JP7428426B2 - Collagen production promoter - Google Patents

Description

The present invention relates to collagen production promoters, as well as cosmetic compositions, food and drink compositions, cell culture compositions, wound healing pharmaceutical compositions, and bone formation promoting compositions containing the collagen production promoters.

Collagen is present in all multicellular animals, and is the most abundant protein in vertebrates, existing outside cells. Collagen forms insoluble fibers that are extremely resistant to tension in connective tissues such as bones, teeth, cartilage, tendons, ligaments, skin, and the fibrous structures of blood vessels, so it acts as a main component that resists strain forces. It is known.

Furthermore, it is known that collagen consists of three polypeptide chains, and each peptide chain is cross-linked with a compound having a 3-hydroxypyridinium structure, and its decomposition product, a 3-hydroxypyridinium derivative, There have been no reports that it exhibits physiological effects through receptors.

In addition, collagen is an important component for skin elasticity and moisturizing function, and it is known that a decrease in the amount of collagen causes a decrease in skin tension and elasticity, and the appearance of aging-like symptoms such as rough skin and wrinkles. It is being For this reason, research has been carried out on food materials, cosmetic materials, or pharmaceutical compositions that increase the amount of collagen in the skin, with the aim of maintaining skin health or suppressing skin aging.

On the other hand, bone metabolism is normally maintained by a balance between osteoclasts, which degrade old bone, and osteoblasts, which produce new bone, and calcium phosphate is deposited around type I collagen fibers secreted by osteoblasts. It is known that bone is formed into hydroxyapatite.

In recent years, with the aging of the population and the increase in basic diseases such as diabetes, the number of patients with various bone diseases such as fractures and osteoporosis caused by a decline in bone mass and quality has been increasing. As mentioned above, bone mass and bone quality are maintained by a balance between bone resorption (bone decomposition) and bone formation during healthy conditions, but due to factors such as decreased hormone secretion due to aging and menopause, bone resorption becomes predominant. This is known to cause bones to become brittle. To deal with this, treatments such as administering oral calcium preparations, vitamin D ₃ preparations, parathyroid hormone preparations, etc. to suppress the function of osteoclasts are generally practiced.

Regarding collagen production promoters, for example, Patent Document 1 describes compounds represented by 1-acetoxy-1-(2,4-diacetoxyphenyl)-2-propene. Patent Document 2 describes an anti-aging product characterized by containing a synthetic peptide composed of 3 to 8 amino acids or a derivative thereof, and a hydrolyzed collagen or a derivative thereof having a molecular weight in the range of 500 to 5000. External skin preparations are described.
In addition, pyridinoline, which is a representative of the compound of the present application, is a known collagen degrading component as described in Non-Patent Document 1, and is used as a diagnostic agent for osteoporosis as described in Patent Documents 3 and 4. It is being

Japanese Patent Application Publication No. 2009-79004 JP2011-042613A Special Publication No. 05-502942 Japanese Patent Application Publication No. 05-209870

Daisaburo Fujimoto, Takahiko Moriguchi, Torao Ishida, and Hiroshi Hayashi:‘The structure of pyridinoline, a collagen crosslink.’Biochem. Biophysics. Res. Commun. 84, 52-57 (1978).

Oral calcium preparations, vitamin D ₃ preparations, parathyroid hormone preparations, etc. are commonly used to treat bone diseases such as bone fractures and osteoporosis, which can cause loss of appetite, general malaise, osteonecrosis of the jaw, etc. However, there has been a need for a treatment method for bone diseases that directly acts on osteoblasts to increase collagen synthesis and promote bone formation. Furthermore, even when ingesting commonly available collagen peptides, it is necessary to ingest a large amount in order to experience its effects, and there has been a need for ingredients that can efficiently promote collagen production.

An object of the present invention is to provide a novel collagen production promoter that can efficiently promote collagen production. Furthermore, the main object is to provide cosmetic compositions, food and drink compositions, compositions for cell culture, pharmaceutical compositions for wound healing, and compositions for promoting bone formation that contain the collagen production promoter.

As a result of intensive studies to solve the above problems, the present inventors discovered that 3-hydroxypyridinium derivatives have the ability to promote collagen production, and completed the present invention.
That is, the present invention provides the following collagen production promoters, cosmetic compositions containing the collagen production promoters, food and drink compositions, cell culture compositions, wound healing pharmaceutical compositions, bone formation promoting compositions, and a collagen degradation product.

（式（１）中、Ａ^１はそれぞれ独立して水酸基、炭素原子数１～１０のアルコキシ基、Ｎ末端で結合するアミノ酸数１～１００のペプチド構造、水素原子、アミノ基（－ＮＲ^４ _２）、又は炭素原子数１～１０の炭化水素基を、Ａ^２はそれぞれ独立して水素原子、炭素原子数１～１０の炭化水素基、アシル基（－ＣＯＲ^５）、又はＣ末端で結合するアミノ酸数１～１００のペプチド構造を、Ｒはそれぞれ独立して水素原子、又は炭素原子数１～１０の炭化水素基を、Ｒ^１はそれぞれ独立して単結合、又は水酸基、アミノ基（－ＮＲ^４ _２）及びオキサ基（－Ｏ－）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の２価の炭化水素基を、Ｒ^２はそれぞれ独立して水酸基、カルボキシル基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の炭化水素基を、Ｒ^３は水素原子、下記式（２）で表される構造、又は水酸基、カルボキシル基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の炭化水素基を、Ｒ^４はそれぞれ独立して水素原子又は炭素原子数１～１０の炭化水素基を、Ｒ^５は炭素原子数１～１０の炭化水素基を、ｍ及びｎはそれぞれ独立して０～４の整数を表す。但し、ｍ及びｎは、ｍ＋ｎが０～４の整数となる数値である。）

（式（２）中、Ａ^１は式（１）中のＡ^１に独立して水酸基、炭素原子数１～１０のアルコキシ基、Ｎ末端で結合するアミノ酸数１～１００のペプチド構造、水素原子、アミノ基（－ＮＲ^４ _２）、又は炭素原子数１～１０の炭化水素基を、Ａ^２は式（１）中のＡ^２に独立して水素原子、炭素原子数１～１０の炭化水素基、アシル基（－ＣＯＲ^５）、又はＣ末端で結合するアミノ酸数１～１００のペプチド構造を、Ｒは式（１）中のＲに独立して水素原子、又は炭素原子数１～１０の炭化水素基を、Ｒ^４は式（１）中のＲ^４に独立してそれぞれ独立して水素原子又は炭素原子数１～１０の炭化水素基を、Ｒ^５は式（１）中のＲ^５に独立して炭素原子数１～１０の炭化水素基を、Ｒ^６は単結合、又は水酸基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の２価の炭化水素基を表す。）
この特徴によれば、簡便、簡単にコラーゲン産生を促進することができる。 In order to solve the above problems, the collagen production promoter of the present invention is characterized by containing a 3-hydroxypyridinium derivative represented by the following general formula (1) as an active ingredient.

(In formula (1), A ¹ is each independently a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, a peptide structure having 1 to 100 amino acids bonded at the N-terminus, a hydrogen atom, an amino group (-NR ⁴ ₂ ), or a hydrocarbon group having 1 to 10 carbon atoms, and each A ² is independently bonded to a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, an acyl group (-COR ⁵ ), or a C-terminus. A peptide structure having 1 to 100 amino acids, R each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ¹ each independently represents a single bond, or a hydroxyl group, an amino group (-NR R ₂ each represents a divalent hydrocarbon group having 1 to 10 carbon atoms which may have at least one functional group selected from ^the group consisting of ⁴ 2 ) and oxa group (-O-); A hydrocarbon group having 1 to 10 carbon atoms, which may have at least one functional group independently selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ), is R ³ is a hydrogen atom, a structure represented by the following formula (2), or a carbon which may have at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ) R ⁴ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ⁵ represents a hydrocarbon group having 1 to 10 carbon atoms, m and Each n independently represents an integer from 0 to 4. However, m and n are numerical values such that m+n is an integer from 0 to 4.)

(In formula (2), A ¹ is independently hydroxyl group, alkoxy group having 1 to 10 carbon atoms, peptide structure having 1 to 100 amino acids bonded at the N-terminus, hydrogen atom ⁾ , an amino group (-NR ⁴ ₂ ), or a hydrocarbon group having 1 to 10 carbon atoms, A ² is a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, independently of A ² in formula (1). group, an acyl group (-COR ⁵ ), or a peptide structure having 1 to 100 amino acids bonded at the C-terminus, where R is a hydrogen atom or a peptide structure having 1 to 10 carbon atoms, independently of R in formula (1). R ⁴ is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms independently of R ⁴ in formula (1), R ⁵ is R ⁵ in formula (1) independently has a hydrocarbon group having 1 to 10 carbon atoms, and R ⁶ has a single bond or at least one functional group selected from the group consisting of a hydroxyl group and an amino group (-NR ⁴ ₂ ). represents a divalent hydrocarbon group having 1 to 10 carbon atoms.)
According to this feature, collagen production can be promoted simply and easily.

Furthermore, according to one embodiment of the collagen production promoter of the present invention, the content of the 3-hydroxypyridinium derivative is 0.00001% by weight or more.
According to this feature, it is possible to exhibit the effect of efficiently promoting collagen production.

Furthermore, the collagen production promoter of the present invention is characterized by containing a 3-hydroxypyridinium derivative derived from a natural product.
According to this feature, since the 3-hydroxypyridinium derivative can be obtained from natural products, there is no need to remove impurities such as catalysts, and it is possible to obtain the effect of easily obtaining a pure material.

Furthermore, one embodiment of the collagen production promoter of the present invention is characterized in that it is a cosmetic composition.
According to this feature, collagen production can be promoted in skin where skin tension and elasticity have decreased due to a decrease in collagen amount, and this can contribute to maintaining skin health and suppressing skin aging. The effects of the invention can be more fully demonstrated.

Furthermore, according to one embodiment of the collagen production promoter of the present invention, it is a food and drink composition. According to this feature, collagen production can be easily promoted by oral administration, and the collagen production promoter can be easily stimulated by oral administration. The effects of the present invention, which can contribute to maintaining health, suppressing skin aging, preventing osteoporosis, etc., and can contribute to extending the lifespan of animals such as pets, can be further exhibited.

Furthermore, one embodiment of the collagen production promoter of the present invention is characterized in that it is a composition for cell culture.
According to this feature, the effects of the present invention, which can easily promote collagen production in regenerative medicine and the like, and can contribute to alternative tests such as animal experiments, can be further exhibited.

Furthermore, one embodiment of the collagen production promoter of the present invention is characterized in that it is a pharmaceutical composition for wound healing.
According to this feature, in regenerative medicine etc., collagen production can be easily promoted, and the effects of the present invention can be further exhibited, which can contribute to skin regeneration such as in the treatment of lacerations and burns.

Furthermore, according to one embodiment of the collagen production promoting agent of the present invention, it is characterized in that it is a composition for promoting bone formation.
According to this feature, in the treatment of osteoporosis and the like, collagen production can be easily promoted, and the effects of the present invention can be further exhibited, which can contribute to the promotion of bone formation.

この特徴によれば、効率的にコラーゲン産生を促すことができるという効果を発揮することができる。 Further, the present invention is a collagen decomposition product characterized by containing 0.015% by weight or more of a 3-hydroxypyridinium partial structure represented by the following general formula (3).

According to this feature, it is possible to exhibit the effect of efficiently promoting collagen production.

この特徴によれば、効率的にコラーゲン産生を促すことができるという効果を発揮することができる。 Furthermore, the present invention is a collagen decomposition product characterized by containing 0.07% by weight or more of 3-hydroxypyridinoline represented by the following general formula (4).

According to this feature, it is possible to exhibit the effect of efficiently promoting collagen production.

According to the present invention, collagen production can be promoted simply and efficiently, and can be used to maintain skin health, suppress skin aging, and treat osteoporosis and the like.

Purity assay of purified PYR by reverse phase HPLC Identification of the structure of PYR by mass spectral analysis Analysis results of RNA expression level of type I collagen type A in human renal tubular epithelial cells Analysis results of RNA expression level of type I collagen type A of TGFβ1 Data showing the effect of CHHP on promoting osteoblast differentiation RT-PCR data on promoting osteoblast collagen production by CHHP

In explaining the details of the present invention, specific examples will be given. However, the present invention is not limited to the following content as long as it does not depart from the spirit of the present invention, and the present invention can be implemented with appropriate changes.

（式（１）中、Ａ^１はそれぞれ独立して水酸基、炭素原子数１～１０のアルコキシ基、Ｎ末端で結合するアミノ酸数１～１００のペプチド構造、水素原子、アミノ基（－ＮＲ^４ _２）、又は炭素原子数１～１０の炭化水素基を、Ａ^２はそれぞれ独立して水素原子、炭素原子数１～１０の炭化水素基、アシル基（－ＣＯＲ^５）、又はＣ末端で結合するアミノ酸数１～１００のペプチド構造を、Ｒはそれぞれ独立して水素原子、又は炭素原子数１～１０の炭化水素基を、Ｒ^１はそれぞれ独立して単結合、又は水酸基、アミノ基（－ＮＲ^４ _２）及びオキサ基（－Ｏ－）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の２価の炭化水素基を、Ｒ^２はそれぞれ独立して水酸基、カルボキシル基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の炭化水素基を、Ｒ^３は水素原子、下記式（２）で表される構造、又は水酸基、カルボキシル基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の炭化水素基を、Ｒ^４はそれぞれ独立して水素原子又は炭素原子数１～１０の炭化水素基を、Ｒ^５は炭素原子数１～１０の炭化水素基を、ｍ及びｎはそれぞれ独立して０～４の整数を表す。但し、ｍ及びｎは、ｍ＋ｎが０～４の整数となる数値である。）

（式（２）中、Ａ^１は式（１）中のＡ^１に独立して水酸基、炭素原子数１～１０のアルコキシ基、Ｎ末端で結合するアミノ酸数１～１００のペプチド構造、水素原子、アミノ基（－ＮＲ^４ _２）、又は炭素原子数１～１０の炭化水素基を、Ａ^２は式（１）中のＡ^２に独立して水素原子、炭素原子数１～１０の炭化水素基、アシル基（－ＣＯＲ^５）、又はＣ末端で結合するアミノ酸数１～１００のペプチド構造を、Ｒは式（１）中のＲに独立して水素原子、又は炭素原子数１～１０の炭化水素基を、Ｒ^４は式（１）中のＲ^４に独立してそれぞれ独立して水素原子又は炭素原子数１～１０の炭化水素基を、Ｒ^５は式（１）中のＲ^５に独立して炭素原子数１～１０の炭化水素基を、Ｒ^６は単結合、又は水酸基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の２価の炭化水素基を表す。）
このコラーゲン産生促進剤によれば、簡便、簡単に効率良くコラーゲン産生を促進することができる。 [Collagen production promoter]
The collagen production promoter of the present invention is characterized by containing a 3-hydroxypyridinium derivative represented by the following general formula (1) as an active ingredient.

(In formula (1), A ¹ is each independently a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, a peptide structure having 1 to 100 amino acids bonded at the N-terminus, a hydrogen atom, an amino group (-NR ⁴ ₂ ), or a hydrocarbon group having 1 to 10 carbon atoms, and each A ² is independently bonded to a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, an acyl group (-COR ⁵ ), or a C-terminus. A peptide structure having 1 to 100 amino acids, R each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ¹ each independently represents a single bond, or a hydroxyl group, an amino group (-NR R ₂ each represents a divalent hydrocarbon group having 1 to 10 carbon atoms which may have at least one functional group selected from ^the group consisting of ⁴ 2 ) and oxa group (-O-); A hydrocarbon group having 1 to 10 carbon atoms, which may have at least one functional group independently selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ), is R ³ is a hydrogen atom, a structure represented by the following formula (2), or a carbon which may have at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ) R ⁴ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ⁵ represents a hydrocarbon group having 1 to 10 carbon atoms, m and Each n independently represents an integer from 0 to 4. However, m and n are numerical values such that m+n is an integer from 0 to 4.)

