KR102285696B1 - A topical pharmaceutical composition for treating or preventing scar - Google Patents

Abstract

Disclosed is a composition for the prevention or treatment of scarring.

Description

A topical pharmaceutical composition for treating or preventing scar

The present invention relates to a topical pharmaceutical composition containing heparin or a pharmaceutically acceptable salt thereof or heparinoid, dexpanthenol and allantoin, for the prevention or treatment of scarring. The pharmaceutical composition according to the present invention can maximize the scar treatment effect, and it is possible to prevent and improve erythema or pigmentation of the scar.

Scar refers to abnormally defective skin tissue in which normal tissue viability is lost and the tissue structure or physiological function of the skin is lost. When the skin or dermis is injured, the body triggers an accurate and rapid wound healing response, and the damaged tissue is reconstructed or created as part of the repair process. Scarring is a normal and essential physiological response to the healing of a wound or wound surface and is a consequence of the wound healing process.

In deeply damaged skin, collagen in the dermis layer (thick cell layer under the epidermis) proliferates excessively, and even after the wound is healed, the thinned skin is pushed out, leaving a scar. Abnormal scars formed by this process are called hypertrophic scars or keloids, and they appear higher than the surface of normal skin, and in severe cases, itchy or painful.

Hypertrophic scarring is a phenomenon in which excessive scarring occurs at the wound site, and it does not grow any more over time. Keloids are irregular and hard fibroids formed by wounds, surgery, burns, and inflammation. Initially, the symptoms are similar to hypertrophic scars, but over time, they grow wider than the wounded area and invade the normal skin, increasing in size and roughening the surface. A surgical procedure is required to remove this fibroid, and it often recurs from the scars of surgery.

As such, abnormal scars may be rounded or reddish, often accompanied by itching or pain. These abnormal scars can be reduced in size or pale in color using scar treatment agents.

A scar is different from the surrounding skin in color, roughness, or flexibility of the skin. When a scar occurs in the visible area, the person is subjected to severe mental stress, and the scar formed in the area where the stretching is caused damages the skin tissue again and the treatment time becomes longer, and the contraction of the surrounding tissue due to stretching is It causes a lot of inconvenience in life.

Conventionally, methods for preventing or improving scars using a silicone gel sheet or silicone ointment have been disclosed, but there are problems in that it is inconvenient to use because of its stickiness, the scar treatment effect is not greater than expected, and the effect of preventing pigmentation or erythema is insignificant. .

As drug therapy, a gel of complex components including heparin, dexpanthenol, onion extract, and allantoin is used.

Heparin, a kind of acidic polysaccharide, loosens the collagen structure, softens the scar tissue structure, and has anti-inflammatory, anti-allergic and anti-swelling actions. In addition, it treats scars by inhibiting the hyperproliferation of fibroblasts and promoting the regeneration of cells and tissues.

Onion extract is contained as an active ingredient in various scar treatment ointments, and has antibacterial and anti-inflammatory effects to reduce pigmentation, and inhibit excessive proliferation of fibroblasts to prevent excessive scar tissue formation.

Dexpanthenol is a derivative of vitamin B5, pantothenic acid, which helps to generate cellular energy to regenerate damaged skin tissue and promote skin function.

Allantoin loosens the scar tissue structure, induces keratolysis and epithelial formation, and increases drug permeability, thereby suppressing the inflammatory response and minimizing scar formation, skin pigmentation and itching.

The complex ingredient gel containing heparin is used for the treatment of surgery, amputation, burns, hypertrophic scars after accidents, keloids, movement-restricted scars, and scars from skin damage for cosmetic purposes.

In addition, attempts have been made to improve the scar treatment effect through the utilization and formulation technology of various active ingredients in relation to scar treatment.

Korean Patent Publication No. 10-2018-0076871 discloses a silicone composition and a scar treatment agent comprising the same, wherein the silicone resin in the scar treatment agent is a mixture of a silicone elastomer, a film former, a silicone fluid and a cyclic siloxane, and the final It is characterized in that it contains 5 to 70% by weight in the formulation.

