoms, an alkylcarboxylate group having 2 to 20 carbon atoms,

,

,

;

A1 is a straight chain, branched or cyclic alkyl group having 1 to 20 carbon atoms, a straight chain, a branched or cyclic alkyl group having 2 to 20 carbon atoms containing an alkenyl group hetero atom, an alkenyl group, a straight chain having 2 to 20 carbon atoms containing a hetero atom, A branched or cyclic heteroalkyl or heteroalkenyl group;

A2, X, Y, Z and R6 are the same or different from each other and are a carbon atom or a hetero atom;

A3 represents a halogen atom, a hetero atom, a straight chain, a branched or cyclic alkyl group of 1 to 20 carbon atoms, an alkenyl group of 2 to 20 carbon atoms, an allyl group of 2 to 20 carbon atoms, a heteroaryl group of 3 to 20 carbon atoms containing a hetero atom ≪ / RTI >

In the photosensitizer containing a chlorine derivative for treating acne according to the present invention, R is a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms;

R1 is a hydrogen atom or an alkylcarboxylate group having 2 to 20 carbon atoms;

A1 is a straight chain, branched or cyclic alkyl group having 1 to 20 carbon atoms, a straight chain, a branched or cyclic alkyl group having 2 to 20 carbon atoms containing an alkenyl group hetero atom, an alkenyl group, a straight chain having 2 to 20 carbon atoms containing a hetero atom, A branched or cyclic heteroalkyl or heteroalkenyl group;

X and Y are nitrogen atoms;

R4 and R5 are the same or different from each other and are a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms;

Z is an oxyethyl group; And

R6 may be an oxygen atom.

In the photosensitizer containing a chlorine derivative for acne treatment or sebum secretion regulation according to the present invention,

R is a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms;

A1 is a straight chain, branched or cyclic alkyl group having 1 to 20 carbon atoms, a straight chain, a branched or cyclic alkyl group having 2 to 20 carbon atoms containing an alkenyl group hetero atom, an alkenyl group, a straight chain having 2 to 20 carbon atoms containing a hetero atom, A branched or cyclic heteroalkyl or heteroalkenyl group;

X and Y are nitrogen atoms;

R4 and R5 are the same or different and each is a hydrogen atom or a straight or branched alkyl group having 1 to 20 carbon atoms;

Z is an oxyethyl group;

R6 is an oxygen atom;

A2 is a nitrogen atom;

A3 may be a straight chain or branched chain alkyl group having 1 to 20 carbon atoms.

In the photosensitizer containing the chlorin derivative for acne treatment or sebum secretion control according to the present invention, the chlorin derivative may be selected from the group consisting of:

3-devinyl-3- [3 '(R, S) -5'-methyl- (1'-pyrazolinyl)] perophorbide-a carboxylate,

3-devinyl-3- [3 '(R, S) -5'-isopropyl- (1'-pyrazolinyl)] perophoride-a carboxylate,

3-devinyl-3- [3 '(R, S) -5'-ethyl-1'-pyrazolinyl)] perophoroid-a carboxylic acid,

3-vinyl-pero-pivalo-a carboxylate

3-vinyl-pero-pivalo-a carboxylate

(R, S) -5'-ethyl-1'-pyrazolinyl)] perovosidic acid, 3-decvinyl-3- [3 ' R, S) -5'-ethyl-1'-pyrazolinyl)] perophoride-a carboxylate,

3- (1-tropon-4-isopropyloxyethyl) -3-devinylpopoboid-a carboxylic acid,

3- (1-Tropon-4-isopropyloxyethyl) -3-devinylpyrrolephosphide-a carboxylate,

3- (1-Troponoxyethyl) -3-devinylphosphobde-a carboxylate,

3- (1-Troponoxyethyl) -3-devinylpyrrole-a carboxylic acid,

2- (2-acetyl-3-oxobutyl) -2-develyl pyrophosphobde-a carboxylate,

2- (3 ', 5 ' -dimethyl-lH-pyrazole-methyl) -2-devinylpyrrole-

2- (2-acetyl-3-oxobutyl) -2-devinylphosphobde-a carboxylate,

2- (3 ', 5 ' -dimethyl-lH-pyrazol-methyl) -2-devinylphephobde-a carboxylate,

2- (2-hydroxymethyl) -2-devinylpropepo-pivalo-a carboxylic acid,

2- (2-acetyl-3-oxobutyl) -2-develyl pyrophosphobde-a carboxylate, and

2- (3 ', 5 ' -dimethyl-lH-pyrazol-methyl) -2-devinylpyrophosphobde-a carboxylate.

In the photosensitizer containing the chlorin derivative for acne treatment or sebum secretion regulation according to the present invention, the light rays capable of photoactivating the chlorin derivative may be ultraviolet rays and visible rays. The wavelength range of the light beam is not particularly limited, but may be 280 nm to 1000 nm, preferably 500 nm to 900 nm, and more preferably 630 nm to 880 nm.

