WO2015141978A1

WO2015141978A1 - Composition for maintaining efficacy of filler

Info

Publication number: WO2015141978A1
Application number: PCT/KR2015/002294
Authority: WO
Inventors: 신현정; 최진규; 김병규; 서대방
Original assignee: (주)아모레퍼시픽
Priority date: 2014-03-20
Filing date: 2015-03-10
Publication date: 2015-09-24

Abstract

The present invention relates to a parenteral composition for maintaining the efficacy of a filler for a long time, containing a collagen hydrolysate as an active ingredient. The composition, according to the present invention, can maintain the efficacy of a hyaluronic acid filler for a longer time, thereby enabling the effect thereof to be maintained irrespective of a smaller frequency of filler operations, and thus there is an advantage of also reducing skin irritation. In addition, there is an advantage of enabling an immediate effect since an administration method is simple as a parenteral administration and enables direct penetration into the skin.

Description

Composition for maintaining the efficacy of the filler

The present invention relates to parenteral compositions that maintain the efficacy of the filler for a long time.

Substances implanted in living tissue should be non-toxic and should be degraded and released by metabolic activity in vivo after completing the desired function. In recent years, cosmetic procedures for implanting certain substances into skin tissue have been rapidly growing. Hyaluronic acid, which is a substance mainly used in such procedures, is known to be metabolized and excreted from a few days after being inserted or implanted into the human body regardless of the concentration of the substance or the type of composition containing the substance. In order to maintain a desired cosmetic effect after the procedure for a long time, there is a demand for a method capable of overcoming the short human metabolic period of hyaluronic acid, and there is an increasing demand for the development of a filler material having a duration of maintenance in the human body for several months or more.

[Preceding technical literature]

[Non-Patent Documents]

(Non-Patent Document 1) Steed, D.L. et al., Clin. Plast. Surg. 25, 397, 1998

It is an object of the present invention to provide a composition which can maintain its efficacy for a long time after hyaluronic acid filler treatment.

In order to achieve the above object, the present invention, the composition for maintaining the hyaluronic acid filler efficacy, the composition for promoting hyaluronic acid synthesis and the parenteral for inhibiting hyaluronidase activity comprising a collagen hydrolysate as an active ingredient To provide a composition.

In addition, the present invention provides a filler surgical kit comprising a hyaluronic acid filler composition and collagen hydrolyzate as an active ingredient.

The composition according to the present invention is useful for promoting the synthesis of hyaluronic acid and inhibiting the activity of hyaluronidase, so that the hyaluronic acid filler efficacy can be maintained for a longer time. Accordingly, the effect can be maintained even if the filler is performed a few times, there is an advantage that the skin irritation is also reduced. In addition, parenteral administration has the advantage that the method of administration is simple and can penetrate directly into the skin, thereby enabling an immediate effect.

Figure 1 is a graph showing that the amount of hyaluronic acid synthesis increased by the treatment of the collagen peptide.

The present invention relates to a parenteral composition for maintaining hyaluronic acid filler efficacy, comprising, as an active ingredient, a collagen hydrolyzate (hydrolyzed collagen) in one aspect.

Collagen is one of the light proteins and contains a small amount of sugar. It is the major constituent of connective tissue matrix and accounts for about 30% by weight of total protein in mammals. It is present in the dermis, cartilage, etc. in the fibrous form of the animal and becomes collagen fibers. The basic unit constituting the fiber is tropocollagen having a molecular weight of about 300,000, a length of 280 nm, and a thickness of 1.5 nm.

The composition, which is an aspect of the present invention, may allow the filler to remain more naturally and longer in the skin after injecting the hyaluronic acid filler.

In another aspect, the present invention relates to a composition for promoting hyaluronic acid synthesis comprising a collagen hydrolyzate as an active ingredient.

The collagen hydrolyzate of the present invention may promote the synthesis of hyaluronic acid by its administration and may enhance the activity or amount of the up-stream enzymes or proteins involved in the synthesis of hyaluronic acid.

In another aspect, the present invention relates to a parenteral composition for inhibiting hyaluronidase activity comprising collagen hydrolyzate as an active ingredient.