(In formula (2), A ¹ is independently hydroxyl group, alkoxy group having 1 to 10 carbon atoms, peptide structure having 1 to 100 amino acids bonded at the N-terminus, hydrogen atom ⁾ , an amino group (-NR ⁴ ₂ ), or a hydrocarbon group having 1 to 10 carbon atoms, A ² is a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, independently of A ² in formula (1). group, an acyl group (-COR ⁵ ), or a peptide structure having 1 to 100 amino acids bonded at the C-terminus, where R is a hydrogen atom or a peptide structure having 1 to 10 carbon atoms, independently of R in formula (1). R ⁴ is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms independently of R ⁴ in formula (1), R ⁵ is R ⁵ in formula (1) independently has a hydrocarbon group having 1 to 10 carbon atoms, and R ⁶ has a single bond or at least one functional group selected from the group consisting of a hydroxyl group and an amino group (-NR ⁴ ₂ ). represents a divalent hydrocarbon group having 1 to 10 carbon atoms.)
According to this collagen production promoter, collagen production can be promoted simply, easily, and efficiently.

[Collagen production mechanism]
Although the mechanism of collagen production of the present invention has not been specifically elucidated, the recognition of the 3-hydroxypyridinium derivative of the present invention by the receptor for advanced glycation end products (RAGE) results in collagen production. It is thought that production is promoted.

Receptor for advanced glycation end products (RAGE) is a protein expressed in a wide variety of cells including smooth muscle cells, hepatocytes, nerve cells, vascular endothelial cells, and monocytes.
As represented by Fischer's lock and key model, the ligand-binding site of a protein is thought to have a structure that is firmly complementary to the ligand, and if the ligand has a 3-hydroxypyridinium substructure, its substitution It is thought that it is not affected by steric hindrance such as groups and is selectively recognized by the receptor for advanced glycation end products (RAGE).

（式（１）中、Ａ^１はそれぞれ独立して水酸基、炭素原子数１～１０のアルコキシ基、Ｎ末端で結合するアミノ酸数１～１００のペプチド構造、水素原子、アミノ基（－ＮＲ^４ _２）、又は炭素原子数１～１０の炭化水素基を、Ａ^２はそれぞれ独立して水素原子、炭素原子数１～１０の炭化水素基、アシル基（－ＣＯＲ^５）、又はＣ末端で結合するアミノ酸数１～１００のペプチド構造を、Ｒはそれぞれ独立して水素原子、又は炭素原子数１～１０の炭化水素基を、Ｒ^１はそれぞれ独立して単結合、又は水酸基、アミノ基（－ＮＲ^４ _２）及びオキサ基（－Ｏ－）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の２価の炭化水素基を、Ｒ^２はそれぞれ独立して水酸基、カルボキシル基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の炭化水素基を、Ｒ^３は水素原子、下記式（２）で表される構造、又は水酸基、カルボキシル基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の炭化水素基を、Ｒ^４はそれぞれ独立して水素原子又は炭素原子数１～１０の炭化水素基を、Ｒ^５は炭素原子数１～１０の炭化水素基を、ｍ及びｎはそれぞれ独立して０～４の整数を表す。但し、ｍ及びｎは、ｍ＋ｎが０～４の整数となる数値である。）

（式（２）中、Ａ^１は式（１）中のＡ^１に独立して水酸基、炭素原子数１～１０のアルコキシ基、Ｎ末端で結合するアミノ酸数１～１００のペプチド構造、水素原子、アミノ基（－ＮＲ^４ _２）、又は炭素原子数１～１０の炭化水素基を、Ａ^２は式（１）中のＡ^２に独立して水素原子、炭素原子数１～１０の炭化水素基、アシル基（－ＣＯＲ^５）、又はＣ末端で結合するアミノ酸数１～１００のペプチド構造を、Ｒは式（１）中のＲに独立して水素原子、又は炭素原子数１～１０の炭化水素基を、Ｒ^４は式（１）中のＲ^４に独立してそれぞれ独立して水素原子又は炭素原子数１～１０の炭化水素基を、Ｒ^５は式（１）中のＲ^５に独立して炭素原子数１～１０の炭化水素基を、Ｒ^６は単結合、又は水酸基及びアミノ基（－ＮＲ^４ _２）からなる群より選択される少なくとも１種の官能基を有していてもよい炭素原子数１～１０の２価の炭化水素基を表す。） [3-Hydroxypyridinium derivative]
The 3-hydroxypyridinium derivative used in the present invention is represented by the following formula (1).

(In formula (1), A ¹ is each independently a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, a peptide structure having 1 to 100 amino acids bonded at the N-terminus, a hydrogen atom, an amino group (-NR ⁴ ₂ ), or a hydrocarbon group having 1 to 10 carbon atoms, and each A ² is independently bonded to a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, an acyl group (-COR ⁵ ), or a C-terminus. A peptide structure having 1 to 100 amino acids, R each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ¹ each independently represents a single bond, or a hydroxyl group, an amino group (-NR R ₂ each represents a divalent hydrocarbon group having 1 to 10 carbon atoms which may have at least one functional group selected from ^the group consisting of ⁴ 2 ) and oxa group (-O-); A hydrocarbon group having 1 to 10 carbon atoms, which may have at least one functional group independently selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ), is R ³ is a hydrogen atom, a structure represented by the following formula (2), or a carbon which may have at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ) R ⁴ each independently represents a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms, R ⁵ represents a hydrocarbon group having 1 to 10 carbon atoms, m and Each n independently represents an integer from 0 to 4. However, m and n are numerical values such that m+n is an integer from 0 to 4.)

(In formula (2), A ¹ is independently hydroxyl group, alkoxy group having 1 to 10 carbon atoms, peptide structure having 1 to 100 amino acids bonded at the N-terminus, hydrogen atom ⁾ , an amino group (-NR ⁴ ₂ ), or a hydrocarbon group having 1 to 10 carbon atoms, A ² is a hydrogen atom, a hydrocarbon group having 1 to 10 carbon atoms, independently of A ² in formula (1). group, an acyl group (-COR ⁵ ), or a peptide structure having 1 to 100 amino acids bonded at the C-terminus, where R is a hydrogen atom or a peptide structure having 1 to 10 carbon atoms, independently of R in formula (1). R ⁴ is a hydrogen atom or a hydrocarbon group having 1 to 10 carbon atoms independently of R ⁴ in formula (1), R ⁵ is R ⁵ in formula (1) independently has a hydrocarbon group having 1 to 10 carbon atoms, and R ⁶ has a single bond or at least one functional group selected from the group consisting of a hydroxyl group and an amino group (-NR ⁴ ₂ ). represents a divalent hydrocarbon group having 1 to 10 carbon atoms.)

In the present invention, the 3-hydroxypyridinium derivative represented by general formula (1) includes not only the compound itself but also its isomers, mixtures, pharmaceutically acceptable salts, solvates, and prodrugs thereof. What can be included is within the scope of common technical knowledge. Examples of prodrugs include those described in Japanese translation of PCT publication No. 2016-519659. Prodrug structures related to hydroxyl groups include, but are not limited to, acyloxyalkyl (e.g., acyloxymethyl, acyloxyethyl) esters, alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphate esters, sulfonate esters, sulfate esters, and esters. esters such as disulfides, ethers (e.g. alkyl ethers), amides, carbamates, hemisuccinates, dimethylaminoacetate, and phosphorylmethylcarbonyls.

The "alkoxy group having 1 to 10 carbon atoms" of A1 in formula ( ¹ ) and formula (2) means that the hydrocarbon group in the alkoxy group has a branched structure, a cyclic structure, and a carbon-carbon unsaturated bond ( (carbon-carbon double bond, carbon-carbon triple bond), and may be any of a saturated hydrocarbon group, an unsaturated hydrocarbon group, an aromatic hydrocarbon group, etc. do. The number of carbon atoms in the alkoxy group is usually 6 or more when the hydrocarbon group in the alkoxy group is an aromatic hydrocarbon group. On the other hand, when the hydrocarbon group of the alkoxy group is other than an aromatic hydrocarbon group, the number is preferably 8 or less, more preferably 6 or less, and may be 3 or less.
Specific examples of "alkoxy groups having 1 to 10 carbon atoms" include methoxy group, ethoxy group, n-propoxy group, i-propoxy group, n-butoxy group, i-butoxy group, s-butoxy group, t- Butoxy group, n-pentyloxy group, 2,2-dimethylpropoxy group, cyclopentyloxy group, n-hexyloxy group, cyclohexyloxy group, n-heptyloxy group, 2-methylpentyloxy group, n-octyloxy group, Examples include 2-ethylhexyloxy group, n-nonyloxy group, n-decyloxy group, phenyloxy group, and vinyloxy group.

The "hydrocarbon group having 1 to 10 carbon atoms" of A ¹ , A ² , R, R ⁴ and R ⁵ in formula (1) and formula (2) is a branched structure, a cyclic structure, and a carbon-carbon non-carbon group. It may have each of the saturated bonds (carbon-carbon double bond, carbon-carbon triple bond), and may be any of a saturated hydrocarbon group, an unsaturated hydrocarbon group, an aromatic hydrocarbon group, etc. It means that. The number of carbon atoms in the hydrocarbon group is usually 6 or more when the hydrocarbon group is an aromatic hydrocarbon group. On the other hand, when the hydrocarbon group is other than an aromatic hydrocarbon group, the number is preferably 8 or less, more preferably 6 or less, and may be 3 or less.
Specific examples of "hydrocarbon groups having 1 to 10 carbon atoms" include methyl group, ethyl group, n-propyl group, i-propyl group, cyclopropyl group, n-butyl group, i-butyl group, s-butyl group. group, t-butyl group, 2,2-dimethyl-1-propyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-heptyl group, 2-methylpentyl group, n-octyl group, 2-ethylhexyl group, Examples include n-nonyl group, n-decyl group, phenyl group, and vinyl group.

A carbon atom that may have at least one functional group selected from the group consisting of a hydroxyl group, an amino group (-NR ⁴ ₂ ), and an oxa group (-O-) in R ¹ in formula (1) The "divalent hydrocarbon group" in "a divalent hydrocarbon group having numbers 1 to 10" means a hydrocarbon group having two bonding sites. Furthermore, the expression "may have at least one functional group selected from the group consisting of a hydroxyl group, an amino group (-NR ⁴ ₂ ), and an oxa group (-O-)" refers to hydrogen of a hydrocarbon group. This means that the atom may be substituted with a hydroxyl group or an amino group, and that an oxa group may be introduced into the carbon skeleton of the hydrocarbon group. The hydrocarbon preferably contains at least one functional group selected from the group consisting of a hydroxyl group, an amino group, and an oxa group (-O-). Specific examples of the optional divalent hydrocarbon group having 1 to 10 carbon atoms include methylene group, oxymethylene group, ethylene group, dimethyl ether group, propylene group, butylene group, hydroxymethylene group, hydroxy Ethylene group, 1-hydroxypropanylene group, 2-hydroxypropanylene group, hydroxybrene group, aminomethylene group, aminoethylene group, 1-aminopropanyl group, 2-aminopropanyl group, aminobutylene group, vinylene group, etc. can be mentioned.

R ⁶ in formula (2) is a divalent group having 1 to 10 carbon atoms which may have at least one functional group selected from the group consisting of a hydroxyl group and an amino group (-NR ⁴ ₂ ) ``hydrocarbon group'', ``may have at least one functional group selected from the group consisting of hydroxyl group and amino group'' and ``divalent hydrocarbon group having 1 to 10 carbon atoms'', Same meaning as above.
Specific examples of "a divalent hydrocarbon group having 1 to 10 carbon atoms which may have at least one functional group selected from the group consisting of a hydroxyl group and an amino group" include a methylene group and an ethylene group. , propylene group, butylene group, hydroxymethylene group, hydroxyethylene group, 1-hydroxypropanylene group, 2-hydroxypropanylene group, hydroxybrene group, aminomethylene group, aminoethylene group, 1-aminopropanyl group, 2- Examples include aminopropanyl group, aminobutylene group, vinylene group, and the like.

In formula (1) and formula (2), ^A1 "peptide structure with 1 to 100 amino acids bonded at the N-terminus" is not only a peptide structure composed of two or more amino acids, but also a peptide structure composed of one amino acid. This means that the amino acid structure is also included. Furthermore, "bonded at the N-terminus" means that A ¹ is bonded to the carbonyl group (>C=O) at the N-terminus of the peptide structure or the amino group of the amino acid structure.
Specific examples of one amino acid structure include glycine structure, alanine structure, valine structure, leucine structure, isoleucine structure, methionine structure, proline structure, phenylalanine structure, tryptophan structure, serine structure, threonine structure, asparagine structure, glutamine structure, and tyrosine structure. structure, essential amino acid structures such as cysteine structure, lysine structure, arginine structure, histidine structure, aspartic acid structure, and glutamic acid structure, modified amino acid structures such as hydroxylysine structure, allicin structure, hydroxyallysine structure, and hydroxyproline structure, and collagen structure. Examples of amino acid structures included in the structure include glycine structure, proline structure, hydroxyproline structure, lysine, hydroxylysine structure, allicine structure, and hydroxyallysine structure.
When the "peptide structure having 1 to 100 amino acids bonded at the N-terminus" is a peptide structure composed of 2 or more amino acids, the number of amino acids is preferably 50 or less, more preferably 20 or less, and even more preferably 10 or less. , most preferably 3 or less.
Similarly, types of amino acids with a peptide structure composed of two or more amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, asparagine, glutamine, tyrosine, cysteine, and lysine. , essential amino acids such as arginine, histidine, aspartic acid, and glutamic acid, modified amino acids such as hydroxylysine, allicin, hydroxyallysin, and hydroxyproline, and amino acids included in the structure of collagen.

In formula (1) and formula (2), ^A2 "peptide structure with 1 to 100 amino acids bonded at the C-terminus" is not only a peptide structure composed of two or more amino acids, but also a peptide structure composed of one amino acid. This means that the amino acid structure is also included. In addition, "bonded at the C-terminus" means that A ² is bonded to the amino group (>NR) to which A 2 is bound at the C-terminus of the peptide structure or the carbonyl group of the amino acid structure.
Specific examples of one amino acid structure include glycine structure, alanine structure, valine structure, leucine structure, isoleucine structure, methionine structure, proline structure, phenylalanine structure, tryptophan structure, serine structure, threonine structure, asparagine structure, glutamine structure, and tyrosine structure. structure, essential amino acid structures such as cysteine structure, lysine structure, arginine structure, histidine structure, aspartic acid structure, and glutamic acid structure, modified amino acid structures such as hydroxylysine structure, allicin structure, hydroxyallysine structure, and hydroxyproline structure, and collagen structure. Examples include amino acid structures included in the structure, and particularly preferred are glycine structure, proline structure, hydroxyproline structure, lysine, hydroxylysine structure, allicine structure, and hydroxyallysine structure.
When the "peptide structure with 1 to 100 amino acids bonded at the N-terminus" is a peptide structure composed of 2 or more amino acids, the number of amino acids is preferably 50 or less, more preferably 20 or less, and even more preferably 10 or less. , most preferably 3 or less.
Similarly, types of amino acids with a peptide structure composed of two or more amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophan, serine, threonine, asparagine, glutamine, tyrosine, cysteine, and lysine. , essential amino acids such as arginine, histidine, aspartic acid, and glutamic acid, modified amino acids such as hydroxylysine, allicin, hydroxyallysin, and hydroxyproline, and amino acids included in the structure of collagen.