A light-sensitive agent containing a chlorine derivative for the treatment of acne or sebum secretion according to the present invention is characterized in that the light source for irradiating the light is an ultraviolet radiation emitter, a light emitting diode, a laser diode, a dye laser, A lamp, a mechanically filtered fluorescent light source, a mechanically filtered incandescent and filament light source.

The present invention also provides a composition for photodynamic therapy comprising a therapeutically effective amount of a choline derivative having the structure of the above formula (1) or (2) having photoactivating properties as an active ingredient for acne treatment or sebum secretion regulation.

In a photodynamic therapy composition containing a therapeutically effective amount of the choline derivative according to the present invention, the choline derivative is used in an amount of 0.001 to 99 wt%, preferably 0.001 to 30 wt%, more preferably 0.001 wt% % ≪ / RTI > to 20% by weight of the composition. In order to obtain sufficient photosensitizing effect and therapeutic effect of a sufficient amount of the chlorine derivative, the content of the chlorine derivative is preferably 0.001% by weight or more.

In a composition for photodynamic therapy comprising a therapeutically effective amount of a choline derivative according to the present invention, the composition may be used in liquid, semi-solid, solid or aerosol form, for example, as an aqueous or nonaqueous suspension, , An ointment, a gel, a syrup, a suppository, a tablet, a capsule or a droplet spray, and the like.

In a photodynamic therapy composition containing a therapeutically effective amount of the choline derivative according to the present invention, the composition may further comprise an excipient necessary for the formulation as described above. The composition may further contain a preservative selected from the group consisting of conventional preservatives, stabilizers, buffers, pH adjusting agents, sweeteners, flavors and dyes, depending on the requirements of storage and administration conditions, have. In addition, the composition may further comprise one or more other drugs of the desired therapeutic effect.

In a composition for photodynamic therapy containing a therapeutically effective amount of the choline derivative according to the present invention, the choline derivative having a photosensitizing activity contained in the composition is light-irradiated before light irradiation, or light And may be optically activated by irradiation.

The present invention also provides a kit for photodynamic therapy comprising a chlorin derivative having the structure of Formula 1 or 2 and a light source for irradiation in vivo or in vitro.

The chlorine derivative having the structure of formula (1) or (2) according to the present invention is used as a new photosensitizer and exhibits an acne treatment or sebaceous gland inhibiting effect. The chlorin derivative having the structure of formula (I) or (II) according to the present invention is expected to be commercially used in the pharmaceutical industry as a novel acne remedy or sebum secretion inhibitor.

Hereinafter, the present invention will be described in more detail by way of examples. However, the present invention is not limited by the following examples.

<Examples>

Example 1: Preparation of chlorine derivatives

Dichloromethane (60 ml) and diazoethane solution (25 ml) were added to methyl pheophobide-a (MPa, 146 mg) and reacted. Respectively. The resulting solution was removed in vacuo, hydrolyzed with aqueous NaOH solution, neutralized with dilute hydrochloric acid and then chromatographed on a silica gel column to give the desired compound 3-Devinyl-3- [3 '(R, S) (1'-pyrazolinyl)] pheophorbide-a carboxylic acid.

Example 2: Preparation of chloropyridyl ester

Add acetone (1000 ml) to Spirulina and stir for 12 hours. Remove the filtrate under vacuum, add 200 ml of methylene chloride, transfer to a separatory funnel, add 300 ml of diluted hydrochloric acid solution several times, Followed by chromatography on a silica gel column to obtain 250 mg of the target compound 3-vinyl-pheophorbide-carboxylic acid phythyl ester.

Example 3: Preparation of the preparation of chloromethyl ester

Methanol (1000 ml) containing 5% sulfuric acid was added to 500 g of spirulina and stirred for 12 hours. After filtration, the filtrate was removed in vacuo and the residue was chromatographed on a silica gel column to obtain 220 mg of the target compound 3-vinyl- &Lt; / RTI &gt;

Example  4: Chlorine  Effect of derivatives on acne improvement

4-1. The acne improvement effect of the chlorin derivative according to Example 1

In order to confirm the acne improvement effect of the chlorin derivative prepared in Example 1, a single-blind randomized clinical trial was conducted. Twenty patients with mild to moderate facial acne vulgaris were enrolled in this study. An LED Phototherapy Mask was used in which the preparation containing 10% of the chlorin derivative prepared in Example 1 was coated on the faces of the patients and red light (660 nm) and infrared rays (880 nm) were irradiated. The investigation was carried out for 3 weeks at intervals of 2 weeks for 6 weeks according to the following procedure, and the number of inflammatory lesions was counted to observe the degree of improvement (Fig. 1). The number of inflammatory lesions before and after the administration of the chlorin derivatives is averaged, and is shown in Table 1 below.

(1) Deep cleansing

(2) If there is a pustule -> extraction

(3) Alcohol disinfection

(4) Applying a photosensitizer containing 10% of the chlorin derivative according to Example 1

(5) Penetration of photosensitizer

(6) Lightly cleanse with ethanol

(7) LED irradiation: Red & IR wavelength is investigated simultaneously (15 ~ 20 minutes)

(8) After cleansing, calm and after treatment with a calm pack.