The collagen hydrolyzate can inhibit or reduce the amount of hyaluronidase activity to prevent the degradation of hyaluronic acid and thus promote the synthesis of hyaluronic acid, and can maintain the efficacy of the filler for a long time.

In view of the above, the collagen hydrolyzate may include a collagen peptide, specifically, a collagen tripeptide.

In the present specification, the collagen peptide is a peptide having a molecular weight of 500 ~ 1,000 Da, it can be applied without limitation if the amino acid is bound by a peptide bond.

In the present specification, the collagen hydrolyzate refers to a substance obtained by hydrolyzing collagen and including a peptide having an average molecular weight of 500-5000 Da.

In addition, in the composition of one aspect of the present invention, the collagen hydrolyzate may include more than 10% by weight of collagen tripeptide, based on the total weight of the collagen hydrolyzate, without being limited thereto, 7% or more, 9% or more, It may be more than 11%, more than 13%, more than 15%, more than 17%, more than 19%.

As used herein, the term "hyaluronic acid filler" may refer to a filler based on hyaluronic acid (HA). The hyaluronic acid is one of complex polysaccharides composed of amino acids and uronic acids, and is a high molecular compound composed of N-acetylglucosamine and glucuronic acid. The filler may refer to a complementary material which is directly injected or inserted into skin cells to fill wrinkles or dent scars. The filler may be used for various purposes, such as to relieve curvature of the skin, replenishment of moisture, and the like, without limitation. The filler may be performed over the entire body, and specifically, may include a face, a neck, and the like.

Maintaining the 'efficacy of the filler' herein includes increasing the content of hyaluronic acid, which is the main component of the filler, so that the injected filler degrades more slowly or promotes the synthesis of hyaluronic acid in vivo.

The composition of the present invention can be used for a long time without limiting the effects such as relaxation of the skin curvature by the filler, filling of the feeling of moisture and the like. Specifically, the filler can slow the injection cycle, thereby reducing skin irritation and having an advantage of being economical.

As used herein, the term “parenteral” refers to all kinds of administration methods other than oral administration, and may specifically mean transdermal, topical or subcutaneous administration, but is not limited thereto.

In a composition, which is an aspect of the present invention, the composition may include 0.01 to 50% by weight of collagen hydrolyzate based on the total weight of the composition. Within this range, the composition may promote the synthesis of hyaluronic acid to maintain the efficacy of the hyaluronic acid filler for a long time. From the above point of view, the composition of the present invention is 0.05 to 48% by weight, 0.1 to 46% by weight, 0.5 to 44% by weight of the total composition, and the total weight of the composition. It may comprise 1 to 42% by weight relative to the total weight of the composition or 5 to 40% by weight of the collagen hydrolyzate.

Specifically, the collagen peptide may include collagen tripeptides of Glycine (Gly) -X-Y, and X and Y may include all kinds of amino acids that are normally present in nature. In addition, the X and Y may be the same or different kinds of amino acids.

In one aspect of the present invention, the collagen hydrolyzate may comprise a collagen tripeptide of Gly-X-Y.

In one aspect of the present invention, wherein X and Y include the same or different amino acids, the amino acids are glycine (Glycine, Gly), alanine (Alanine, Ala), valine (Valine, Val) , Leucine, Leu, Isoleucine, Ile, Threonine, Thr, Serine, Serine, Cysteine, Cys, Methionine, Met, Aspartic acid, Asp Asparagine, Asn, Glutamic acid, Glu, Glutamine, Gln, Lysine, Lys, Arginine, Arg, Histidine, His, Phenylalanine, Phe ), Tyrosine (Tyr), tryptophan (Trp) and proline (Proline, Pro).

Specifically, the collagen tripeptide may include glycine-proline-hydroxyproline, the X may be proline, and the Y may be hydroxyproline, but is not limited thereto.

In a composition which is an aspect of the present invention, the composition may be a pharmaceutical composition.

When the composition according to the present invention is applied to medicines, the composition can be formulated into a parenteral dosage form in the form of a solid, semi-solid or liquid by adding a commercially available inorganic or organic carrier as the active ingredient.