R ² and R ³ in formula (1) have a carbon atom number of 1 which may have at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ ); ~10 hydrocarbon groups", "may have at least one functional group selected from the group consisting of hydroxyl group, carboxyl group, and amino group (-NR ⁴ ₂ )" and "hydrocarbon group" , has the same meaning as above.
The number of carbon atoms in the hydrocarbon group is usually 6 or more when the hydrocarbon group is an aromatic hydrocarbon group. On the other hand, when the hydrocarbon group is other than an aromatic hydrocarbon group, the number is preferably 8 or less, more preferably 6 or less, and may be 3 or less.
Specific examples of "a hydrocarbon group having 1 to 10 carbon atoms which may have at least one functional group selected from the group consisting of a hydroxyl group, a carboxyl group, and an amino group (-NR ⁴ ₂ )" include: , methyl group, ethyl group, n-propyl group, i-propyl group, cyclopropyl group, n-butyl group, i-butyl group, s-butyl group, t-butyl group, 2,2-dimethyl-1-propyl group, cyclopentyl group, n-hexyl group, cyclohexyl group, n-heptyl group, 2-methylpentyl group, n-octyl group, 2-ethylhexyl group, n-nonyl group, n-decyl group, phenyl group, vinyl group, 2-hydroxyethyl group, 3-hydroxypropyl group, 2-carboxylethyl group, 4-carboxylbutyl group, 5-carboxypentyl group, 2-hydroxy-4-amino-5-carboxypentyl group, 2-amino-2- Examples include carboxyethyl group, 3-amino-3-carboxypropyl group, etc., preferably 2-hydroxyethyl group, 3-hydroxypropyl group, 2-carboxylethyl group, 4-carboxylbutyl group, 5-carboxypentyl group. , 2-hydroxy-4-amino-5-carboxypentyl group, 2-amino-2-carboxyethyl group, and 3-amino-3-carboxypropyl group.

Furthermore, the 3-hydroxypyridinium derivative represented by formula (1) has a counter anion. Examples of the counter anion include halogen ions such as chloride ion and bromide ion, acetate ion, and trifluoroacetate ion.

The molecular weight of the 3-hydroxypyridinium derivative represented by the formula (1) is 10,000 or less, may be 5,000 or less, further may be 1,000 or less, particularly may be 700 or less, and may be 500 or less. Furthermore, it may be less than 500, 480 or less, or 450 or less.

Specific examples of the 3-hydroxypyridinium derivative represented by the formula (1) include compounds having structures represented by the following formulas (1a) to (1e).

式中ｉはそれぞれ独立に１～１０の整数であり、好ましくは１～５の整数を示す。さらに、ｊはそれぞれ１～１０の整数であり、好ましくは１～５の整数を示す。

In the formula, i is each independently an integer of 1 to 10, preferably an integer of 1 to 5. Further, each j is an integer of 1 to 10, preferably an integer of 1 to 5.

The collagen production promoter of the present invention may be composed of only one type of compound corresponding to the 3-hydroxypyridinium derivative represented by the above formula (1), or may be composed of only one type of compound corresponding to the 3-hydroxypyridinium derivative represented by the above formula (1). It may contain two or more types of compounds corresponding to hydroxypyridinium derivatives. It is characterized by containing 0.00001% by weight or more of the 3-hydroxypyridinium derivative represented by the above formula (1) as an active ingredient (two types corresponding to the 3-hydroxypyridinium derivative represented by the above formula (1)). When the above compound is contained, the layer content of the compound is preferably 0.0001% by weight or more, more preferably 0.001% by weight or more, particularly preferably 0.01% by weight or more, and most preferably 0.001% by weight or more. It is 1% by weight or more. More preferably, it is 1% by weight or more, and more preferably 5% by weight or more. The upper limit of the content of the collagen production promoter is not particularly limited, but is preferably 50% by weight or less, more preferably 80% by weight or less, and most preferably 100% by weight. The ability to promote collagen production is exhibited by derivatives having a 3-hydroxypyridinium partial structure, but as the content of the 3-hydroxypyridinium partial structure increases, the number of molecules recognized by RAGE increases, The collagen production effect can be more effectively exerted.

The 3-hydroxypyridinium partial structure has a structure represented by the following formula (3).

The collagen production promoter of the present invention may contain other components, but the 3-hydroxypyridinium derivative represented by formula (1) contains 0.0% of all the components contained in the collagen production promoter. The content is preferably 0.05% by weight or more. Furthermore, it is preferably at least 0.01% by weight, particularly preferably at least 0.1% by weight, even more preferably at least 1% by weight, particularly preferably at least 10% by weight.

Other ingredients contained in the collagen promoter include amino acids, proteins, collagen-derived ingredients not containing 3-hydroxypyridinium derivatives, vitamin C, and the like.

The form of the collagen production promoter is not particularly limited, and can be set depending on the applied formulation, dosage form, form, use, etc. of the product. For example, it can be prepared into an aqueous solution, a glucose solution, a buffer-containing solution, a biocompatible liquid, a liquid, an emulsion, a cream, a powder, a granule, a pill, an ointment, and the like.

Target cells are not limited as long as the effects of the present invention can be achieved, but collagen production by acting on human proximal tubular epithelial cells, osteoblasts, epidermal epithelial cells, and fibroblasts can be significantly promoted.

[Method for producing 3-hydroxypyridinium derivative]
The 3-hydroxypyridinium derivative in the present invention may be produced by organic synthesis or by purifying a natural product. As a method for purifying and producing natural products, for example, it can be obtained by decomposing collagen.

(Production method by organic synthesis)
As a method for producing by organic synthesis, for example, a method of reacting glyceraldehyde and 6-aminohexanoic acid, and a method of reacting glyceraldehyde and 6-aminohexanoic acid with Nα-protected-O-protected-lysine and 5 , 6-epoxy-2-N-protected-O-protected-(2S)-2-aminohexanoic acid ester.
It can also be obtained by adding various substituents to commercially available 3-hydroxypyridine derivatives. For example, by reacting 3-hydroxypyridine with 6-bromohexanoic acid, 3-hydroxypyridinium derivatives can be easily obtained.

(Production method by collagen decomposition)
Collagen can be decomposed by treatment with acid, alkali, enzyme, etc.

The collagen is not particularly limited, and includes, for example, collagen derived from mammals such as cows and pigs, collagen derived from fish such as sharks, and collagen derived from birds such as chickens and ostriches. Collagen is contained in large amounts in the bones, skin, scales, etc. of mammals, fish, birds, etc., and it can be obtained by subjecting these various materials to conventional treatments such as degreasing, demineralization, and extraction. Obtainable.

-Hydrolysis conditions The conditions for the hydrolysis reaction are not particularly limited, but are preferably, for example, pH 2.5 to 8.0. More preferably the pH is 2.5 to 5.5.
The decomposition temperature is not particularly limited, but is, for example, 10°C to 100°C, preferably 20°C to 50°C, particularly preferably 25°C to 30°C.
The time for the hydrolysis reaction is not particularly limited, but can be, for example, 1 minute to 200 hours, preferably 60 minutes to 100 hours, particularly preferably 120 minutes to 24 hours.

-Enzymatic decomposition Conditions for enzymatic digestion with trypsin The temperature for enzymatic digestion with trypsin is not particularly limited, but it is usually carried out at, for example, 10°C to 100°C. Further, a temperature of 30°C to 70°C is more preferable because collagen is degraded well.

After the hydrolysis process, it is necessary to deactivate the enzyme, as is usually done. Specifically, although not particularly limited, the enzyme can be inactivated, for example, by heating at 70 to 100°C for 1 second to 3 hours.

- Purification of decomposed products The decomposed products obtained by hydrolysis can be purified through purification operations such as column chromatography, cation exchange chromatography, solid phase extraction, and reversed phase HPLC.

- Identification of purified product The obtained purified product is identified by fluorescence spectroscopy, NMR, GPC, mass spectrometry, etc.

[Collagen decomposition products]
The present invention is a collagen decomposition product containing 0.015% by weight or more of the 3-hydroxypyridinium partial structure represented by the above formula (3). Further, the collagen degradation product of the present invention may contain 0.02% by weight or more of a 3-hydroxypyridinium partial structure, further may contain 0.03% by weight or more, and may further contain 0.05% by weight or more. It may be contained in an amount of 0.1% by weight or more, furthermore it may be contained in an amount of 0.2% by weight or more, and furthermore it may be contained in an amount of 0.5% by weight or more.
The collagen decomposition product of the present invention contains a higher concentration of 3-hydroxypyridinium partial structure than general collagen decomposition products.

The collagen decomposition product containing 0.015% by weight or more of the 3-hydroxypyridinium partial structure of the present invention can be produced by decomposing collagen, and the 3-hydroxypyridinium derivative present as a crosslinked part of collagen is separated. , obtained by fractionation.

Methods for preparative separation and fractionation are not limited, but examples include column chromatography, ion exchange chromatography, gel filtration chromatography, HPLC, electrophoresis, centrifugation, solid-liquid extraction, liquid separation, filtration, electrodialysis, and GPC. By performing operations such as , distillation, recrystallization, reprecipitation, and distillation, a collagen decomposition product containing 0.015% by weight or more of a 3-hydroxypyridinium partial structure can be obtained.

Furthermore, the present invention is a collagen decomposition product containing 0.07% by weight or more of 3-hydroxypyridinoline represented by the above formula (4). Further, the collagen decomposition product of the present invention may contain 3-hydroxypyridinoline in an amount of 0.08% by weight or more, further may contain 0.1% by weight or more, and may contain 3-hydroxypyridinoline in an amount of 0.3% by weight or more. It may be contained in an amount of 0.5% by weight or more, further may be contained in an amount of 1.0% by weight or more, and further may be contained in an amount of 2.0% by weight or more.
The collagen degradation product of the present invention contains a higher concentration of 3-hydroxypyridinoline than general collagen degradation products.

The collagen decomposition product containing 0.07% by weight or more of 3-hydroxypyridinoline of the present invention can be produced by decomposing collagen, and the 3-hydroxypyridinoline present as a crosslinked portion of collagen is separated. It is obtained by separating and fractionating.

Methods for preparative separation and fractionation are not limited, but examples include column chromatography, ion exchange chromatography, gel filtration chromatography, HPLC, electrophoresis, centrifugation, solid-liquid extraction, liquid separation, filtration, electrodialysis, and GPC. By performing operations such as , distillation, recrystallization, reprecipitation, and distillation, a collagen decomposition product containing 0.07% by weight or more of 3-hydroxypyridinoline can be obtained.

[Analysis method of collagen degradation product]
As a method for measuring the concentration of 3-hydroxypyridinium partial structure and 3-hydroxypyridinoline in collagen decomposition products, for example, collagen or collagen decomposition products can be mixed with 3-hydroxypyridinoline, which is a crosslinking component. decompose or re-decompose to the extent that it can be isolated.
The method of decomposition or re-decomposition is to add 6M hydrochloric acid to collagen or collagen decomposition product and hydrolyze it at 110°C for 24 hours under nitrogen atmosphere to decompose it to the extent that 3-hydroxypyridinoline can be isolated. can do.
Then, the concentration of 3-hydroxypyridinoline can be measured by measuring the area of the fraction having absorbance at the specific absorption wavelength of 295 nm of 3-hydroxypyridinoline.
Furthermore, after determining the concentration of 3-hydroxypyridinoline, the ratio of the molecular weight of the 3-hydroxypyridinium partial structure to the molecular weight of 3-hydroxypyridinoline was calculated to determine the concentration of 3-hydroxypyridinium in the collagen decomposition product. The concentration of the structure can be calculated.
For example, if 1 part by weight of 3-hydroxypyridinoline (PYR) is contained in 100 parts by weight of collagen decomposition product, it is found that 0.212 parts by weight of the 3-hydroxypyridinium partial structure is contained.
Molecular weight of 3-hydroxypyridinium partial structure (91 g/mol)
Molecular weight of 3-hydroxypyridinoline (PYR) (429g/mol)

[General collagen degradation products]
In a typical collagen degradation product, the content of 3-hydroxypyridinoline is less than 0.07% by weight. Further, the content of the 3-hydroxypyridinium partial structure is less than 0.0148% by weight.
This is because it is known that 0.16 3-hydroxypyridinolines are contained per collagen, and it can be calculated based on this fact.
For example, it can be calculated from the molecular weight of one collagen (approximately 100,000), the molecular weight of 3-hydroxypyridinoline (229 g/mol), and the molecular weight of the 3-hydroxypyridinolium partial structure (91 g/mol). See Fujimoto et al J. Biochem. 83, 863-867 (1978)).

[Applications of collagen promoter]
The application of the collagen promoter is also not particularly limited, and can be set depending on the purpose. For example, it can be used as a cosmetic composition or a food composition. Furthermore, it can be applied to living organisms to improve skin conditions and promote wound healing. Furthermore, it can be added to a culture medium or a culture solution to promote the formation of collagen-containing tissues and bone tissues such as artificial tissues and scaffold materials.

Collagen whose production can be promoted is not particularly limited, and includes collagens such as type I collagen and type II collagen, but it can be used particularly for the production of type I collagen, which is present in large amounts in bones and skin.

- Type I collagen Type I collagen consists of two A1 chains and one A2 chain, and is known to be present in large amounts in bones and skin as described above.

By increasing the expression of the gene (Col1a1) encoding the type I collagen a1 chain, it is possible to promote collagen production, and maintain the amount of type I collagen by promoting the production of type I collagen. This is known to be effective in preventing and improving wrinkles and sagging. Furthermore, promotion of type I collagen production is also effective in improving skin wound healing.
Furthermore, 80% of the organic matter in bones is made up of type I collagen, and it is known that calcium phosphate is deposited around type I collagen fibers secreted by osteoblasts to form hydroxyapatite and bone is formed.
Therefore, by promoting the production of type I collagen, bones are regenerated, and it can be applied to the treatment of osteoporosis.

(Cosmetic composition)
The cosmetic composition of the present invention is characterized by containing the collagen production promoter described above.
The cosmetic composition of the present invention can promote the production of collagen in the epidermis and dermis of the skin, and can contribute to maintaining skin health or suppressing skin aging.

The cosmetic composition of the present invention can be produced by preparing the collagen production promoter described above together with a suitable medium or carrier.
The amount of the collagen production promoter to be added is not limited, but it cannot be strictly defined because it varies depending on the structure of the compound, the area of application, the age and characteristics of the target, the form of the cosmetic composition, etc. The blending amount is not particularly limited, and for example, it is preferably contained in the composition at 0.001% by weight or more, more preferably at least 0.01% by weight, particularly preferably at least 0.1% by weight. The amount is most preferably 1% by weight or more, and more preferably 3% by weight or more.
The cosmetic composition of the present invention may contain other collagen-derived components (especially peptides), but among all the collagen-derived components (especially peptides) contained in the cosmetic composition of the present invention, It is preferable that the compound represented by formula (1) and its derivatives account for 10% by weight or more, preferably 20% by weight or more, particularly preferably 50% by weight or more.

The cosmetic composition of the present invention may contain other components as long as they do not impair the effects of the present invention. Other ingredients include, for example, whitening agents, anti-aging agents, humectants, anti-aging agents, hair growth agents, sebum care/acne care agents, bactericidal/antibacterial agents, astringents, ultraviolet absorbers, and the like. Further, compounds that can improve collagen production ability, such as vitamin C, can also be blended.
Furthermore, the cosmetic composition of the present invention can be prepared in an appropriate form, such as liquid, milky lotion, cream, powder, granule, microencapsulation, etc., as desired.
In addition, the cosmetic composition of the present invention can be used to create facial washes, soaps, cleansers, serums, foundations, all-in-one gels, sunscreens, body soaps, antiperspirants, lotions, lotions, tonics, creams, milky lotions, ointments, Various cosmetics and cosmetics such as packs, masks, lipsticks, bath additives, and hair styling products can also be manufactured according to conventional methods.

The application site of the cosmetic composition is not particularly limited as long as the effects of the present invention can be achieved, and the cosmetic composition can be applied to various sites such as the face, body, and hair. Additionally, since the relationship between collagen production by scalp hair follicle stem cells and hair has become known, applying it to the scalp can be expected to be effective in preventing hair thinning.
The cosmetic composition of the present invention has the effect of significantly promoting collagen production in skin fibroblasts, and can be used for maintaining skin health or inhibiting skin aging.

(Food and drink composition)
The edible composition of the present invention is characterized by containing the collagen production promoter described above.
The edible composition of the present invention can easily promote collagen production by oral administration, and is effective in maintaining skin health, inhibiting skin aging, preventing osteoporosis, and preventing diseases in pets.
The edible composition in the present invention refers to foods, beverages, luxury goods, supplements, pet foods, etc. that are ingested orally. The collagen production promoter of the present invention can be contained in these, but the form thereof is not particularly limited, such as breads, noodles, etc. that can be main dishes, cheese, sausages, ham, processed seafood products, etc. It can be used as side dishes, beverages such as fruit juice drinks, milk drinks, and carbonated drinks, and luxury goods such as cakes, cookies, jellies, candies, puddings, and yogurts. Further, the form of the supplement is not particularly limited, and may be in the form of a tablet, capsule, soft capsule, or energy drink.