Korean Patent Publication No. 10-0844831 contains onion extract, allantoin and sodium heparin, and mixes alginate, chitosan, gum, synthetic polymer base, preservative and alkaline emulsifier to stabilize the system, resulting in phase separation and recrystallization of active ingredients A composition without it is disclosed. The composition is characterized in that it contains 0.3 to 1% of allatoin and 0.01% to 0.03% of sodium heparin, based on the total weight of the composition.

Korean Patent Publication No. 10-1397114 discloses a composition in which allantoin, onion extract, and heparin sodium as active ingredients, and allantoin, a sparingly soluble active ingredient, is solubilized using methylpyrrolidone and dl-α-tocopherol acetate. there is. Among 100 parts by weight of the total composition, the weight ratio of allantoin, onion extract and heparin sodium is 1: 5-15: 0.01-0.1 parts by weight, and allantoin has a particle size of 100-500 μm.

However, the effect of the developed scar treatment agent is not satisfactory. Therefore, it is necessary to develop a formulation capable of maximizing the scar treatment effect and improving scar erythema or pigmentation by increasing the absorption of the active ingredient.

Korean Patent Publication No. 10-2018-0076871 Korean Patent Publication No. 10-0844831 Korean Patent Publication No. 10-1397114

An object of the present invention is to provide a formulation capable of maximizing a scar treatment effect and improving scar erythema or pigmentation by increasing the absorption of an active ingredient. In addition, an object of the present invention is to provide a pharmaceutical composition for treating and preventing scars with improved feeling of use and increased convenience by reducing the stickiness of the composition.

In order to achieve the above object, the present invention exhibits a scar treatment effect by dissolving, dispersing and mixing the active ingredient, and also prevents and improves erythema or pigmentation of the scar as a thin film layer is formed, and reduces the stickiness of the composition. decreased to improve the usability.

Specifically, the composition of the present invention comprises (a) heparin or a pharmaceutically acceptable salt thereof (eg, heparin sodium) or heparinoid as an active ingredient; (b) dexpanthenol; And (c) it relates to a pharmaceutical composition for treating or preventing scars, including allantoin, and further containing silicone oil.

In the present invention (a) the content of heparin or a pharmaceutically acceptable salt or heparinoid is 0.07 to 0.9 wt% (preferably 0.15 to 0.3 wt%) based on the total weight of the composition,

The content of dexpanthenol is 3 to 20% by weight (preferably 7 to 14% by weight) based on the total weight of the composition,

The content of allantoin is 2 to 9% by weight (preferably 3 to 7% by weight) based on the total weight of the composition,

The content of the silicone oil is preferably 3 to 70% by weight (preferably 3 to 30% by weight) based on the total weight of the composition.

In the present invention, the heparin or a pharmaceutically acceptable salt or heparinoid may be included in an amount of 200 to 900 IU in 1 g of the pharmaceutical composition.

In the present invention, (a) heparin or a pharmaceutically acceptable salt or heparinoid thereof and (b) dexpanthenol exist in a dissolved state in the composition, and (c) allantoin is dissolved and particles in the composition may exist in a supersaturated state.

In the present invention, the allantoin particles have a d(0.9) particle size of 60-100 μm, preferably a d(0.9) particle size of 60-80 μm.

The pharmaceutical composition according to the present invention may be a liquid formulation, a gel formulation or an ointment formulation, and may be a topical composition.

In the present invention, as the silicone oil, dimethicone, polysilicone-11 (Polysilicone-11), polysilicone-15 (Polysilicone-15), polysilicon-8 (Polysilicone-8), polysilicone-17 ( Polysilicone-17), Hydrogen Dimethicone, Lauryl Dimethicone, Cyclopentasiloxane, Cyclohexasiloxane, Trisiloxane, Methyl Trimethicone ), phenyl dimethicone, dimethicone copolyol, dimethicone copolyol acetate, silicone glycol copolyol, dimethicone, methylpolysiloxane, methylphenylpolysiloxane, dimethiconecopolyolmethylether, methylcyclo At least one selected from the group consisting of polysiloxane, dimethylpolysiloxane, hexamethyldisiloxane and caprylylmethylpolysiloxane may be used, and preferably dimethicone, dimethicone copolyol, dimethicone copolyol acetate, dimethicone copolyol . At least one selected from the group consisting of polydimethylsiloxane and methylpolysiloxane may be used, and more preferably polydimethylsiloxane may be used.

The composition of the present invention may further comprise Carbopol.