Examples of preparations for parenteral administration include injections, drops, ointments, lotions, sprays, suspensions, emulsions, suppositories, and the like. In order to formulate the active ingredient of the present invention, it can be easily formulated according to the conventional method, and surfactants, excipients, coloring agents, spices, preservatives, stabilizers, buffers, suspensions, and other commonly used auxiliaries can be suitably used.

The pharmaceutical composition according to the present invention may be administered parenterally, topically, transdermally, subcutaneously.

In addition, the dosage of the active ingredient will vary depending on the age, sex and weight of the subject to be treated, the specific disease or pathology to be treated, the severity of the disease or pathology, the route of administration and the judgment of the prescriber. Dosage determination based on these factors is within the level of skill in the art. Typical dosages are from 0.001 mg / kg / day to 2000 mg / kg / day, more specifically from 0.5 mg / kg / day to 1500 mg / kg / day.

The pharmaceutical composition of the present invention may be for removing or alleviating scars, and may be for reconstructing or restoring damaged or collapsed skin tissue. The scar and damaged / collapsed skin tissue may mean that the trace remains on the skin due to various causes, for example, the surface of the skin may be uneven and recessed. The cause may include, for example, an image or a wound.

In the composition which is one aspect of the present invention, the composition may be a cosmetic composition.

Cosmetic compositions according to the invention may be provided in all formulations suitable for topical application. For example, dispersions of oil phases in solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, surfactant-containing cleansing, oils, powder foundations, emulsion foundations, wax foundations, sprays, water phases Emulsions, emulsions obtained by dispersing the aqueous phase in the oil phase, in the form of solids, powders, foams, or softeners, astringents, nutrients, eye creams, nourishing creams, massage creams, cleansing creams, cleansing foams, cleansing water, It may be provided in the form of a powder, an essence, a pack. Compositions of such formulations may be prepared according to conventional methods in the art.

The cosmetic composition according to the present invention may include other ingredients in addition to the above-mentioned substances within the range not impairing the main effect, preferably giving a synergistic effect to the main effect. In addition, the cosmetic composition according to the present invention may further include a moisturizer, an emulsifier, a UV absorber, a preservative, a fungicide, an antioxidant, a pH adjuster, organic and inorganic pigments, flavors, coolants or limiting agents. The blending amount of the above components can be easily selected by those skilled in the art within the range that does not impair the object and effect of the present invention, the blending amount may be 0.01 to 5% by weight, specifically 0.01 to 3% by weight based on the total weight of the composition. have.

The present invention in another aspect hyaluronic acid filler composition; It may be a filler surgical kit comprising a composition comprising a collagen hydrolyzate as an active ingredient.

In view of the above, the hyaluronic acid filler composition may be an injection.

In a kit of one aspect of the present invention, the kit further includes instructions, and the instructions may be administered by injection injection of the hyaluronic acid, it may be disclosed that transdermal administration of the composition of another aspect of the present invention.

The filler may be applied to the skin surface to be absorbed into the skin and inserted into the skin. For example, the administration of the hyaluronic acid filler composition (hereinafter referred to as a filler procedure) may be by injection administration of a composition containing a hyaluronic acid filler, and is not limited to the number of times.

The composition comprising the collagen hydrolyzate of the present invention may be used before the filler procedure.

In view of the above, the instructions may include transdermal administration of the collagen hydrolyzate-containing composition for 1 to 50 days, followed by injection administration of the hyaluronic acid filler composition.

For example, the composition containing collagen hydrolyzate may be applied to the skin for 1 to 50 days, 10 to 50 days, 10 to 40 days, 10 to 30 days, 10 to 20 days, 20 to 50 days, 20 to 40 days, 20 days to After transdermal administration for 30 days, 25 days to 45 days, 25 days to 35 days, 30 days to 50 days, or 30 to 40 days, a filler procedure may be performed.

In addition, the composition containing the collagen hydrolyzate may be used at the same time or after the filler treatment, or before or after the filler treatment.