The amount of the collagen production promoter in the food and drink composition is not particularly limited, and for example, it is preferably contained in the composition at 0.001% by weight or more, more preferably at least 0.01% by weight, The content is particularly preferably 0.1% by weight or more, most preferably 1% by weight or more, and even more preferably 3% by weight or more.

(Composition for cell culture)
The cell culture composition of the present invention is characterized by containing the collagen production promoter described above.
The composition for cell culture of the present invention can easily generate a collagen membrane, and can contribute to regenerative medicine, an alternative to animal experiments, etc. The method for producing the composition for cell culture is not particularly limited, but for example, , can be produced by adding the collagen production promoter described above to a general culture solution or the like. Further, the above-mentioned collagen production promoter can be produced by preparing it as a component of a culture medium or culture solution.

The proportion of the collagen production promoter in the cell culture composition varies depending on the cells, culture medium, type of culture solution, etc., and cannot be specified uniformly, but it is preferably contained at 0.001% by weight or more in the composition, for example. , more preferably 0.01% by weight or more, particularly preferably 0.1% by weight or more, most preferably 1% by weight or more, and even more preferably 3% by weight or more.
The cell culture composition of the present invention may contain other collagen-derived components (especially peptides), but among all the collagen-derived components (especially peptides) contained in the cell culture composition of the present invention, It is preferable that the compound represented by formula (1) and its derivatives account for 10% by weight or more, preferably 20% by weight or more, particularly preferably 50% by weight or more.

The cell culture composition of the present invention may contain other components as long as the effects of the present invention are not impaired. Examples of other components include inorganic salts, carbon sources, various vitamins, buffers, cell growth factors, amino acids, and serum. Further, compounds that can improve collagen production such as DTPA, TPEN, or ACA, or compounds that can enhance collagen production such as vitamin C or its derivatives can also be blended.

The cell culture composition of the present invention has the effect of significantly promoting collagen production in cultured cells, and can be used, for example, for culturing artificial skin to promote the formation of artificial tissues. . Furthermore, it can be used to prepare scaffold materials for regenerative medicine, and can be used to promote the formation of collagen-containing tissues.

(Pharmaceutical composition for wound healing)
The pharmaceutical composition for wound healing of the present invention is characterized by containing the collagen production promoter described above. The pharmaceutical composition for wound healing of the present invention is used to promote wound healing, such as skin regeneration for lacerations and burn treatments.

The pharmaceutical composition for wound healing of the present invention can be produced according to conventional methods. For example, it can be produced by preparing the collagen production promoter described above together with a pharmaceutically acceptable carrier.
The pharmaceutical composition for wound healing of the present invention may contain a pharmaceutically acceptable carrier, known additives, or other pharmaceutically active ingredients, as long as the effects of the present invention are achieved. can. Further, a compound that enhances collagen production, such as vitamin C or a derivative thereof, can also be blended.

The blending ratio of the collagen production promoter in the pharmaceutical composition for wound healing of the present invention varies depending on the application site, the age of the application target, the form of the pharmaceutical composition, etc., and cannot be uniformly specified. The content is preferably 0.001% by weight or more, more preferably 0.01% by weight or more, particularly preferably 0.1% by weight or more, most preferably 1% by weight or more, and more preferably 3% by weight. That's all.
The pharmaceutical composition for wound healing of the present invention may contain other collagen-derived components (especially peptides), but all collagen-derived components (especially peptides) contained in the pharmaceutical composition for wound healing of the present invention may contain other collagen-derived components (especially peptides). ), preferably 10% by weight or more, preferably 20% by weight or more, particularly preferably 50% by weight or more, is preferably occupied by the compound represented by formula (1) of the present invention and its derivatives.

The pharmaceutical composition for wound healing of the present invention can be set in an appropriate form as desired. For example, it can be in the form of a dry powder, gel, cream, ointment, suspension, solution or biocompatible synthetic or natural solid matrix.
Furthermore, it is also possible to use it by applying it onto a base material such as a film and attaching it to the skin.

(Composition for promoting bone formation)
The composition for promoting bone formation of the present invention is characterized by containing the collagen production promoter described above. The composition for promoting bone formation of the present invention can be used for the prevention and treatment of osteoporosis.
The composition for promoting bone formation of the present invention can be made into a formulation that can be administered orally as a supplement, or can be used by directly injecting it into the trunk. Examples of such preparations include tablets such as orally disintegrating tablets, chewable tablets, and dispersible tablets, capsules, granules, powders, oral solutions, syrups, oral jellies, aqueous solutions, glucose solutions, etc. Can be done.

In the composition for promoting bone formation of the present invention, pharmaceutically acceptable excipients, binders, lubricants, isotonic agents, stabilizers, preservatives, flavoring agents, solubilizing agents, and Agents, emulsifiers, etc. can be further added.
The composition for promoting bone formation of the present invention can be produced by a conventionally known method. For example, in the case of tablets, they can be formulated using the following steps. That is, weighing, primary mixing (mixing active ingredients, excipients, binders, disintegrants, etc. uniformly), granulation, sieving, secondary mixing (mixing lubricants, etc.), coating (as necessary) This is a manufacturing method that involves steps such as , packaging, etc.

Since the composition for promoting bone formation of the present invention activates osteoblasts, it can repair bones or increase bone density by locally delivering it to a bone defect of a patient. The drug carrier mixture used in this case is prepared by mixing with, for example, calcium phosphate cement powder. Depending on the particular embodiment, a drug carrier mixture may be combined with a suitable bone matrix material to form a bone composition of the invention. Alternatively, the bone repair composition may include a collagen sponge. The bone composition can then be applied to the treatment site, such as by implantation or injection into the bone defect site. It can also be applied to implants.

The content of the collagen production promoter in the composition for promoting bone formation of the present invention is not particularly limited, but for example, it is preferably contained in the composition at 0.001% by weight or more, more preferably at least 0.01% by weight, especially Preferably it is 0.1% by weight or more, most preferably 1% by weight or more, and even more preferably 3% by weight or more.
The composition for promoting bone formation of the present invention may contain other collagen-derived components (especially peptides), but all collagen-derived components (especially peptides) contained in the composition for promoting bone formation of the present invention may contain other collagen-derived components (especially peptides). ), preferably 10% by weight or more, preferably 20% by weight or more, particularly preferably 50% by weight or more, is preferably occupied by the compound represented by formula (1) of the present invention and its derivatives.

ＰＹＲを以下に示す方法に従って調製した。
ウシアキレス腱コラーゲン１ｇ（Ｓｉｇｍａ）に６Ｍ 塩酸（アミノ酸自動分析用）を１０ｍｌ加え、加水分解装置（Ｗａｔｅｒｓ，Ｐｉｃｏ・Ｔａｇ）を用いて窒素置換下、１１０℃で２４時間加水分解を行った。加水分解物を孔径０．２μmのフィルター（ＡＤＶＡＮＴＥＣ，ＤＩＳＭＩＣ－２５ＣＳ）で濾過したのち、ロータリーエバポレーター（ＥＹＥＬＡ，Ｎ－１１００，ＳＢ―１１００，Ａ１０００Ｓ）により塩酸を除去・乾燥させることによりコラーゲン加水分解物を得た。コラーゲン加水分解物を１０ｍＭ酢酸ナトリウムバッファーに溶解したのち、１０Ｍ水酸化ナトリウム水溶液を加えｐＨ４．０に調整した。これを陽イオン交換クロマトグラフィー（ＦＰＣ３５００）に供し、０．５Ｍ ＮａＣｌを含有する１０ｍＭ 酢酸ナトリウムバッファーにより目的の画分を溶出させた。溶出画分をロータリーエバポレーターにより濃縮したのち、０．１％ＨＦＢＡに溶解し、Ｓｅｐ－ＰａｋＣ１８・３５ｃｃ Ｖａｃ Ｃａｒｔｒｉｄｇｅ（Ｗａｔｅｒｓ，ＷＡＴ０４３３４５）を用いた固相抽出に供した。０．１％ＨＦＢＡにより非吸着画分および塩を溶出させたのち、２０％アセトニトリルにより目的画分を溶出させた。溶出画分をロータリーエバポレーターにより濃縮したのち、少量の０．１％ＨＦＢＡに溶解させた。これを孔径０．４５μmのフィルター（ＡＤＶＡＮＴＥＣ，ＤＩＳＭＩＣ－０３ＣＰ）を用いて濾過した後、逆相ＨＰＬＣ（Ｉｎｅｒｔｓｉｌ ＯＤＳ－４、ＧＬ Ｓｃｉｅｎｃｅ）に供し、０．１％ＨＦＢＡを含有する５０％アセトニトリルにより分離した。ＰＹＲの特異的吸収波長２９５ｎｍに対する吸光度を有する画分を単離し、さらにこれを逆相ＨＰＬＣ（Ｉｎｅｒｔｓｉｌ ＯＤＳ－３、ＧＬ Ｓｃｉｅｎｃｅ）に供して０．１％ＨＦＢＡを含有する５０％アセトニトリルにより分離することにより精製し、ＰＹＲ（上記一般式（４））を得た。
得られた化合物の蛍光スペクトルを図１に示す。またマススペクトル結果を図２に示す。
特異的蛍光及びマススペクトル解析から、得られた化合物はＰＹＲであることを確認できる。 The present invention will be described below with reference to Examples, but the present invention is not limited thereto.
<Example 1>
(1) Preparation of 3-hydroxypyridinoline (PYR)

PYR was prepared according to the method shown below.
10 ml of 6M hydrochloric acid (for automatic amino acid analysis) was added to 1 g of bovine Chilles tendon collagen (Sigma), and hydrolysis was performed at 110° C. for 24 hours under nitrogen substitution using a hydrolysis device (Waters, Pico Tag). After filtering the hydrolyzate with a filter with a pore size of 0.2 μm (ADVANTEC, DISMIC-25CS), hydrochloric acid was removed and dried using a rotary evaporator (EYELA, N-1100, SB-1100, A1000S) to obtain a collagen hydrolyzate. I got it. After the collagen hydrolyzate was dissolved in a 10 mM sodium acetate buffer, a 10 M aqueous sodium hydroxide solution was added to adjust the pH to 4.0. This was subjected to cation exchange chromatography (FPC3500), and the desired fraction was eluted with 10 mM sodium acetate buffer containing 0.5 M NaCl. The eluted fraction was concentrated using a rotary evaporator, then dissolved in 0.1% HFBA, and subjected to solid phase extraction using a Sep-Pak C18 35cc Vac Cartridge (Waters, WAT043345). After eluting the non-adsorbed fraction and salt with 0.1% HFBA, the target fraction was eluted with 20% acetonitrile. The eluted fraction was concentrated using a rotary evaporator and then dissolved in a small amount of 0.1% HFBA. This was filtered using a filter with a pore size of 0.45 μm (ADVANTEC, DISMIC-03CP), subjected to reverse phase HPLC (Inertsil ODS-4, GL Science), and separated using 50% acetonitrile containing 0.1% HFBA. did. A fraction having an absorbance at the specific absorption wavelength of PYR of 295 nm was isolated, and further subjected to reverse phase HPLC (Inertsil ODS-3, GL Science) and separated by 50% acetonitrile containing 0.1% HFBA. PYR (general formula (4) above) was obtained.
The fluorescence spectrum of the obtained compound is shown in FIG. Moreover, the mass spectrum results are shown in FIG.
Specific fluorescence and mass spectral analysis confirm that the obtained compound is PYR.

(2) Evaluation of collagen production promoting effect The collagen production promoting effect of the compound was evaluated by the following method.
(2-1) Preparation of sample Human proximal tubular epithelial cell line (HK-2, Riken Cell Bank) was seeded in a cell culture dish to a cell number of 1 x ¹⁰⁶ cells, containing 10% FBS. The cells were cultured in DMEM medium for 72 hours. PYR was added as a test compound to the cultured cells and cultured for 24 hours. As a comparative example, a sample was also prepared for a system in which PYR was not added.

Sample group Sample 1) Control (no PYR added)
Sample 2) PYR 10 μM added Sample 3) PYR 50 μM added

(2-2) Measurement of Collagen Production Amount With respect to the sample group prepared in (2-1) above, the production amount of collagen was analyzed by RT (reverse transcription)-PCR method according to the following procedure.
After removing the medium from the culture dish and washing it twice with PBS solution for 5 minutes, 1 ml of TRIzol (Ambion) was added to dissolve the cells and collected into a microtube (WATSON). After adding 400 μl of chloroform and stirring, an aqueous layer was obtained by centrifugation. 500 μl of isopropanol was added to the obtained aqueous layer fraction to precipitate RNA. The supernatant was removed by centrifugation, and the resulting RNA was washed with 75% ethanol and then dissolved in water. cDNA was synthesized by reverse transcription using 2 μg of RNA as a template, (dT) ₁₈ primer, and AMV Reverse transcriptase (Takara Shuzo). PCR measurements were performed using cDNA obtained from each sample group as a template, primers specific to type I collagen a1 (Col1a1), and Hybripol DNA Polymerase. The amplified product after the reaction was subjected to agarose electrophoresis, and the band intensity was measured and evaluated. The expression intensity of GAPDH, which is constantly observed, was used as a control to correct the numerical values.

For PYR (Sample 2 and Sample 3), the results of the analysis of the mRNA expression level of type I collagen type A in human renal tubular epithelial cells obtained are shown in FIG. The intensity values in the figure are expressed as a percentage of the expression intensity of each sample when the control is set as 100. Furthermore, the analysis results of staining intensity are shown in Table 1. The intensity values in the table are expressed as a percentage of the staining intensity of each sample when the control is set as 100.

Expression level of type I collagen a1 (Col1a1) (average value)

From Figure 3 and Table 1, it was confirmed that PYR (Samples 2 and 3) had significantly improved collagen production compared to the control (Sample 1), suggesting that it has collagen production enhancing activity. It was done.

(3) Evaluation of TGFβ expression promoting effect related to collagen production The TGFβ expression promoting effect of the compound was evaluated using the following method.
(3-1) Preparation of sample A rat proximal tubular epithelial cell line (NRK52E, Riken Cell Bank) was seeded in a cell culture dish to a cell number of 1 x ¹⁰⁶ cells, and DMEM medium containing 10% FBS was used. The cells were cultured for 72 hours. PYR was added as a test compound to the cultured cells and cultured for 24 hours. As a comparative example, a sample was also prepared for a system in which PYR was not added.

Sample group Sample 4) Control (no PYR added)
Sample 5) PYR 10 μM added Sample 6) PYR 50 μM added

(3-2) Measurement of Collagen Production Amount For the sample group prepared in (3-1) above, the production amount of collagen was analyzed by RT (reverse transcription)-PCR method according to the following procedure.
After removing the medium from the culture dish and washing it twice with PBS solution for 5 minutes, 1 ml of TRIzol (Ambion) was added to dissolve the cells and collected into a microtube (WATSON). After adding 400 μl of chloroform and stirring, an aqueous layer was obtained by centrifugation. 500 μl of isopropanol was added to the obtained aqueous layer fraction to precipitate RNA. The supernatant was removed by centrifugation, and the resulting RNA was washed with 75% ethanol and then dissolved in water. cDNA was synthesized by reverse transcription using 2 μg of RNA as a template, (dT) ₁₈ primer, and AMV Reverse transcriptase (Takara Shuzo). Using the cDNA obtained from each sample group as a template, PCR measurements were performed using TGFβ1-specific primers and Hybripol DNA Polymerase. The amplified product after the reaction was subjected to agarose electrophoresis, and the band intensity was measured and evaluated. The expression intensity of GAPDH, which is constantly observed, was used as a control to correct the numerical values.

For PYR (Sample 5 and Sample 6), the results of the analysis of the mRNA expression level of TGFβ1 in rat renal tubular epithelial cells obtained are shown in FIG. The intensity values in the figure are expressed as a percentage of the expression intensity of each sample when the control is set as 100. Furthermore, the analysis results of staining intensity are shown in Table 1. The intensity values in the table are expressed as a percentage of the staining intensity of each sample when the control is set as 100.