The present invention provides the following effects.

First, since the composition according to the present invention contains silicone oil, it can be applied gently to the skin without feeling of foreign body, is convenient because it is not sticky, and when applied to a scar, it dries quickly and forms a thin silicone film to protect the scar and block UV rays And it is effective in preventing and improving erythema or pigmentation of scars due to its antioxidant effect, thereby increasing scar treatment and improvement.

Second, since the composition according to the present invention contains Carbopol, it has an effect of improving stickiness.

1 is a graph comparing scar elevation index (SEI) values for a composition of the present invention and a composition of a comparative example.

The present invention relates to an active ingredient comprising (a) heparin or a pharmaceutically acceptable salt thereof (eg, heparin sodium) or heparinoid; (b) dexpanthenol; And (c) it relates to a pharmaceutical composition for treating or preventing scars, including allantoin, and further containing silicone oil.

In the present invention (a) the content of heparin or a pharmaceutically acceptable salt thereof (eg, heparin sodium) or heparinoid is 0.07 to 0.9 wt% (preferably 0.15 to 0.3 wt%) based on the total weight of the composition %)ego,

The content of dexpanthenol is 3 to 20% by weight (preferably 7 to 14% by weight) based on the total weight of the composition,

The content of allantoin is 2 to 9% by weight (preferably 3 to 7% by weight) based on the total weight of the composition,

The content of the silicone oil is preferably 3 to 70% by weight (preferably 3 to 30% by weight) based on the total weight of the composition.

1 g of the composition of the present invention contains 0.7 to 9 mg (preferably 1.5 to 3 mg) of heparin or a pharmaceutically acceptable salt or heparinoid thereof.

Heparin is a substance composed of alternating α-1,4 bonds between D-glucosamine and D-glucuronic acid. Heparin is a drug used to prevent blood clotting by inhibiting the action of thrombin. Used for thrombosis, etc. Usually, bruising cream contains 400 IU/g and scar ointment contains 50 IU/g. The low content of heparin reduces collagen production to soften the wound, and suppresses the overgrowth of fibroblasts with anti-inflammatory action to suppress scarring and soften the skin, helping other ingredients in the ointment to be absorbed well into the skin. give. It also has the effect of reducing itching caused by wounds.

1 g of the composition according to the invention contains 30 to 200 mg (preferably 70 to 140 mg) of dexpanthenol.

Dexpanthenol is a derivative of pantothenic acid, which is a type of vitamin B5. It is called provitamin of vitamin B5 and has high safety. Dexpanthenol promotes wound healing, regenerates damaged skin tissue, and reduces pigmentation in scars by causing skin tissue regeneration, hydration to the stratum corneum, and alleviating inflammation. In addition, it helps the allantoin component to be absorbed into the skin, increasing the scar treatment effect.

1 g of the composition according to the invention contains 20 to 90 mg (preferably 30 to 70 mg) of allantoin.

Allantoin is a substance produced by oxidation of uric acid present in the allantois of mammals, and has the chemical name (2,5-dioxo-4-imidazolidinyl)urea, and is represented by the following Chemical Formula 1 has the structure of:

[Formula 1]

Allantoin softens the scar tissue structure, has a scar healing effect through keratolysis and epithelial formation, and relieves itching. In addition, by increasing drug permeability, it suppresses the inflammatory response and reduces skin pigmentation and scar formation.

1 g of the composition according to the present invention contains 30 to 700 mg (preferably 30 to 300 mg) of silicone oil.

By including the silicone oil, the composition of the present invention may have both the effect of hiding scars and the effect of preventing or treating scars. Silicone oil is a biocompatible raw material that is harmless to the human body, is safe, can be applied gently to the skin, is convenient because it is not sticky, and when applied to a scar, it dries quickly and forms a thin silicone film to protect the scar and create a moisture environment. By providing pressure, the permeability of the drug is increased, collagen deposition is reduced, and scarring is greatly improved. In addition, it is effective in preventing and improving erythema or pigmentation of scars by UV blocking and antioxidant effects, thereby enhancing the effects of scar prevention, treatment and improvement, and also providing a pharmaceutical composition excellent in flexibility, waterproofness and moisturizing properties. there is.