Specifically, after a filler procedure, transdermal administration may be performed after 1 to 20 days, 1 to 15 days, 1 to 10 days, 1 to 5 days, 1 to 4 days, 1 to 3 days, or 1 to 2 days. The collagen hydrolyzate may be transdermally administered within 24 hours, 20 hours, 15 hours, 10 hours, 5 hours, 3 hours or 1 hour after the filler procedure.

The collagen hydrolyzate can prolong the efficacy duration of the filler by such use.

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, and it will be apparent to those skilled in the art that the scope of the present invention is not to be construed as being limited by these examples.

Preparation Example 1 Preparation of Collagen Peptides

The collagen peptide used as an active ingredient in the present invention is purchased from Jellice Co., Ltd. (HATC, Jellice Co., JAPAN), a complex containing 15% or more of a tripeptide such as glycine-proline-hydroxyflorin form to be.

Experimental Example 1 Hyaluronic Acid Synthesis Promoting Ability in Keratinocytes

HaCaT cells, a human-derived keratinocyte cell line (Dr NE Fusenig, Deutsches Krebs forschungszentrum, Heidelberg, Germany), were cultured in DMEM medium containing 10% FBS under conditions of 37 ° C. and 5% CO ₂ . Cells were cultured in 96 well plates, and when incubated at 80% or more, the cells were incubated for 24 hours in exchange for medium containing no FBS. Thereafter, the collagen peptide of Preparation Example 1 was dissolved in PBS at a concentration of 200 times and treated to a final concentration of 100 ppm and 200 ppm, respectively, and incubated for 24 hours. After 24 hours, the medium was recovered and used for a hyaluronic acid assay (HR assay), and cell viability quantitative assay (CCK8 assay) was performed using the remaining cells.

CCK8 assay (Dojindo) and hyaluronic acid assay (Echelon) were tested according to the kit provider's protocol, and the quantified hyaluronic acid values were corrected by dividing the cell viability values.

As a result, as shown in Figure 1, the group treated with the collagen peptide was confirmed that the amount of hyaluronic acid synthesis increased by 30 ~ 44% or more compared to the untreated control group, this synthesis promoting ability to the collagen peptide treatment concentration It was confirmed to be proportional. Therefore, it was confirmed that collagen peptide could promote the synthesis of hyaluronic acid in skin cells.

Experimental Example 2 Inhibitory Activity of Hyaluronidase

In order to investigate whether the main component of the filler inhibits hyaluronic acid hydrolysis, the effect of inhibiting the activity of hyaluronidase was observed.

To 50 μL of 0.1 M hyaluronidase enzyme solution (7,900 units / mL), collagen peptide was added 20 μL each to a final concentration of 0.2, 0.4, 0.6, 0.8, 1.0 mg / mL, and 12.5 mM 200 μL of CaCl ₂ was mixed and incubated for 20 minutes on an aqueous solution at 37 ° C. The control group was added with distilled water instead of collagen peptide and incubated for 20 minutes in an aqueous solution. 250 μL of 0.1M hyaluronic acid solution (12 mg / 5 mL) was added to the hyaluronidase enzyme solution activated with Ca ²⁺ , and then incubated for 40 minutes in an aqueous solution. After incubation, 100 μL of 0.4 N NaOH solution and 100 μL of 0.4 M potassium tetraborate were added to the reaction mixture, followed by cooling for 3 minutes in a boiling water bath. To the cooled reaction, 3.28 mL of dimethyl aminobenzaldehyde solution (4 g of p-dimethylamino-benzaldehyde, 350 mL of 100% acetic acid and 50 mL of 10 N HCl) was added to the reaction mixture, followed by incubation for 20 minutes in a 37 ° C water bath. Absorbance was measured at nm.

As a result, as can be seen in Table 1, the collagen peptide was found to be excellent in inhibiting the activity of hyaluronidase. In addition, the efficacy was confirmed to be dependent on the concentration of the collagen peptide.