Expression level of TGFβ1 (average value)

From Figure 4 and Table 2, it was confirmed that PYR (Samples 5 and 6) has a significantly increased expression level of TGFβ1 when compared with the control (Sample 4), and has collagen production enhancement activity. From this, it can be seen that it is useful as a cosmetic composition and a composition for food and drink.
As described in a non-patent literature (Jeon et al. J. Phys. Ther. Sci. 27, 1485-1490 2015), increased TGF-β expression and increased type I collagen production are effective for wound healing. It is a well-known fact that this is true. The collagen promoter of the present invention, which increases the expression of TGF-β and increases the expression of type I collagen, is useful as a pharmaceutical composition for wound healing.

<Example 2>
(1) Preparation of 1-(5-carboxypentyl)-3-hydroxy-5-hydroxymethylpyridinium (CHHP)

2M glyceraldehyde and 0.1M 6-aminohexanoic acid were reacted in 0.2M phosphate buffer (pH 7.4) at 50°C for 72 hours. The reaction solution was subjected to solid phase extraction using Sep-PakC18 35cc Vac Cartridge (Waters, WAT043345). A non-adsorbed fraction eluted with water was obtained and concentrated using a rotary evaporator, then dissolved in a small amount of water, and the pH was adjusted to 2.0 by adding trifluoroacetic acid (TFA). This solution was again subjected to Sep-Pak C18 35cc Vac Cartridge, and the fraction eluted with 20% acetonitrile aqueous solution was concentrated. The concentrated solution was subjected to reverse phase HPLC (Inertsil ODS-3, GL Science) and separated using 50% acetonitrile containing 0.05% TFA. Purified CHHP (the above general formula (5)) was obtained by isolating a fraction having absorbance at 291 nm, the specific absorption wavelength of CHHP.

(2) Evaluation of bone formation promoting effect (2-1) Mouse skull-derived cell line (MC3T3-E1, RIKEN BioResource Center) was seeded in a cell culture dish (NUNC) at a cell count of 1 x 10 ⁶ cells. The cells were cultured in αMEM medium containing 10% FBS, 25 μg/ml ascorbic acid, and 5 mM β-glycerophosphate to differentiate into osteoblasts. CHHP as a test compound was added to this and cultured for 24 hours.
The osteogenesis promoting effect was evaluated based on the osteoblast differentiation promoting effect or the bone matrix collagen production promoting effect.
Osteoblast differentiation was evaluated by the expression level of alkaline phosphatase and enzyme activity. MC3T3-E1 cells were cultured in differentiation medium for 14 days and then further cultured in differentiation medium supplemented with CHHP for 7 days. After culturing, the medium was removed and the dish was washed, and the cells were collected with a buffer (20 mM Tris, pH 7.5) containing detergent (0.1% NP-40) and protease inhibitors, and sonicated. The cells were disrupted to obtain a cell extract. The cell extract was added to a buffer (pH 10.0) containing a substrate for alkaline phosphatase, and reacted at 37°C for 1 hour. After the reaction, the product (p-nitrophenol) generated from the substrate was evaluated by absorbance increase at 405 nm.
FIG. 4 shows data (relative values to the control without addition) showing the effect of CHHP on increasing alkaline phosphatase activity, that is, promoting osteoblast differentiation.

(2-2) Furthermore, similarly to human renal tubular epithelial cells, the promoting effect of CHHP on collagen production in osteoblast cells was evaluated by RT-PCR, and the results are shown in FIG.

Sample group Sample 7) Control (no CHHP added)
Sample 8) CHHP 1 μM added Sample 9) CHHP 10 μM added

Expression level of type I collagen a1 (Col1a1) (average value)

From Figure 5, Figure 6, and Table 3, it was confirmed that CHHP (Samples 8 and 9) had a markedly improved collagen production compared to the control (Sample 7), and had an osteoblast differentiation promoting effect. It was also suggested that.

Non-patent literature (Gun Korei, Yoshiaki Deyama, Tomoya Kudo, Yoshitaka Yoshimura, Kuniaki Suzuki: "Effect of estrogen on various ATPases in osteoblast-like MC3T3-E1 cells" Hokkaido Dental Journal 33, 175-184 (2013) (http:/ /hdl.handle.net/2115/52456)), bones are formed through a process in which calcium phosphate and the like are accumulated in a collagen matrix produced by osteoblasts. Therefore, it is a well-known fact that compounds that promote collagen production and differentiation of osteoblasts increase bone mass and can serve as therapeutic and preventive agents for osteoporosis. Furthermore, as stated in the same non-patent document, the expression of alkaline phosphatase (ALP) increases in osteoblasts as they differentiate. From this, it is a well-known fact that compounds that increase ALP activity have an osteoblast differentiation-promoting effect, and therefore can serve as therapeutic and preventive agents for osteoporosis.
As stated in the same non-patent document, mouse MC3T3-E1 cells have characteristics similar to human osteoblasts and are a cell line commonly used for functional analysis of osteoblasts. Therefore, it can be said that promotion of collagen production and increase in ALP expression in MC3T3-E1 cells can be indicators of promotion of bone formation.

・Examination of the interaction between the receptor for advanced glycation end products (RAGE) and 3-hydroxypyridinium derivatives (1) Analysis of RAGE ligand using the Biacore system Soluble RAGE was expressed as a recombinant protein in Escherichia coli, and affinity column chromatography was performed. It was purified using lithography. When purified recombinant RAGE protein was immobilized on a sensor chip and pyridinoline and CHHP were added as analytes, a concentration-dependent binding response was detected. Kinetics analysis revealed that the dissociation constants K _D were 179 μM (PYR) and 393 μM (CHHP). Furthermore, when a pyridinoline peptide having a peptide structure was analyzed, a specific interaction was confirmed.
These results demonstrated that the 3-hydroxypyridinium derivative exhibits specific affinity for the receptor for advanced glycation end products (RAGE).

These results confirmed that the 3-hydroxypyridinium derivative of the present invention is specifically recognized by the receptor for advanced glycation end products (RAGE), suggesting that collagen production is promoted.

(Preparation of 3-hydroxypyridinoline (PYR)-containing collagen degradation product)
10 L of 6M hydrochloric acid was added to 1 kg of fish collagen, and hydrolysis was performed at 110° C. for 24 hours. The hydrolyzate was filtered through a filter with a pore size of 0.2 μm (manufactured by ADVANTEC), and then neutralized with a 10M aqueous sodium hydroxide solution. Next, this was dried to obtain a collagen hydrolyzate.
After the collagen hydrolyzate was dissolved in a 10 mM sodium acetate buffer, a 10 M aqueous sodium hydroxide solution was added to adjust the pH to 4.0. This was subjected to cation exchange chromatography, and the desired fraction was eluted with 10 mM sodium acetate buffer containing 0.5 M NaCl. The eluted fraction was dried to obtain a PYR-containing collagen degradation product.

[Prescription example]
Next, examples of formulations in which the PYR-containing collagen decomposition product of the present invention is applied to cleaning products, skin care cosmetics, makeup cosmetics, hair care cosmetics, sunscreen/UV care cosmetics, foods, and drinks will be shown. However, the technical scope of the present invention is not limited by these prescription examples.

(Prescription example 1)
A soap was prepared according to the following recipe.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Coconut fatty acid 20.00
Palm oil fatty acid 20.00
Glycerin 6.00
Na hydroxide (85%) 15.75
EDTA-2Na 0.20
Sodium citrate 0.50
water remainder

(Prescription example 2)
A body soap (transparent type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 10.00
Coconut fatty acid 5.00
Citric acid 1.00
Glycerin 3.00
Hydroxide K 5.68
EDTA-4Na 0.20
Sodium gluconate 1.00
Dioleic acid PEG-120 methylglucose 2.00
water remainder

(Prescription example 3)
A body soap (pearl type) was prepared using the following recipe.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 10.00
Cocoyl methyl taurine Na, water 10.00
(NIKKOL CMT-30)
Sodium laureth sulfate, water (27% aqueous solution) 22.20
PEG-150 distearate 3.00
(NIKKOL CDS-6000P)
Sodium laureth-5 carboxylate, water 20.00
(NIKKOL AKYPO RLM 45NV)
Lauryl betaine, water 10.00
(NIKKOL AM-301)
BG 5.00
Glycol distearate 2.00
(NIKKOL Aesthetic Pearl 15V)
Citric acid appropriate amount EDTA-2Na 0.10
Preservative (appropriate amount) Water (remainder)

(Prescription example 4)
A body soap (hypoallergenic body soap using an amino acid surfactant) was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 10.00
Cocoyl Glutamine San TEA, water (30% aqueous solution 30.00
Sodium trideceth-4 carboxylate 5.00
(NIKKOL ECTD-3NEX)
Sodium cocoamphoacetate, water () 10.00
(NIKKOL AM-101)
PEG-50 hydrogenated castor oil 0.50
(NIKKOL HCO-50)
BG 5.00
EDTA-2Na 0.10
Preservative (appropriate amount) Water (remainder)

(Prescription example 5)
A body soap (body soap using a combination of soap and anionic surfactant) was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 10.00
Coconut oil fatty acid K/myristic acid K combination liquid 40.00
Lauroyl methylalanine Na, water 20.00
(NIKKOL Alaninate LN30)
Coconut oil fatty acid PEG-7 glyceryl 5.00
(NIKKOL TMGCO-7)
Cocamide DEA 3.00
Glycerin 15.00
BG 5.00
EDTA-3Na 0.05
Preservative (appropriate amount) Water (remainder)

(Prescription example 6)
A facial cleansing foam was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Lauric acid 10.00
Palmitic acid 12.00
Stearic acid 10.00
Lauriloyl methyl taurine Na 5.00
(NIKKOL LMT)
Glyceryl stearate (SE) 2.00
(NIKKOL MGS-BSEV)
PEG-6, PEG32 10.00
Glycerin 10.00
Sorbitol (70% aqueous solution) 5.00
Olive fruit oil 1.00
(NIKKOL olive oil)
Preservative appropriate amount K hydroxide 7.00
water remainder

(Prescription example 7)
A facial cleansing foam (containing an amino acid surfactant) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Citric acid 0.15
EDTA-2Na 0.05
BG 15.00
Glycerin 10.00
Cocamide DEA 3.00
Sodium cocoyl methyltaurine, water 4.00
(NIKKOL CMT-30)
Lauroyl methylalanine Na, water 8.00
(NIKKOL Alaninate LN-30)
Cocamidopropyl betaine, water 8.00
(NIKKOL AM-3130N)
Preservative Appropriate amount Ethanol 3.00
water remainder

(Prescription example 8)
A facial cleansing foam (containing phosphoric acid surfactant) was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Laureth-1 phosphate, water 7.50
(NIKKOL Hosten HLP-1)
Arginine 4.40
DPG 4.00
Preservatives Appropriate amount Cocoyl methyl taurine Na, water 5.00
(NIKKOL CMT-30)
PEG-20 glyceryl triisostearate 4.00
(NIKKOL TGI-20)
Pentylene glycol 2.00
Glyceryl caprylate 1.00
Glycerin 1.00
Chelating agent appropriate amount citric acid 0.25
water remainder

(Prescription example 9)
A cleansing oil (bicontinuous type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl-10 pentysostearate 6.30
(NIKKOL Decaglyn 5-ISV)
Polyglyceryl-6 laurate 11.70
(NIKKOL Hexaglyn 1-L)
Polyglyceryl diisostearate-10 2.00
(NIKKOL Decaglyn 2-ISV)
Methylheptyl laurate 58.30
(NIKKOL GS-MHL)
Myristic acid 0.80
Mixed vegetable oil 3.00
(NIKKOL NATURAL OILS-1)
Cyclopentasiloxane 10.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Ethanol 1.50
Preservative (appropriate amount) Water (remainder)

(Prescription example 10)
A cleansing cream (O/W type, wash-off and wipe-off type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
PEG-6 sorbitan stearate 2.00
(NIKKOL TS-106V)
Polysorbate 60 0.80
(NIKKOL TS-10V)
Glyceryl stearate 1.20
(NIKKOL MGS-BV2)
Cetearyl alcohol 3.50
Squalane 45.00
(NIKKOL Sugar Squalane)
Methylheptyl laurate 5.00
(NIKKOL GS-MHL)
Dimethicone (350mPa・s) 0.20
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 10.00
Glycerin 2.00
Carboxyvinyl polymer (2% aqueous solution) 5.00
(NTC-CARBOMER 380)
Preservative Appropriate amount Stearyl methyl taurine Na 0.30
(NIKKOL SMT)
Hydroxide K 0.035
water remainder

(Prescription example 11)
Cleansing milk (O/W type, both rinse and wipe type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Cyclopentasiloxane 5.00
Diphenylsiloxyphenyl trimethicone 5.00
Methylheptyl laurate 5.00
(NIKKOL GS-MHL)
Squalane 3.00
(NIKKOL Sugar Squalane)
Coconut oil fatty acid PEG-7 glyceryl 10.00
(NIKKOL TMGCO-7)
Tri(behenic acid/isostearic acid/eicosandioic acid) glyceryl cetearyl alcohol
0.50
Sorbitan isostearate 1.00
(NIKKOL SI-10RV)
Sorbeth Tetraoleate-30 1.00
(NIKKOL GO-430 NV)
Polysorbate 60 1.00
(NIKKOL TS-10V)
Aqueous component:
PYR-containing collagen decomposition product 1.00
Glycerin 10.00
BG 3.00
Carboxyvinyl polymer (2% aqueous solution) 10.00
(NTC-CARBOMER 381)
(Acrylates/alkyl acrylate (C10-30) crosspolymer (for high viscosity) (2% aqueous solution)) 5.00
EDTA-2Na 0.05
Preservative appropriate amount K hydroxide 0.07
water remainder

(Prescription example 12)
A cleansing gel (oil-based type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
PPG-6 decyltetradeceth-30 12.00
(NIKKOL PEN-4630)
Octyldodeceth-25 4.00
Squalane 2.00
(NIKKOL Sugar Squalane)
Cetyl ethylhexanoate 6.40
(NIKKOL CIO)
Triethylhexanoin 40.00
(NIKKOL Trifat S-308)
Glycerin 12.00
Methylgluceth-10 3.00
(NIKKOL BMG-10)
Aqueous component:
PYR-containing collagen decomposition product 1.00
Sorbitol (70% aqueous solution) 8.00
DPG 4.00
water remainder

(Prescription example 13)
A cleansing gel (liquid crystal type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
PEG-40 hydrogenated castor oil 8.00
(NIKKOL HCO-40)
PEG-50 hydrogenated castor oil 8.00
(NIKKOL HCO-50)
Triethylhexanoin 60.00
(NIKKOL Trifat S-308)
Glycerin 16.80
water remainder

(Prescription example 14)
A cleansing gel (O/W type, wash-off type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Isododecane 20.00
Cetyl ethylhexanoate 10.00
(NIKKOL CIO)
Cyclopentasiloxane 10.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Complex emulsifier 4.50
(NIKKOL Nikomulus SE W)
BG 5.00
Preservative appropriate amount K hydroxide 0.05
water remainder

(Prescription example 15)
A cleansing gel (aqueous type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Coconut oil fatty acid PEG-7 glyceryl 10.00
(NIKKOL TMGCO-7)
PEG-20 glyceryl triisostearate 4.50
(NIKKOL TGI-20)
PEG-20 Sorbitan Isostearate 3.50
(NIKKOL TI-10V)
Stearic acid PEG-45 2.00
(NIKKOL MYS-45V)
DPG 20.00
Preservatives Appropriate amount Water-based ingredients:
PYR-containing collagen decomposition product 1.00
Methylgluceth-10 5.00
(NIKKOL BMG-10)
Carboxyvinyl polymer 0.40
(NTC-CARBOMER 380)
Hydroxide K 0.14
EDTA-2Na 0.10
water remainder