The composition according to the invention may contain an appropriate amount of carbopol. Carbopol is a substance that acts as a thickener and also acts as a bioadhesion to increase biological capacity and control the release of insoluble components in suspensions or emulsions. It is widely used in hair products such as shampoos, styling gels, and mousses, and skin products such as creams, lotions, sunblocks, shower gels, and depilatories. Representative examples of Carbopol include Carbomer 940 and Carbomer 941.

Carbomer 940 is a high molecular weight polymer crosslinked with acrylic acid, dried under vacuum at 80° C. for 1 hour, and contains 56 to 68% of carboxylic acid groups (-COOH), and 0.5% of Carbomer 940 ( The viscosity of water) is 40,000 - 60,000 cps.

Carbomer 941 is a high molecular weight polymer crosslinked with acrylic acid, dried under vacuum at 80° C. for 1 hour, and contains 56 - 68% carboxylic acid groups (-COOH), 0.5% Carbomer 941 The viscosity of (water) is 4,000 - 11,000 cps.

The particle size (particle size) of allantoin used in the composition of the present invention can be controlled using various known methods. For example, a ball mill, a bead mill, a roll mill, a rotor mill, a jet mill, a jet mill, The particles can be made small by milling the raw material using a milling machine such as a Fitz mill. The milling may be performed in a dry process or a wet process, and the final particle size is in the range according to the present invention (for example, 60 to 100 μm, Preferably, it is possible to reduce the particle diameter so that it can exist within 60 to 80 μm, d (0.9)).

In the present specification, the particle size d(0.9) refers to the diameter of the particle at a point reaching 90% of the total volume by accumulating from the particle having the smaller particle diameter in the entire particle size distribution curve.

The composition according to the present invention may include additional additives to maximize the medicinal effect of the above active ingredients and facilitate administration, and may be prepared in various pharmaceutical formulations such as gels, creams, liquids, and ointments.

For example, the composition according to the present invention may include, as an additive, a thickener, a base, a solvent, a preservative, a pH adjuster, a flavoring agent, a humectant, and the like.

Further, the present invention relates to a method for preparing a pharmaceutical composition for the treatment of scars comprising the steps of:

(a) dissolving or dispersing Carbopol in a solvent or dispersion medium (eg, purified water or a mixture of alcohol and purified water);

(b) dispersing sodium heparin or a salt thereof or heparinoid, dexpanthenol and allantoin into the solution or dispersion prepared in step (a);

Step (c) of mixing the dispersion prepared in step (b) and silicone oil.

The method for preparing the pharmaceutical composition according to the present invention may further include the step (d) of mixing by adding an additive.

[Example]

Hereinafter, the present invention will be described in detail by way of Examples. However, the following examples are only illustrative of the present invention, and the content of the present invention is not limited by the following examples.

Example 1-4: Preparation of a composition according to the type of silicone oil

The compositions of Examples 1 to 4 were prepared in the following manner with the compositions and contents shown in Table 1 below:

Carbopol was dispersed or dissolved in 15 g of purified water, dissolved by adding sodium heparin and dexpanthenol, and then allantoin was added to the mixture and dissolved or dispersed to prepare a mixture. Silicone oil was added by type, and then additives such as propyl paraoxybenzoate, polysorbate 80, concentrated glycerin, fragrance, and trolamine were added. Thereafter, purified water was added so that the total weight of the composition was 100 g, and then the compositions of Examples 1 to 4 were prepared by stirring.

content
(g/100g) Example 1 Example 2 Example 3 Example 4 heparin sodium
(200IU/mg) 0.25
(50,000IU) 0.25
(50,000IU) 0.25
(50,000IU) 0.25
(50,000IU) allantoin 5 5 5 5 dexpanthenol 10 10 10 10 dimethicone 10 Dimethicone Copolyol 10 polydimethylsiloxane 10 Phenyldimethicone 10 Polysorbate 80 3.7 3.7 3.7 3.7 concentrated glycerin 20 20 20 20 carbopol 0.7 0.7 0.7 0.7 Spices 0.1 0.1 0.1 0.1 propyl paraoxybenzoate 0.1 0.1 0.1 0.1 trollamine 0.8 0.8 0.8 0.8 Purified water appropriate amount appropriate amount appropriate amount appropriate amount total amount 100g 100g 100g 100g

Example 5-9: Preparation of a composition according to the amount of silicone oil used