Before After Reduction rate Number of inflammatory lesions 12.31 + - 11.56 4.38 ± 3.88 64.42%

As shown in Table 1, the number of inflammatory lesions was decreased from 12.31 ± 11.56 before treatment to 4.38 ± 3.88 after 3 treatments, which was about 65% By showing a statistically significant chirality, it was confirmed that the chlorin derivative prepared according to Example 1 was effective for the treatment of acne.

4-2. The acne improvement effect of the chlorinpityl ester according to Example 2

Using the same method as in Example 4-1, the acne remediation effect of the chlorophyll ester prepared in Example 2 was measured. The number of inflammatory lesions before and after the administration of the chlorpentyl ester was averaged, and is shown in Table 2 below.

Before After Reduction rate Inflammatory lesion 12.00 ± 11.03 4.25 ± 3.91 64.58%

Comparison of the number of inflammatory lesions before treatment showed that the number of inflammatory lesions decreased from 12.00 ± 11.03 before treatment to 4.25 ± 3.91 after 3 treatments as shown in Table 2, By showing a statistically significant chirality, it was confirmed that the chlorinpityl ester prepared according to Example 2 was effective in the treatment of acne.

4-3. Effect of chlorin methyl ester according to Example 3 on acne improvement

The acne improvement effect of the chlorinomethyl ester prepared in Example 3 was measured using the same method as in Example 4-1. The number of inflammatory lesions before and after the administration of chlorin methyl ester was averaged and is shown in Table 3 below.

Before After Reduction rate Inflammatory lesion 12.44 + - 11.53 4.45 ± 3.85 64.22%

As shown in Table 3, the number of inflammatory lesions was reduced from 12.44 ± 11.53 before treatment to 4.45 ± 3.85 after 3 treatments, and the reduction rate of inflammatory lesions was about 65% By showing a statistically significant chime, it was confirmed that the chlorinemethyl ester prepared according to Example 3 was effective for the treatment of acne.

Example 5 Effect of Reduction of sebum Secretion by Choline Derivatives

5-1. The acne improvement effect of the chlorin derivative according to Example 1

The amount of sebum secretion was measured using the same method as in Example 4, and the degree of improvement was observed. The average amount of sebum secretion before and after administration of the chlorin derivative is shown in Table 4 below.

Before After Reduction rate Sebum secretion amount 9.62 ± 2.66 4.08 ± 2.14 57.59%

As can be seen from the above Table 4, the reduction rate was about 60%, from 9.62 ± 2.66 before treatment to 4.08 ± 2.14 after 3 treatments, which shows statistically significant difference. As a result, It was confirmed that the derivative had an effect of inhibiting sebum secretion.

5-2. The acne improvement effect of the chlorinpityl ester according to Example 2

The sebum secretion amount of the chlorophyll ester prepared in Example 2 was measured using the same method as in Example 5-1, and the degree of improvement was observed. The average amount of sebum secretion before and after the administration of the chlorpentyl ester was shown in Table 5 below.

Before After Reduction rate Sebum secretion amount 9.61 ± 2.68 4.12 ± 2.11 57.12%

As can be seen from Table 5, the reduction rate was about 60%, from 9.61 ± 2.68 before treatment to 44.12 ± 2.11 after 3 treatments. This shows statistically significant difference, It was confirmed that the phytate ester had an inhibitory effect on sebum secretion.

5-3. Effect of chlorin methyl ester according to Example 3 on acne improvement

Using the same method as in Example 5-1, sebaceous secretion amount of the chlorinomethyl ester prepared in Example 3 was measured and the degree of improvement was observed. The average amount of sebum secretion before and after the chlorin methyl ester was shown in Table 6 below.

Before After Reduction rate Sebum secretion amount 9.54 + - 2.57 4.01 ± 2.02 57.97

As can be seen from the above Table 6, the reduction rate was about 60%, which was 4.01 ± 2.02 after three treatments at 9.54 ± 2.57 before treatment. This shows a statistically significant difference, Methyl ester was found to have an inhibitory effect on sebum secretion.

It is to be understood that the specific structural or functional descriptions are illustrative only for the purpose of illustrating embodiments of the present invention and that the embodiments of the present invention may be embodied in various forms and that all changes, &Lt; / RTI &gt;

Claims (7)

A photosensitizer comprising a chlorine derivative for the treatment of acne or inhibition of sebum secretion,
The choline derivative may be a 3-devinyl-3- [3 '(R, S) -5'-methyl- (1'-pyrazolinyl)] perophoride- -Carboxylic acid ester and 3-vinyl-perofovide-acarboxylic acid ester,
Wherein said choline derivative exhibits a photosensitizing activity against light rays in the range of 660 nm to 880 nm.
The method according to claim 1,
Wherein the chlorine derivative is contained in an amount of 0.001 wt% to 30 wt%.
A photosensitizer according to any one of claims 1 and 2, and
A kit for the treatment of photodynamic acne and inhibition of sebum secretion, comprising a light source generating a light beam having a wavelength in the range of 660 nm to 880 nm.
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