(Prescription example 16)
A cleansing lotion (wipe type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Coconut oil fatty acid PEG-7 glyceryl 4.00
(NIKKOL TMGCO-7)
Lauric acid PEG-10 4.00
(NIKKOL MYL-10)
PEG-50 hydrogenated castor oil 2.00
(NIKKOL HCO-50)
Preservatives Appropriate amount Hydroxylated lecithin, glycerin 0.50
(NIKKOL Lecithinol SH50)
Aqueous component:
PYR-containing collagen decomposition product 1.00
Cocoyl arginine ethyl PCA 0.10
Citric acid 0.005
Sodium citrate 0.03
EDTA-2Na 0.03
water remainder

(Prescription example 17)
A makeup remover (two-layer type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Cyclopentasiloxane 20.00
Methylheptyl laurate 20.00
(NIKKOL GS-MHL)
Aqueous component:
PYR-containing collagen decomposition product 1.00
Ethanol 3.00
Coconut oil fatty acid PEG-7 glyceryl 0.20
(NIKKOL TMGCO-7)
PPG-4 Seteth-10 0.10
(NIKKOL PBC-33)
PEG-400 0.05
Na chloride 0.50
EDTA-3Na 0.02
Cocoyl arginine ethyl PCA 0.05
water remainder

(Prescription example 18)
A vanishing cream (petroleum-based surfactant free) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Stearic acid 15.00
Isopropyl palmitate 2.00
(NIKKOL IPP)
Lanolin 1.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Sorbitol (70% aqueous solution) 8.00
Hydroxide K 1.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 19)
A vanishing cream was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polysorbate 60 2.00
(NIKKOL TS-10V)
Sorbeth Tetraoleate-30 0.50
(NIKKOL GO-430NV)
Glyceryl stearate, glyceryl stearate (SE), PEG-10 stearate
0.50
(NIKKOL MGS-DEXV)
Stearic acid 7.00
Setanol 3.00
Cetyl palmitate 3.00
(NIKKOL N-SPV)
Paraffin (135°F) 3.00
Jojoba seed oil 7.00
(NIKKOL Jojoba Oil S)
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 7.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 20)
An emollient cream was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Stearic acid PEG-40 2.00
(NIKKOL MYS-40V)
Glyceryl stearate, glyceryl stearate (SE), PEG-10 stearate
5.00
(NIKKOL MGS-DEXV)
Stearic acid 2.00
Setanol 2.00
Squalane 12.00
(NIKKOL Sugar Squalane)
Macadamia seed oil 4.00
(NIKKOL macadamia nut oil)
Dimethicone (300mPa・s) 0.20
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 7.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 21)
A moisture cream was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Functional lipid complex 3.00
(NIKKOL Nikolipid 81S)
Setanol 2.00
Caprylic/capric triglyceride 4.00
(NIKKOL Triester F-810)
Low melting point wax 4.00
(NIKKOL Niko Wax LM)
Pyridoxine trihexyldecanoate 1.00
(NIKKOL VB6-IP)
Ethylhexylglycerin, glyceryl caprate 0.40
(NIKKOL Nicoguard 88)
Dimethicone (high polymerization) 1.00
Diphenylsoxyphenyl trimethicone 2.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 5.00
Glycerin 5.00
Hydroxypropyl methylcellulose 0.20
Carbomer 0.30
(NTC-CARBOMER 380)
Betaine 2.00
Arginine 0.30
water remainder

(Prescription example 22)
A moisture cream (lecithin emulsion) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Hydrogenated lecithin 2.00
(NIKKOL Resinol S-10)
Myristyl alcohol 2.00
Behenyl alcohol 3.00
(NIKKOL Behenyl Alcohol 80)
Cetyl palmitate 2.00
(NIKKOL N-SPV)
Triethylhexanoin 10.00
(NIKKOL Trifat S-308)
Squalane 8.00
(NIKKOL Sugar Squalane)
Jojoba seed oil 1.00
(NIKKOL Jojoba Oil S)
Dimethicone (350mPa・s) 1.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 5.00
Glycerin 8.00
Xanthan gum 0.10
water remainder

(Prescription example 23)
Anti-aging cream (liquid crystal type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Complex emulsifier 5.00
(NIKKOL Nikomulus LC)
Cetearyl alcohol 3.00
Low melting point wax 0.20
(NIKKOL Niko Wax LM)
Squalane 5.00
(NIKKOL Sugar Squalane)
Triethylhexanoin 5.00
(NIKKOL Trifat S-308)
Pentaerythrityl tetraethylhexanoate 5.00
Cyclopentasiloxane 3.00
Dimethicone (350mPa・s) 0.20
Aqueous component:
PYR-containing collagen decomposition product 1.00
Glycerin 10.00
Pentylene glycol 2.00
BG 8.00
Carbomer 0.20
(NTC-CARBOMER 380)
Xanthan gum 0.10
Preservative appropriate amount K hydroxide 0.05
Hyaluronate Na (1% aqueous solution) 1.00
Polysaccharide aqueous solution 5.00
(FUCOGEL1.5P)
water remainder

(Prescription example 24)
A light cream (lecithin, polymer emulsion) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Batyl alcohol 0.20
(NIKKOL Bacyl Alcohol EX)
Hydrogenated lecithin 0.30
(NIKKOL Resinol S-10)
Glyceryl stearate 1.50
(NIKKOL MGS-BV2)
Cetyl ethylhexanoate 1.00
(NIKKOL CIO)
Diphenyl dimethicone 3.00
Dimethicone (6mPa・s) 4.00
Dimethicone (350mPa・s) 1.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Complex emulsifier 5.00
(NIKKOL Nicomulus LH)
Pentylene glycol 2.00
BG 4.00
Glycerin 5.00
Glycyrrhizic acid 2K 0.10
Preservative (appropriate amount) Water (remainder)

(Prescription example 25)
An anti-acne cream was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Ascorbyl tetrahexyl decanoate 10.00
(NIKKOL VC-IP)
Hydrogenated lecithin 0.10
(NIKKOL Resinol S-10)
Batyl alcohol 1.00
(NIKKOL Bacyl Alcohol EX)
Behenyl alcohol 2.00
(NIKKOL Behenyl Alcohol 65)
Glyceryl stearate, PEG-60 glyceryl stearate 2.00
(NIKKOL MGS-150V)
Cetyl palmitate 3.00
(NIKKOL N-SPV)
Dimethicone (100mPa・s) 0.20
Hydrogenated palm oil, palm kernel oil, palm oil 4.00
(NIKKOL Trifat PS-45H)
Olefin oligomer 4.00
(NIKKOL Synseran 4SP)
Tocopherol 0.10
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 5.00
Glycerin 3.00
Xanthan gum 0.04
Hydroxyethyl cellulose 0.04
Citric acid 0.02
Sodium citrate 0.03
Preservative (appropriate amount) Water (remainder)

(Prescription example 26)
An eye cream was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Caprylic/capric triglyceride, tocopheryl retinoate 2.00
(NIKKOL Tocoletinoate-10)
Hydrogenated lecithin 0.50
(NIKKOL Resinol S-10)
Polyglyceryl myristate-10 3.00
(NIKKOL Decaglyn 1-M)
Oleyl glyceryl 2.00
(NIKKOL Serakyl Alcohol)
Cetyl palmitate 4.00
(NIKKOL N-SPV)
Squalane 10.00
(NIKKOL Sugar Squalane)
Triethylhexanoin 8.00
(NIKKOL Trifat S-308)
Setanol 6.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Glycerin 3.00
Xanthan gum 0.20
Preservative (appropriate amount) Water (remainder)

(Prescription example 27)
A massage cream was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Seteth-20 2.00
(NIKKOL BC-20)
Glyceryl stearate 4.00
(NIKKOL MGS-BV2)
Setanol 2.00
Cetyl palmitate 2.00
(NIKKOL N-SPV)
Vaseline 6.00
Squalane 30.00
(NIKKOL Sugar Squalane)
Triethylhexanoin 5.00
(NIKKOL Trifat S-308)
Meadowfoam oil 3.00
(NIKKOL meadowfoam oil)
Dimethicone (300mPa・s) 0.20
Aqueous component:
PYR-containing collagen decomposition product 1.00
Carbomer 0.20
(NTC-CARBOMER380)
Glycerin 15.00
Preservative appropriate amount TEA 0.10
water remainder

(Prescription example 28)
A massage cream (emulsified with beeswax and borax) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
PEG-20 Sorbitan Cocoate 3.00
(NIKKOL TL-10)
Glyceryl stearate (SE) 2.70
(NIKKOL MGS-ASEV)
Mineral oil (#70) 25.00
Ethylhexyl palmitate 22.00
(NIKKOL IOP)
Beeswax 3.00
Stearic acid 1.30
Setanol 1.00
Dimethicone (350mPa・s) 0.10
Aqueous component:
PYR-containing collagen decomposition product 1.00
Carbomer 0.20
(NTC-CARBOMER381)
BG 5.00
Preservative appropriate amount TEA 0.50
Sodium borate 0.50
water remainder

(Prescription example 29)
A hand cream (W/O type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl-2 isostearate 2.50
(NIKKOL DGMIS)
Polyglyceryl polyricinoleate 1.50
(NIKKOL Hexaglyn PR-15)
Squalane 4.00
(NIKKOL Sugar Squalane)
Diphenylsiloxyphenoxytrimethicone 5.00
Glycerin 10.00
Tocopherol acetate 0.10
Aqueous component:
PYR-containing collagen decomposition product 1.00
Sodium alginate 0.10
BG 5.00
Mg sulfate 0.10
Preservative (appropriate amount) Water (remainder)

(Prescription example 30)
An emollient cream (amino acid gel emulsion, W/O type) was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl-6 polyricinoleate 1.50
(NIKKOL Hexaglyn PR-15)
Polyglyceryl-2 oleate 0.50
(NIKKOL DGMO-CV)
Mineral oil (#70) 8.00
Triethylhexanoin 5.00
(NIKKOL Trifat S-308)
Aqueous component:
PYR-containing collagen decomposition product 1.00
Sodium glutamate 1.00
Glycerin 5.00
Na chloride 2.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 31)
An emollient cream (organic modified clay mineral gel emulsion, W/Si type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
W/O composite emulsifier 4.00
(NIKKOL Nikomulus WO)
Cyclopentasiloxane 7.00
Silicone compound product 5.00
(NIKKOL SILBLED-91)
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 5.00
Glycerin 25.00
Preservative Appropriate amount Sodium hyaluronate (1% aqueous solution) 1.00
Polysaccharide aqueous solution (FUCOGEL1.5P) 1.00
Acetyl hydroxyproline (AHYP) 0.10
Na chloride 0.50
EDTA-2Na 0.10
water remainder

(Prescription example 32)
A hand cream was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl myristate-10 1.20
(NIKKOL Decaglyn 1-M)
Hydrogenated lecithin 0.50
(NIKKOL Resinol S-10)
Glyceryl stearate, glyceryl stearate (SE), PEG-10 stearate
1.00
(NIKKOL MGS-DEXV)
Stearic acid 4.00
Setanol 4.00
Cetyl palmitate 2.00
(NIKKOL N-SPV)
Squalane 4.00
(NIKKOL Sugar Squalane)
Hexyldecyl isostearate 2.00
(NIKKOL ICIS)
Octyldodecyl myristate 4.00
(NIKKOL ODM-100)
Dimethicone (300mPa・s) 0.20
Aqueous component:
PYR-containing collagen decomposition product 1.00
DPG 5.00
Preservative appropriate amount FOMBLIN (fluorine oil) emulsion base 3.00
(NIKKOL NET-HC-R)
Silicone-containing emulsion base 3.00
(NIKKOL NET-SG-60A)
water remainder

(Prescription example 33)
A hand cream (natural hand cream) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl stearate-10 2.20
(NIKKOL Decaglyn 1-SV)
Hydrogenated rapeseed oil alcohol 3.00
Macadamia seed oil 2.00
(NIKKOL macadamia nut oil)
Caprylic/capric triglyceride 5.00
(NIKKOL Triester F-810)
Star Shea Butter Refined
15.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Xanthan gum 0.10
Glycerin 10.00
BG 10.00
Preservative Appropriate amount Ethanol 3.00
water remainder

(Prescription example 34)
A moisturizing emulsion (lecithin emulsion) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Hydrogenated lecithin 0.80
(NIKKOL Resinol S-10)
Phytosterose 0.20
Stearyl alcohol 0.40
Behenyl alcohol 0.40
(NIKKOL Behenyl Alcohol 80)
Cetyl palmitate 0.80
(NIKKOL N-SPV)
Triethylhexanoin 4.00
(NIKKOL Trifat S-308)
Squalane 3.20
(NIKKOL Sugar Squalane)
Jojoba seed oil 0.40
(NIKKOL Jojoba Oil S)
Dimethicone (350mPa・s) 0.40
Aqueous component:
PYR-containing collagen decomposition product 1.00
Xanthan gum 0.10
Glycerin 3.20
BG 5.00
Carbomer 0.06
(NTC-CARBOMER381)
Preservative appropriate amount Arginine 0.07
water remainder

(Prescription example 35)
An emulsion (liquid crystal type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Complex emulsifier 4.00
(NIKKOL Nikomulus LC)
Cetearyl alcohol 1.00
Olefin oligomer 4.00
(NIKKOL Synseran 4SP)
Meadowfoam oil 1.00
(NIKKOL meadowfoam oil)
Dimethicone (350mPa・s) 0.50
Ethylhexylglycerin, glyceryl caprate 0.50
(NIKKOL Nicoguard 88)
Aqueous component:
PYR-containing collagen decomposition product 1.00
BG 4.00
Glycerin 1.00
PEG-6, PEG-32 1.00
Lecithin, lysophosphatidic acid, lysolecithin 0.10
Carbomer 0.15
(NTC-CARBOMER381)
Arginine 0.11
EDTA-2Na 0.10
Ethanol 5.00
Watermelon fruit extract, apple fruit extract, lentil fruit extract (Aqua-Speed)
3.00
water remainder

(Prescription example 36)
A moisturizing emulsion (only natural ingredients) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl stearate-10 2.00
(NIKKOL Decaglyn 1-SV)
Sorbitan sesquistearate 1.00
(NIKKOL SS-15V)
Hydrogenated rapeseed oil alcohol 1.80
Star Shea Butter Refined
2.00
Methylheptyl isostearate 3.00
(NIKKOL GS-MHIS)
Methylheptyl laurate 3.00
(NIKKOL GS-MHL)
Squalane 5.00
(NIKKOL Sugar Squalane)
Mixed vegetable oil 1.00
(NIKKOL NATURAL OILS-1)
Lavender oil 0.20
Aqueous component:
PYR-containing collagen decomposition product 1.00
Xanthan gum 0.10
BG 1.00
Glycerin 5.00
Preservative appropriate amount Polysaccharide aqueous solution (FUCOGEL 1.5P) 1.00
water remainder

(Prescription example 37)
A whitening emulsion was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl pentasteate-10 1.00
(NIKKOL Decaglyn 5-SV)
Stearic acid PEG-40 1.00
(NIKKOL MYS-40V)
Behenyl alcohol 1.70
(NIKKOL Behenyl Alcohol 65)
Glyceryl stearate 1.00
(NIKKOL MGS-BV2)
Triethylhexanoin 5.50
(NIKKOL Trifat S-308)
Squalane 3.50
(NIKKOL Sugar Squalane)
Jojoba seed oil 1.00
(NIKKOL Jojoba Oil S)
Cyclopentasiloxane 5.00
Diphenyl dimethicone 3.50
Aqueous component:
PYR-containing collagen decomposition product 1.00
Xanthan gum 0.30
Stearoylmethyltaurine Na 0.60
(NIKKOL SMT)
DPG 2.00
BG 3.00
Preservative: Appropriate amount of ascorbic phosphate Mg 3.00
(NIKKOL VC-PMG)
Polysaccharide aqueous solution (FUCOGEL1.5P) 0.50
Hyaluronate Na (1% aqueous solution) 0.50
Sodium glutamate 0.50
EDTA-4Na 0.10
Sodium pyrosulfite 0.20
water remainder