Table 1

Collagen Peptide Concentration (mg / ml)	0.2	0.4	0.6	0.8	1.0
Hyaluronidase activity inhibition rate (%)	30.4	32.8	48.6	75.2	82.4

Experimental Example 3 Retention of Hyaluronic Acid Filler in Biological Tissues

Clinical evaluation was conducted to investigate the effect of cosmetic application containing collagen on the sustained effect of hyaluronic acid filler.

Six women who were required to improve their nasolabial folds were selected and divided into three groups, control and experimental groups. The control group did not apply cosmetics containing collagen for one month, and the experimental group applied cosmetics containing collagen to the face for one month. One month later, the experimental group was injected with one filler into both nasolabial folds, and visited 15 days, 1 month, 2 months and 3 months after the injection for clinical evaluation. Clinical evaluation was performed using the Wrinkle Severity Rating Scale (WSRS), which was evaluated by a specialist and evaluated on a 1 to 5 point scale. In Table 2, a lower score means no visible wrinkles.

TABLE 2

division	Control	Experimental group
Just before injection	4.67	4.67
15th	1.00	1.00
1 month	2.33	1.33
2 months	3.33	2.33
3 months	3.67	2.67

As can be seen in Table 2, it was confirmed that the experimental group receives a lower evaluation score than the control group over time after the filler injection. This has been found by administering the present invention composition as the volume of the initial injecting filler maintains its effect over time or the effect of the filler slowly decreases.

In addition, a method of measuring the global aesthetic improvement scale (GAIS), which evaluates the satisfaction of the patient who received the procedure, was also performed, and the results are shown in Table 3 below.

TABLE 3

division	Control	Experimental group
very good		1 person
Slightly satisfied		2 people
usually	2 people
Slightly dissatisfied	1 person
very unsatisfied

As can be seen in Table 3, the experimental group showed satisfaction as the effect of the filler is maintained for a longer time, while the control group was confirmed to show the satisfaction below the average.

Hereinafter, the formulation examples of the composition according to the present invention, but the pharmaceutical composition and cosmetic composition is applicable to a variety of formulations, which is intended to explain in detail only, not intended to limit the present invention.

Formulation Example 1 Flexible Cosmetic (Skin Lotion)

Table 4

Compounding ingredient	Content (% by weight)
Collagen Peptides of Preparation Example 1	0.1
glycerin	3.0
Butylene glycol	2.0
Propylene glycol	2.0
Carboxy Vinyl Polymer	0.1
Fiji-12 nonylphenyl ether	0.2
Polysorbate 80	0.4
ethanol	10.0
Triethanolamine	0.1
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 2 Nutritious Longevity (Milk Lotion)

Table 5

Compounding ingredient	Content (% by weight)
Collagen Peptides of Preparation Example 1	0.5
glycerin	3.0
Butylene glycol	3.0
Propylene glycol	3.0
Carboxy Vinyl Polymer	0.1
Beeswax	4.0
Polysorbate 60	1.5
Caprylic / Capric Triglycerides	5.0
Squalane	5.0
Sorbitassquioleate	1.5
Liquid paraffin	0.5
Cetearyl Alcohol	1.0
Triethanolamine	0.2
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 3 Nutrition Cream

Table 6

Compounding ingredient	Content (% by weight)
Collagen Peptides of Preparation Example 1	1.0
glycerin	3.0
Butylene glycol	3.0
Liquid paraffin	7.0
Beta Glucan	7.0
Carbomer	0.1
Caprylic / Capric Triglycerides	3.0
Squalane	5.0
Cetearyl Glucoside	1.5
Sorbitan stearate	0.4
Polysorbate 60	1.2
Triethanolamine	0.1
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 4 Massage Cream

TABLE 7

Compounding ingredient	Content (% by weight)
Collagen Peptides of Preparation Example 1	1.5
glycerin	8.0
Butylene glycol	4.0
Liquid paraffin	45.0
Beta Glucan	7.0
Carbomer	0.1
Caprylic / Capric Triglycerides	3.0
Beeswax	4.0
Cetearyl Glucoside	1.5
Sesqui oleic acid sorbitan	0.9
Vaseline	3.0
paraffin	1.5
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