The compositions of Examples 5 to 9 were prepared with the compositions and contents shown in Table 2 below. The manufacturing method follows the manufacturing method of Examples 1-4.

content
(g/100g) Example 5 Example 6 Example 7 Example 8 Example 9 heparin sodium
(200IU/mg) 0.25
(50,000IU) 0.25
(50,000IU) 0.25
(50,000IU) 0.25
(50,000IU) 0.25
(50,000IU) allantoin 5 5 5 5 5 dexpanthenol 10 10 10 10 10 Dimethicone Copolyol One 5 10 20 30 Polysorbate 80 3.7 3.7 3.7 3.7 3.7 concentrated glycerin 20 20 20 20 20 carbopol 0.7 0.7 0.7 0.7 0.7 Spices 0.1 0.1 0.1 0.1 0.1 propyl paraoxybenzoate 0.1 0.1 0.1 0.1 0.1 trollamine 0.8 0.8 0.8 0.8 0.8 Purified water appropriate amount appropriate amount appropriate amount appropriate amount appropriate amount total amount 100g 100g 100g 100g 100g

Example 10-11: allantoin Preparation of the composition according to the particle

The compositions of Examples 10 and 11 were prepared with the compositions and contents shown in Table 3 below. The manufacturing method is according to the manufacturing method of Example 1-4.

content
(g/100g) Example 10 Example 11 heparin sodium
(200IU/mg) 0.25
(50,000IU) 0.25
(50,000IU) allantoin 5 (100um) 5 (75um) dexpanthenol 20 20 Dimethicone Copolyol 3 5 Polysorbate 80 3.7 3.7 concentrated glycerin 20 20 carbopol 0.7 0.7 Spices 0.1 0.1 propyl paraoxybenzoate 0.1 0.1 trollamine 0.8 0.8 Purified water appropriate amount appropriate amount total amount 100g 100g

comparative example 1-2: commercially available for scar treatment gel

In Comparative Examples 1 and 2, Dermatix Ultra and Contractubex, which are currently commercially available gels for scar treatment, were used.

Experimental example One: scar model used SEI evaluation

The back area of SD rats is removed, and the epithelium and dermis are deleted in two places (left and right) per animal with a size of Ø10 (10 mm in diameter). When epithelialization was completed 4 weeks after the wound occurred, the compositions of Comparative Examples 1 and 2 and Examples 1, 2, 5, 8, and 10 were applied to the wound site in 66 rats for 4 weeks, respectively. Treatment, and histological evaluation to measure the Scar Elevation Index (SEI). This is shown in FIG. 1 .

As shown in FIG. 1 , the composition according to the present invention has a small size of the scar as compared with Comparative Examples 1 and 2.

Claims (11)

heparin or a pharmaceutically acceptable salt or heparinoid thereof;
dexpanthenol;
allantoin; and
As a pharmaceutical composition for scar treatment or prevention containing silicone oil,
The content of heparin or a pharmaceutically acceptable salt thereof or heparinoid is 0.07 to 0.9 wt% based on the total weight of the total composition,
The content of dexpanthenol is 3 to 20% by weight based on the total weight of the composition,
The content of allantoin is 2 to 9% by weight based on the total weight of the composition,
The silicone oil is dimethicone copolyol, and a pharmaceutical composition for the prevention or treatment of scars, characterized in that 1 to 30% by weight based on the total weight of the composition. The pharmaceutical composition according to claim 1, wherein the allantoin particles have a d (0.9) particle size of 60-100 μm. The pharmaceutical composition according to claim 1, wherein the allantoin particles have a d (0.9) particle size of 60 to 80 μm. delete The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition is a liquid formulation, a gel formulation, or an ointment formulation. delete delete delete The pharmaceutical composition according to claim 1, wherein the pharmaceutical composition contains 200 to 900 IU of heparin or a pharmaceutically acceptable salt or heparinoid in 1 g of the pharmaceutical composition. According to claim 1,
(a) heparin or a pharmaceutically acceptable salt or heparinoid thereof and (b) dexpanthenol are present in a dissolved state in the composition,
(c) Allantoin is a pharmaceutical composition, characterized in that it is dissolved in the composition and supersaturated with particles. The pharmaceutical composition according to claim 1, further comprising Carbopol.

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