(Prescription example 38)
A milky lotion (α gel milky lotion) was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Cetyl phosphate 0.70
(NIKKOL Pure Phos α)
Batyl alcohol 0.50
(NIKKOL Bacyl Alcohol EX)
Setanol 1.50
Squalane 2.00
(NIKKOL Sugar Squalane)
Dimethicone (6mPa・s) 3.00
Aqueous component:
PYR-containing collagen decomposition product 1.00
Arginine 0.50
Glycerin 10.00
BG 5.00
Betaine 0.50
Hyaluronate Na (1% aqueous solution) 1.00
Carbomer 0.15
(NTC-CARBOMER381)
Preservatives Appropriate amount Watermelon fruit extract, apple fruit extract, lentil fruit extract (Aqua-Speed)
1.00
water remainder

(Prescription example 39)
Body milk was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Polyglyceryl myristate-10 2.10
(NIKKOL Decaglyn1-M)
Hydrogenated lecithin 0.60
(NIKKOL Resinol S-10)
Stearic acid 0.50
Behenyl alcohol 1.60
(NIKKOL Behenyl Alcohol 65)
Cetyl palmitate 0.60
(NIKKOL N-SPV)
Hydrogenated polydecene 6.00
Cetyl ethylhexanoate 6.00
(NIKKOL CIO)
Triethylhexanoin 6.00
(NIKKOL Trifat S-308)
Aqueous component:
PYR-containing collagen decomposition product 1.00
Carbomer 0.10
(NTC-CARBOMER380)
Glycerin 5.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 40)
A softening lotion was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Glycerin 5.00
DPG 4.00
PEG-20 0.50
Xanthan gum 0.05
Citric acid 0.02
Sodium citrate 0.10
EDTA-2Na 0.05
BG 4.00
PEG-60 hydrogenated castor oil 0.50
(NIKKOL HCO-60)
Preservative appropriate amount Polysaccharide aqueous solution (FUCOGEL 1.5P) 2.00
Watermelon fruit extract, apple fruit extract, lentil fruit extract (Aqua-Speed)
3.00
water remainder

(Prescription example 41)
A moisture lotion was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Glycerin 3.00
Sorbitol (70% aqueous solution) 2.00
DPG 4.00
Xanthan gum 0.05
Hydroxyethyl cellulose 0.05
Acetyl hydroxyproline 5.00
Arginine 5.00
Hyaluronate Na (1% aqueous solution) 1.00
Citric acid 0.05
Sodium citrate 0.01
PCA-Na (50% aqueous solution) 1.00
BG 5.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 42)
An astringent lotion was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
PEG-60 hydrogenated castor oil 1.00
(NIKKOL HCO-60)
Ethanol 15.00
Preservative appropriate amount PEG-8 1.00
BG 5.00
Zinc paraphenolsulfonate 0.20
Citric acid 0.10
pH buffer (appropriate amount) Flavor (appropriate amount) Colorant (appropriate amount) Water (remainder)

(Prescription example 43)
A cleansing lotion was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Coconut oil fatty acid PEG-7 glyceryl 4.00
(NIKKOL TMGCO-7)
Lauric acid PEG-10 4.00
(NIKKOL MYL-10)
PEG-50 hydrogenated castor oil 2.00
(NIKKOL HCO-50)
Preservatives Appropriate amount Hydroxylated lecithin, glycerin 0.50
(NIKKOL Resinol SH-50)
Cocoyl arginine ethyl PCA 0.10
Citric acid 0.005
Sodium citrate 0.03
EDTA-2Na 0.03
water remainder

(Prescription example 44)
Carmine lotion was prepared according to the following recipe.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Glycyrrhizic acid 2K 0.10
PCA-Na 2.50
EDTA-2Na 0.10
BG 6.00
Preservatives Appropriate amount Hypericum perforatum extract, burdock root extract, soapwort leaf extract, sage leaf extract, Calendula flower extract, hop cone extract, lemon fruit extract, BG, water
4.00
(Fitelen EGX-252 (BG))
Iron oxide 0.15
Zinc oxide 0.50
Kaolin 1.00
water remainder

(Prescription example 45)
A lotion (nanoemulsion type) was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Hydroxyproline (L-hydroxyproline) 0.10
BG 1.00
DPG 1.00
PEG-32 0.30
PEG-150 0.20
Pentylene glycol 2.50
Citric acid 0.03
Sodium citrate 0.04
EDTA-2Na 0.10
Preservative Appropriate amount Nanoemulsion base containing fat-soluble vitamin C derivative 5.00
(NIKKOL Solble VCIP)
water remainder

(Prescription example 46)
Moisture gel (lecithin emulsion) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Hydrogenated lecithin 1.00
(NIKKOL Resinol S-10PLUS)
Glycerin 15.00
BG 6.00
PEG-32 2.00
Xanthan gum 0.08
(Acrylates/Alkyl acrylate (C10-30)) Crosspolymer (for high viscosity)
0.30
Hydroxyethylcellulose 0.08
Hexyl dimethylolpropionate 0.50
(NIKKOL Niko Guard 6)
Diphenyl dimethicone 1.00
Cyclopentasiloxane 4.00
Arginine 0.30
Hyaluronate Na (1% aqueous solution) 1.00
Polysaccharide aqueous solution (FUCOGEL1.5P) 3.00
Perilla leaf extract, ethanol 0.30
(Perilla extract NA FREE)
water remainder

(Prescription example 47)
An all-in-one gel was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Polyglyceryl-6 polyricinoleate 0.50
(NIKKOL Hexaglyn PR-15)
Dimethicone (10mPa・s) 1.40
Dimethicone (350mPa・s) 0.60
Cyclopentasiloxane 0.20
Carbomer 0.20
(NTC-CARBOMER380)
(Acrylates/Alkyl acrylate (C10-30)) Crosspolymer (for high viscosity)
0.10
Hydroxypropyl methylcellulose 0.20
Glycerin 15.00
BG 6.00
Sorbitol (70% aqueous solution) 3.00
Ethanol 3.00
Hexyl dimethylolpropionate 0.70
(NIKKOL Niko Guard 6)
Hydroxide K 0.10
Nanoemulsion base containing vitamins etc. 1.00
(NIKKOL Nicosome Vitamin ABCE)
nanoemulsion base containing fermented products, etc. 5.00
(NIKKOL Nikosome SML)

(Prescription example 48)
An anti-aging serum was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
BG 2.00
DPG 3.00
Pentylene glycol 4.00
Glycerin 7.00
Xanthan gum 0.02
(Acrylates/Alkyl acrylate (C10-30)) Crosspolymer (for high viscosity)
0.10
(Acrylates/Alkyl acrylate (C10-30)) Crosspolymer (for low viscosity)
0.20
Preservative appropriate amount Arginine 0.10
Ascorbic tetrahexyldecanoate 1.00
(NIKKOL VC-IP)
Diphenyl dimethicone 3.00
Cyclopentasiloxane 7.00
Tocopherol 0.10
EDTA-2Na 0.10
water remainder

(Prescription example 49)
An anti-aging serum (liposome formulation) was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Carbomer 0.54
(NTC-CARBOMER380)
BG 4.00
diglycerin 4.00
PEG-20 1.00
Maltitol (75% aqueous solution) 1.00
Hydroxide K 0.18
Hydroxyproline (L-hydroxyproline) 0.50
Silicone emulsion base 1.00
(NIKKOL NET-813-1)
Polyhydric alcohol blended liposome 1.00
(NIKKOL Aquasome BH)
Polysaccharide aqueous solution (FUCOGEL1.5P) 3.00
Hyaluronate Na (1% aqueous solution) 3.00
Ethanol 3.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 50)
A whitening serum (transparent type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Xanthan gum 0.40
Hydroxyethyl cellulose 0.40
BG 3.00
Glycerin 3.00
Hyaluronic acid (1% aqueous solution) 5.00
Preservative appropriate amount Mg ascorbate phosphate 3.00
(NIKKOL VC-PMG)
Sodium citrate 0.50
EDTA-4Na 0.10
water remainder

(Prescription example 51)
A moisturizing serum (semi-transparent type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Hydrogenated lecithin 0.60
(NIKKOL Resinol S-10)
BG 6.00
PEG-32 1.00
Glycerin 15.00
Hydroxyethylcellulose 0.08
(Acrylates/Alkyl acrylate (C10-30)) Crosspolymer (for high viscosity)
0.20
Preservative appropriate amount Arginine 0.20
EDTA-2Na 0.10
Pyridoxine trihexyldecanoate 1.00
(NIKKOL VB6-IP)
Cyclopentasiloxane 5.00
Batyl alcohol 0.10
(NIKKOL Bacyl Alcohol EX)
Tocopherol 0.10
water remainder

(Prescription example 52)
A peel-off pack (gel type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Polyvinyl alcohol 15.00
Carboxymethyl cellulose 5.00
BG 5.00
Buffer Appropriate amount Ethanol 12.00
Ores-20 0.50
(NIKKOL BO-20V)
Fragrance (appropriate amount) Preservative (appropriate amount) Water (remainder)

(Prescription example 53)
A clay pack was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 25.00
Bentonite 12.00
Kaolin 13.00
Titanium oxide 2.00
Seteth-20 1.00
(NIKKOL BC-20V)
BG 10.00
Glycerin 10.00
Preservative appropriate amount Polyvinyl alcohol 1.00
water remainder

(Prescription example 54)
A cream pack was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 25.00
Squalane 10.00
(NIKKOL Sugar Squalane)
Caprylic/capric triglyceride 5.00
(NIKKOL Triester F-810)
Ascorbyl tetrahexyl decanoate 2.00
(NIKKOL VC-IP)
Vaseline 3.00
Stearyl alcohol 3.00
Stearic acid PEG-55 0.80
(NIKKOL MYS-55V)
Glyceryl stearate 2.20
(NIKKOL MGS-BV2)
Cetyl palmitate 2.00
(NIKKOL N-SPV)
Dimethicone (350mPa・s) 0.50
Tocopherol 0.10
Hydroxyethyl cellulose 0.10
BG 5.00
Glycerin 7.00
Preservatives Appropriate amount Titanium oxide, Al hydroxide 2.00
Stearoylmethyltaurine Na 0.05
(NIKKOL SMT)
Citric acid 0.01
EDTA-2Na 0.05
Ethylgothioneine, water (THIOTAINE) 1.00
water remainder

(Prescription example 55)
A makeup base was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Complex emulsifier 4.00
(NIKKOL Nikomulus LC)
Cetearyl alcohol 1.00
Squalane 5.00
(NIKKOL Sugar Squalane)
Phenyl trimethicone 5.00
Polypropylsilsesquioxane (alkyl acrylate/dimethico) copolymer, cyclopentasiloxane 1.00
Carbomer 0.15
(NTC-CARBOMER381)
Hydroxyethyl acrylate/acryloyldimethyltaurine (Na) copolymer
0.30
EDTA-2Na 0.10
Preservative appropriate amount Arginine 0.05
BG 4.00
Glycerin 1.00
Pigment grade titanium oxide (appropriate amount) Red iron oxide (appropriate amount) (HDI/trimethylolhexyllactone) crosspolymer, silica, polymethyl methacrylate, mica, titanium oxide 3.00
Watermelon fruit extract, apple fruit extract, lentil fruit extract (Aqua-Speed)
3.00
Ethanol 5.00
water remainder

(Prescription example 56)
An oil-based foundation was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Talc Remainder Kaolin 15.00
Pigment grade titanium oxide 15.00
Red iron oxide (appropriate amount) Yellow iron oxide (appropriate amount) Black iron oxide (appropriate amount) Solid paraffin 3.00
Microcrystalline wax 6.00
Beeswax 2.00
Vaseline 12.00
Lanolin acetate 1.00
Squalane 6.00
(NIKKOL Sugar Squalane)
Isopropyl palmitate 18.00
(NIKKOL IPP)
Preservative appropriate amount

(Prescription example 57)
A foundation (O/W type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Complex emulsifier 2.50
(NIKKOL Nicomulus 41)
Glyceryl stearate 1.00
(NIKKOL MGS-BV2)
Batyl alcohol 0.30
(NIKKOL Bacyl Alcohol 100)
Cetearyl alcohol 1.00
Diethylaminohydroxybenzoyl hexyl benzoate 2.00
Ethylhexyl methoxycinnamate 10.00
Isononyl isononanoate 2.00
Cyclopentasiloxane 7.00
Dimethicone (10mPa・s) 3.00
Pigment grade titanium oxide 6.00
Red iron oxide (appropriate amount) Yellow iron oxide (appropriate amount) Black iron oxide (appropriate amount) Glycerin 5.00
Dipropylene glycol 5.00
Silicic acid (Al/Mg) 0.50
Stearoylmethyltaurine Na 0.50
(NIKKOL SMT)
EDTA-2Na 0.05
Preservative appropriate amount xanthan gum 0.30
water remainder

(Prescription example 58)
A foundation (W/O type) was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Complex emulsifier 5.00
(NIKKOL Nikomulus WO)
Silicone compound product 2.50
(NIKKOL SILBLED-91)
Cyclopentasiloxane, (dimethicone/vinyl dimethicone) crosspolymer 2.00
Cyclopentasiloxane 20.00
Dimethicone (6mPa・s) 2.50
Diphenylsiloxyphenyl trimethicone 2.50
(alkyl acrylate/dimethicone) copolymer, cyclopentasiloxane 1.00
Pentaerythrityl tetraethylhexanoate 2.00
Diisostearyl malate 1.00
(NIKKOL DISM)
(HDI/trimethylolhexyllactone) crosspolymer, silica, 3.00
Silicone treated pigment grade titanium oxide 7.00
Silicone-treated red iron oxide (appropriate amount) Silicone-treated yellow iron oxide (appropriate amount) Silicone-treated black iron oxide (appropriate amount) Glycerin 8.00
BG 3.00
Na chloride 0.50
EDTA-2Na 0.05
Ethanol 3.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 59)
A dual-use foundation was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Silicone-treated talc Balance silicone-treated mica 40.00
Silicone treated fine particle titanium oxide 5.00
Silicone treated pigment grade titanium oxide 15.00
Silicone-treated red iron oxide (appropriate amount) Silicone-treated yellow iron oxide (appropriate amount) Silicone-treated black iron oxide (appropriate amount) Zinc stearate 0.10
Nylon powder 0.20
Squalane 4.00
(NIKKOL Sugar Squalane)
Solid paraffin 0.50
Dimethicone (10mPa・s) 4.00
Triethylhexanoin 5.00
(NIKKOL Trifat S-308)
Ethylhexyl methoxycinnamate 1.00
Preservative appropriate amount

(Prescription example 60)
A powder foundation was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Sericite remainder talc 5.00
Mica 10.00
Fine particle titanium oxide 5.00
Pigment grade titanium oxide 10.00
Red iron oxide (appropriate amount) Yellow iron oxide (appropriate amount) Black iron oxide (appropriate amount) Squalane 1.50
(NIKKOL Sugar Squalane)
Triethylhexanoin 5.00
(NIKKOL Trifat S-308)
Ethylhexylglycerin, glyceryl caprate 0.40
(NIKKOL Nicoguard 88)

(Prescription example 61)
A lipstick was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Colorant Appropriate amount Diisostearyl malate Balance Polyethylene 5.00
Ceresin 6.00
Microcrystalline wax 3.00
Triethylhexanoin 20.00
(NIKKOL Trifat S-308)
Cetyl ethylhexanoate 7.00
(NIKKOL CIO)
Hydrogenated polyisobutene 2.00
Antioxidant appropriate amount

(Prescription example 62)
A transparent lip gloss was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Palmitic acid dextrin 4.50
Mineral oil 25.00
Diisostearyl malate remainder (NIKKOL DISM)
Polyglyceryl-2 triisostearate 5.50
(NIKKOL DGTIS)
Antioxidant appropriate amount Hydrogenated polyisobutene 40.00

(Prescription example 63)
Nail enamel was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Nitrocellulose 14.00
(phthalic anhydride/trimellitic anhydride/glycols) copolymer 16.00
Acetyltributyl citrate 5.00
Ethyl acetate 20.00
Butyl acetate Balance Ethanol Appropriate amount Isopropanol Appropriate amount Pigment Appropriate amount Stearalkonium hectorite Appropriate amount