[Formulation Example 5] Pack

Table 8

Compounding ingredient	Content (% by weight)
Collagen Peptides of Preparation Example 1	0.1
glycerin	4.0
Polyvinyl alcohol	15.0
Hyaluronic acid extract	5.0
Beta Glucan	7.0
Allantoin	0.1
Nonyl Phenyl Ether	0.4
Polysorbate 60	1.2
Ethanol preservative	6.0 quantity
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 6 Ointment

Table 9

Compounding ingredient	Content (% by weight)
Collagen Peptides of Preparation Example 1	0.1
glycerin	8.0
Butylene glycol	4.0
Liquid paraffin	15.0
Beta Glucan	7.0
Carbomer	0.1
Caprylic / Capric Triglycerides	3.0
Squalane	1.0
Cetearyl Glucoside	1.5
Sorbitan stearate	0.4
Cetearyl Alcohol	1.0
Beeswax	4.0
Preservative, coloring, flavoring	Quantity
Purified water	Remaining amount

Formulation Example 7 Injection

Collagen peptide of Preparation Example 1 ............ 200 mg

Sterile Distilled Water for Injection ...

pH adjuster ...

According to the conventional method for preparing an injection, the amount of the above ingredient was prepared per ampoule (2 ml).

As described above in detail the specific parts of the present invention, it is apparent to those skilled in the art that such specific description is merely a preferred embodiment, thereby not limiting the scope of the present invention. something to do. Thus, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

Claims

A parenteral composition for maintaining the efficacy of the hyaluronic acid filler comprising a collagen hydrolyzate as an active ingredient.
A parenteral composition for promoting hyaluronic acid synthesis comprising collagen hydrolyzate as an active ingredient.
A parenteral composition for inhibiting hyaluronidase activity comprising collagen hydrolyzate as an active ingredient.
The method according to any one of claims 1 to 3,

The collagen hydrolyzate comprises a collagen tripeptide.
The method of claim 4, wherein

The collagen tripeptide, 10% by weight or more based on the total weight of the collagen hydrolyzate, composition.
The method of claim 4, wherein

The collagen tripeptide, 15% by weight or more based on the total weight of the collagen hydrolyzate, composition.
The method according to any one of claims 1 to 3,

The composition comprises 0.01 to 50% by weight of collagen hydrolyzate, based on the total weight of the composition.
The method of claim 4, wherein

The collagen tripeptides include collagen tripeptides of Glycine (Gly) -X-Y,

Wherein X and Y are amino acids.
The method of claim 8,

X and Y include the same or different amino acids,

The amino acids are glycine (Gly), alanine (Alanine, Ala), valine (Valine, Val), leucine (Leucine, Leu), isoleucine (Isoleucine, Ile), threonine (Threonine, Thr), serine (Serine, Ser ), Cysteine, Cys, Methionine, Met, Aspartic acid (Asp), Asparagine (Asn), Glutamic acid (Glu), Glutamine (Gln), Lysine (Lysine) , Lys), Arginine, Arg, Histidine, His, Phenylalanine (Phe), Tyrosine (Tyr), Tryptophan (Trp) and Proline (Proline, Pro) Composition.
The method of claim 8,

X and Y include the same or different amino acids,

Wherein said amino acid is selected from proline and hydroxyproline.
The method of claim 8,

X is proline,

Y is hydroxyproline.
The method according to any one of claims 1 to 3,

The composition is a pharmaceutical composition.
The method according to any one of claims 1 to 3,

The composition is a cosmetic composition.
Hyaluronic acid filler compositions; And

A filler procedure kit comprising the collagen hydrolyzate-containing composition of any one of claims 1 to 3.
The method of claim 14,

The hyaluronic acid filler composition is a kit for injection.
The method of claim 14,

The kit further comprises instructions,

The instructions are administered by injecting the hyaluronic acid filler composition,

A kit comprising the transdermal administration of the collagen hydrolyzate-containing composition.
The method of claim 16,

The above instructions,

After the transdermal administration of the collagen hydrolyzate-containing composition for 20 to 40 days, the kit comprising injection of the hyaluronic acid filler composition.