(Prescription example 64)
A shampoo was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Cocadopropyl betaine 10.00
(NIKKOL AM-3130N)
Sodium laureth sulfate, water 20.00
Laureth sulfate TEA, water 10.00
Cocamide DEA 3.00
Glycol distearate 2.00
(NIKKOL Aesthetic Pearl 10V)
Polyquaternium 10, Na chloride (1.5% aqueous solution) 10.00
BG 3.00
Citric acid (10% aqueous solution) 1.50
EDTA-2Na 0.10
Preservative (appropriate amount) Water (remainder)

(Prescription example 65)
A hypoallergenic shampoo was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Cocoyl methyl taurine Na, water 25.00
(NIKKOL CMT-30)
Lauroyl methylalanine Na, water 15.00
(NIKKOL Alaninate LN-30)
Lauryl betaine, water 20.00
(NIKKOL AM-301)
Lauramid DEA 5.00
PEG-60 hydrogenated castor oil 1.00
(NIKKOL HCO-60)
Glycol distearate 2.00
(NIKKOL Aesthetic Pearl 15V)
Polyquaternium 10, Na chloride (1.5% aqueous solution) 10.00
BG 3.00
Citric acid (10% aqueous solution) 0.40
EDTA-2Na 0.10
Preservative (appropriate amount) Water (remainder)

(Prescription example 66)
A non-silicone shampoo was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
BG 4.00
Sorbitol, water 2.00
Polyquaternium 10 0.50
Citric acid (10% aqueous solution) 0.65
EDTA-2Na 0.10
Preservatives Appropriate amount Cocoyl methyl taurine Na, water 20.00
(NIKKOL CMT-30)
Lauroyl methylalanine Na, water 15.00
(NIKKOL Alaninate LN-30)
Cocamidopropyl betaine, water 15.00
(NIKKOL AM-3130N)
Cocamide DEA 2.00
Laures-2 1.00
(NIKKOL BL-2)
Decyl glucoside, water 10.00
Coconut oil fatty acid PEG-7 glyceryl 1.00
(NIKKOL TMGCO-7)
Stearamidopropyldimethylamine 0.50
(NIKKOL Amidamine MPS)
Perilla leaf extract, ethanol, water 0.30
(Perilla extract NA FREE)
Plant extract mixture 0.10
(Fitelen EGX-232 (BG))
water remainder

(Prescription example 67)
A dry shampoo was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Functional blended raw materials 2.00
(NIKKOL APP-CLEV)
Glycerin fatty acid ester mixture 0.50
(NIKKOL Niko Guard DL)
Ethanol 30.00
water remainder

(Prescription example 68)
A scalp oil shampoo was prepared with the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
(Caprylyl/Capryl) Glucoside, Water 10.00
(GreenAPG PC 0810)
BG 4.00
Sorbitol, water 2.00
Guar hydroxypropyltrimonium chloride 1.00
Preservative appropriate amount citric acid 0.65
EDTA-2Na 0.10
Cocoyl methyl taurine Na, water 20.00
(NIKKOL CMT-30)
Lauroyl methylalanine Na, water 15.00
(NIKKOL Alaninate LN-30)
Cocamidopropyl betaine, water 15.00
(NIKKOL AM-3130N)
Lauric acid PG 2.00
Polyglyceryl laurate-10 3.00
(NIKKOL Decaglyn 1-L)
Squalane 0.30
(NIKKOL Sugar Squalane)
Methylheptyl laurate 0.30
(NIKKOL GS-MHL)
Argania spinosa kernel oil (argan oil) 0.30
Plant/seaweed extract mixture 1.00
(Fitelen EGX-771BG)

(Prescription example 69)
A conditioner was prepared using the following recipe.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Behentrimonium chloride, ethanol 2.40
(NIKKOL CA-2580)
Distearyldimonium chloride, isopropanol, water
0.80
(NIKKOL CA-3475V)
Setanol 5.00
Oleyl alcohol 1.00
Glyceryl stearate 1.00
(NIKKOL MGS-BV2)
Low melting point wax 1.00
(NIKKOL Niko Wax LM)
Olive fruit oil 2.00
(NIKKOL olive oil)
Vaseline 8.00
Dimethicone (100mPa・s) 1.00
Dimethicone (1000mPa・s) 0.50
Tocopherol 0.05
Glycerin 6.00
Preservative (appropriate amount) Water (remainder)

(Prescription example 70)
A non-silicone treatment was prepared using the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Stearamidopropyldimethylamine 3.25
(NIKKOL Amidamine MPS)
Glyceryl stearate 0.50
(NIKKOL MGS-BV2)
Stearyl alcohol 7.00
Sandalwood extract, yellowfin bark extract, barley extract 1.00
(BOIS II)
Methylheptyl laurate 2.00
(NIKKOL GS-MHL)
Phytostearyl isostearate 3.00
Octyldodecanol 3.00
Vaseline 4.00
PG 5.00
Glutamic acid 1.05
Polyoctanium-47, water 2.40
Preservatives Appropriate amount Perilla leaf extract, ethanol, water 0.30
(Perilla extract NA FREE)
Plant extract mixture 0.10
(Fitelen EGX-232 (BG))
Polysaccharide aqueous solution (FUCOGEL1.5P) 3.00
water remainder

(Prescription example 71)
Hair wax was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Complex emulsifier 7.00
(NIKKOL Nikomulus LC)
Cetearyl alcohol 5.00
Behenyl alcohol 2.00
(NIKKOL Behenyl Alcohol 65)
Low melting point wax 1.00
(NIKKOL Niko Wax LM)
Beeswax 10.00
Squalane 1.00
(NIKKOL Sugar Squalane)
Olefin oligomer 5.00
(NIKKOL Synseran 4SP)
Triethylhexanoin 5.00
(NIKKOL Trifat S-308)
Vaseline 5.00
Cyclopentasiloxane 2.00
Dimethicone (6mPa・s) 2.00
Preservative appropriate amount BG 5.00
Glycerin 3.00
EDTA-2Na 0.10
PEG-115M 0.10
Carbomer 10.00
(NTC-CARBOMER 380)
Arginine 0.20
(VP/VA) copolymer, ethanol polytanium-11, water 1.00
water remainder

(Prescription example 72)
A hair gel cream was prepared according to the following formulation.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 1.00
Complex emulsifier 4.50
(NIKKOL Nikomulus SE W)
BG 8.00
Preservative appropriate amount K hydroxide 0.05
EDTA-2Na 0.03
Glycerin 5.00
Squalane 2.50
(NIKKOL Sugar Squalane)
Cyclopentasiloxane 8.00
Dimethicone (10mPa・s) 1.50
Amodimethicone 1.00
Cyclopentasiloxane, dimethiconol 1.00
PEG/PPG-19/19 dimethicone, cyclopentasiloxane
1.00
diethylaminohydroxybenzoylhexyl benzoate,
Ethylhexyl methoxycinnamate 1.50
Tocopherol 0.10
water remainder

(Prescription example 73)
Sunscreen milk (non-chemical, W/O type) was prepared according to the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Fine particle titanium oxide dispersion 30.00
(CM3K40VMJ)
Fine particle zinc oxide dispersion 35.00
(CM3K50XZ4J)
Isododecane 11.50
Trimethylsiloxysilicic acid, cyclopentasiloxane 3.00
(HDI/trimethylolhexyllactone) crosspolymer, silica 3.00
Ethylhexyl palmitate 0.50
(NIKKOL IOP)
(vinyl dimethicone/methicone silsesquioxane) crosspolymer 2.00
PEG-9 polydimethylsiloxyethyl dimethicone 1.00
Aqueous component:
PYR-containing collagen decomposition product 5.00
Glycerin 5.00
Preservative appropriate amount Na citrate 0.20
EDTA-3Na 0.05
water remainder

(Prescription example 74)
A sunscreen cream (non-chemical, W/O type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Fine particle titanium oxide dispersion 35.00
(CM3K40T4J)
Fine particle zinc oxide dispersion 34.00
(CM3KG60XZ4)
Cyclopentasiloxane 9.55
Trimethylsiloxysilicic acid, cyclopentasiloxane 3.00
(HDI/trimethylolhexyllactone) crosspolymer, silica 3.00
Ethylhexyl palmitate 0.50
(NIKKOL IOP)
(vinyl dimethicone/methicone silsesquioxane) crosspolymer 2.00
PEG-9 polydimethylsiloxyethyl dimethicone 1.00
Aqueous component:
PYR-containing collagen decomposition product 5.00
BG 3.00
Preservative appropriate amount Na citrate 0.20
EDTA-3Na 0.05
water remainder

(Prescription example 75)
A sunscreen cream (O/W type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Fine particle titanium oxide dispersion 15.00
(CMIP40VMJ)
Fine particle zinc oxide dispersion 15.00
(CMIP50XZ4J)
Sorbitan stearate 2.00
(NIKKOL SS-10V)
Polyglyceryl myristate-10 0.50
(NIKKOL Decaglyn1-M)
Tocopherol 0.10
Ethylhexyl methoxycinnamate 10.00
Dimethylaminohydroxybenzoylhexyl benzoate 3.00
Aqueous component:
PYR-containing collagen decomposition product 5.00
BG 7.00
Stearoylmethyltaurine Na 0.50
(NIKKOL SMT)
(HDI/trimethylolhexyllactone) crosspolymer, silica 2.00
Xanthan gum (2% aqueous solution) 5.00
Hyaluronate Na (1% aqueous solution) 5.00
Polysaccharide aqueous solution (FUCOGEL1.5P) 1.00
Preservative appropriate amount Complex emulsifier 3.00
(NIKKOL Nicomulus LH)
Ethanol 5.00
water remainder

(Prescription example 76)
A sunscreen gel cream (O/W type) was prepared using the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Fine particle titanium oxide dispersion 22.50
(MCP55ZSJ)
Diethylaminohydroxybenzoyl hexyl benzoate 2.80
Octocrylene 1.00
Sorbitan oleate 0.25
(NIKKOL SO-10V)
Polyglyceryl-10 diisostearate 0.75
(NIKKOL Decaglyn2-ISV)
(Sodium acrylate/Na acryloyldimethyltaurine) copolymer, isohexadecane, polysorbate 80, sorbitan oleate, water 2.00
Mixed vegetable oil 2.50
(NIKKOL NATURAL OILS-1)
Trimethylsiloxysilicic acid, dimethicone 3.00
Aqueous component:
PYR-containing collagen decomposition product 5.00
Glycerin 1.00
BG 1.00
Methyl methacrylate crosspolymer 2.00
Xanthan gum (2% aqueous solution) 5.00
Hyaluronate Na (1% aqueous solution) 5.00
Ethanol 5.00
water remainder

(Prescription example 77)
A BB cream (non-chemical, W/O type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Fine particle titanium oxide dispersion 10.00
(CM3K40T4J)
Fine particle zinc oxide dispersion 25.00
(CM3K50XZ4J)
Cyclopentasiloxane 12.50
PEG-9 polydimethylsiloxyethyl dimethicone 1.00
Cyclopentasiloxane, (dimethicone/vinyl dimethicone) crosspolymer
2.00
(vinyl dimethicone/methicone silsesquioxane) crosspolymer 3.00
Trimethylsiloxysilicic acid, cyclopentasiloxane 3.00
(HDI/trimethylolhexyllactone) crosspolymer, silica 4.00
Silicone dispersion of iron oxide 15.00
(NIKKOL fresh color base)
Aqueous component:
PYR-containing collagen decomposition product 8.00
Glycerin 5.00
BG 2.00
Preservative appropriate amount EDTA-2Na 0.05
L-hydroxyproline 0.10
Hyaluronate Na (1% aqueous solution) 1.00
Na chloride 1.00
water remainder

(Prescription example 78)
A CC cream (non-chemical, O/W type) was prepared with the following formulation.
Ingredient name Amount (mass%)
Oily ingredients:
Fine particle titanium oxide dispersion 27.50
(IOPP40VMJ)
Sorbitan stearate 2.00
(NIKKOL SS-10V)
Triethylhexanoin 2.00
(NIKKOL Trifat S-308)
Cetearyl alcohol 0.50
PEG-60 hydrogenated castor oil 0.50
(NIKKOL HCO-60)
Polysorbate 80 0.20
(NIKKOL TO-10V)
Tocopherol 0.20
Aqueous component:
PYR-containing collagen decomposition product 8.00
BG 4.00
Pentylene glycol 3.00
Methyl methacrylate crisppolymer 2.00
Glycerin 1.00
Stearoylmethyltaurine Na 0.50
(NIKKOL SMT)
Stearoxyhydroxypropyl methylcellulose 0.10
Xanthan gum (2% aqueous solution) 5.00
Hyaluronate Na (1% aqueous solution) 2.00
Preservative appropriate amount Glycyrrhizic acid 2K 0.50
Citric acid 0.20
Sodium citrate 0.03
Silicone dispersion of iron oxide 10.00
(NIKKOL Fresh Color Base AQUA)
water remainder

(Formulation Example 79) Tablet Using a known fluidized bed granulator, the above PYR-containing collagen decomposition product was granulated and coated with a 1% by mass starch aqueous solution to obtain PYR-containing collagen decomposition product granules. The obtained PYR-containing collagen degradation product granules were mixed with other powders in the following formulation, and then tablets (10 mmφ, 300 mg) were produced using a tablet machine.
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product granules 50.0
Lactose 10.0
Starch (for granulation) 0.5
Starch (for powder mixing) 12.0
Maltitol 10.0
Microcrystalline cellulose 15.0
Silicon dioxide 0.5
Magnesium stearate 2.0
By granulating and coating the PYR-containing collagen degradation product with starch, it was possible to suppress tableting problems such as sticking.

(Formulation Example 80) Granule Stick The above-mentioned PYR-containing collagen decomposition product was mixed in the following formulation and then granulated using a known fluidized bed granulator. Note that a 1% by mass dextrin aqueous solution was used as the dextrin for granulation. The obtained granules were filled into sticks to obtain granule sticks (1.2 g/packet).
Ingredient name Amount (mass%)
PYR-containing collagen decomposition product 90.0
Dextrin (for granulation) 1.0
Vitamin B1 0.09
Vitamin B2 0.1
Vitamin B6 0.13
Vitamin B12 0.0002
Niacin 1.4
Pantothenic acid 0.42
Folic acid 0.017
Oil coated vitamin C (VC80%) 4.0
Pine powder fragrance 0.1
Sucrose 2.7328
Stevia 0.01
By using fat-coated vitamin C (manufactured by NOF Corporation), acidity was suppressed and easy-to-eat granules could be obtained. In addition, contact between vitamin C and the PYR-containing collagen decomposition product was prevented, and browning during long-term storage could be prevented. Furthermore, by adding vitamin B2, the product is colored yellow, which has the effect of reducing the difference in discoloration during long-term storage.

(Formulation example 81) Beverage Ingredient name Ingredients PYR-containing collagen decomposition product 5000mg
Hyaluronic acid 10mg
Placenta 10mg
Ceramide 200μg
Coenzyme Q10 1mg
Vitamin C 100mg
Sweetener (sucralose, acesulfame K) appropriate amount Acidulant (citric acid) appropriate amount Water 50mL

The collagen production promoter of the present invention can promote collagen production simply, easily, and efficiently, and is useful for maintaining skin health, suppressing skin aging, and treating osteoporosis, etc.

Claims (5)

Contains 3-hydroxypyridinoline represented by the following general formula (4) or 1-(5-carboxypentyl)-3-hydroxy-5-hydroxymethylpyridinium represented by the following general formula (5) as an active ingredient. Collagen production promoter.

Claim 1, characterized in that it contains 0.00001% by weight or more of the 3-hydroxypyridinoline or the 1-(5-carboxypentyl)-3-hydroxy-5-hydroxymethylpyridinium as an active ingredient. Collagen production promoter. The collagen according to claim 1 or 2, wherein the 3-hydroxypyridinoline or the 1-(5-carboxypentyl)-3-hydroxy-5-hydroxymethylpyridinium is derived from a natural product. Production promoter. A cell culture composition comprising the collagen production promoter according to any one of claims 1 to 3. A pharmaceutical composition for wound healing comprising the collagen production promoter according to any one of claims 1 to 3.

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