CN113749963B - Polypeptide composition for promoting skin microcirculation and application thereof - Google Patents
Polypeptide composition for promoting skin microcirculation and application thereof Download PDFInfo
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- CN113749963B CN113749963B CN202111062517.XA CN202111062517A CN113749963B CN 113749963 B CN113749963 B CN 113749963B CN 202111062517 A CN202111062517 A CN 202111062517A CN 113749963 B CN113749963 B CN 113749963B
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- China
- Prior art keywords
- skin
- polypeptide composition
- carnosine
- microcirculation
- palmitoyl pentapeptide
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4172—Imidazole-alkanecarboxylic acids, e.g. histidine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/494—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with more than one nitrogen as the only hetero atom
- A61K8/4946—Imidazoles or their condensed derivatives, e.g. benzimidazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/40—Chemical, physico-chemical or functional or structural properties of particular ingredients
- A61K2800/59—Mixtures
- A61K2800/592—Mixtures of compounds complementing their respective functions
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Birds (AREA)
- Engineering & Computer Science (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Cosmetics (AREA)
Abstract
The invention provides a polypeptide composition for promoting skin microcirculation and application thereof. The polypeptide composition consists of carnosine and palmitoyl pentapeptide-4. Wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is (1:4) - (4:1). The effective dosage range of the polypeptide composition is 10 mu g/mL-2000 mu g/mL. Compared with a cooling skin feel regulator, the polypeptide composition can increase the content of the skin acetylcholine or inhibit the thrombin activity in skin microvasculature, thereby really achieving the effect of promoting skin microcirculation. Compared with the natural extract, the polypeptide composition has definite composition components and no redundant impurities, avoids hidden skin allergy caused by complex components of the natural extract or residual impurities such as solvents, heavy metals and the like caused by the industrial extraction process, and greatly reduces the risk of toxic and side effects on human bodies. Compared with natural extract, the polypeptide composition has small addition amount in cosmetic or skin external medicine preparation, and can promote skin microcirculation.
Description
Technical Field
The invention relates to the technical field of efficacy cosmetics and medicines, in particular to a polypeptide composition for promoting skin microcirculation and application of the polypeptide composition as a skin microcirculation promoter.
Background
Microcirculation is the flow of blood, lymph and interstitial fluid between cells and tissues that is involved in substances, energy, biological information. It includes both blood circulation between the arterioles and venules, and circulation of lymph and tissue fluids. Skin microcirculation is a complex system. The system consists of two parallel vascular clusters in deep layer and shallow layer, and has effects of storing blood, nourishing skin and maintaining skin microcirculation stable. The change of the skin blood flow is affected by physiological, pathological and environmental factors. The different states of the skin and the local external medicine can cause the change of the blood flow of the skin, thereby changing the microcirculation of the skin, enhancing the activity of skin cells, providing sufficient nutrients and nutrient substances for the skin cells, simultaneously removing the metabolic products and various harmful substances of the cells and reducing the oxidation of collagen fibers.
The following problems are common with compositions currently used to promote skin microcirculation: (1) The skin has instant crunchy and refreshing feeling by adopting cool skin feel regulators such as menthol lactate, menthol, borneol and the like, so as to achieve the false appearance of skin microcirculation, and the effect of promoting skin microcirculation is not really achieved; (2) Natural extract components such as horse chestnut seed extract and safflower extract are adopted to achieve the effect of promoting skin blood circulation. However, natural extracts generally have the disadvantages of low active ingredient content, complex ingredients and undefined main ingredients. A large amount of the additive is required to be added into a cosmetic formula to achieve a certain effect. In addition, in the preparation process of the natural extract, various industrial solvents such as petroleum ether, diethyl ether and the like are often used for extraction in order to improve the extraction rate. Even if there is a step of volatilizing and removing the solvent in the extraction process, a solvent residue is generated in the extraction product. The main components of the natural extract are undefined, the active matter content is low, the effective addition amount is large, and the problem of solvent residue exists, so that the cosmetic is easy to cause the accumulation of irritation to human skin in the use process, and serious skin allergy and other problems can be caused.
Therefore, the development of the composition which has definite components, can promote skin microcirculation, has small addition amount and no toxic or side effect has important significance in the technical field of research and development of efficacy cosmetics and medicines.
Disclosure of Invention
It is a first object of the present invention to avoid the disadvantages of the prior art and to provide a polypeptide composition which promotes skin microcirculation. The polypeptide composition has definite components, can promote skin microcirculation, has small addition amount, and has no toxic or side effect.
The above object of the present invention is achieved by the following technical means.
A polypeptide composition for promoting skin microcirculation is provided, which consists of carnosine and palmitoyl pentapeptide-4.
Preferably, the mass ratio of carnosine to palmitoyl pentapeptide-4 is (1:4) to (4:1).
More preferably, the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:1.
Preferably, the effective dosage of the polypeptide composition is in the range of 10 μg/mL to 2000 μg/mL.
In particular, the polypeptide composition can increase the content of acetylcholine in skin.
In particular, the above polypeptide composition is capable of inhibiting thrombin activity.
In particular, the above polypeptide composition is capable of increasing the acetylcholine content of the skin while inhibiting thrombin activity.
It is a second object of the present invention to provide the use of the above polypeptide composition as a skin microcirculation promoter. The polypeptide composition can increase the content of the skin acetylcholine, and can inhibit the thrombin activity in skin microvasculature, thereby achieving the effect of promoting skin microcirculation.
The above object of the present invention is achieved by the following technical means.
According to one embodiment, the use of the above-described polypeptide composition as an accelerator for promoting skin microcirculation by increasing the acetylcholine content of the skin.
According to one embodiment, the above polypeptide composition is used as an accelerator for promoting skin microcirculation by inhibiting thrombin activity.
According to one embodiment, the use of the above-described polypeptide composition as an accelerator for promoting skin microcirculation by increasing the acetylcholine content of the skin while inhibiting thrombin activity.
The third object of the present invention is to provide an application of the polypeptide composition in preparing cosmetics or external skin medicines for promoting skin microcirculation.
The above object of the present invention is achieved by the following technical means.
Specifically, the cosmetic is a face cleansing cream, a toning lotion, an emulsion, an essence, a cream or a facial mask. The cosmetic prepared from the polypeptide composition can increase the content of the skin acetylcholine, inhibit the thrombin activity in skin microvasculature, achieve the effect of promoting skin microcirculation, and ensure the supply of skin nutrition.
Specifically, the skin external medicine is spray, gel, cream or local patch. The medicine prepared from the polypeptide composition can increase the content of the skin acetylcholine, inhibit the thrombin activity in skin microvasculature, achieve the effect of promoting skin microcirculation and relieve the symptom of skin discomfort.
The invention provides a polypeptide composition for promoting skin microcirculation, which consists of carnosine and palmitoyl pentapeptide-4. Compared with a cooling skin feel regulator, the polypeptide composition can increase the content of the skin acetylcholine, and can inhibit the thrombin activity in skin microvasculature, thereby really achieving the effect of promoting skin microcirculation. Compared with the natural extract, the polypeptide composition has definite composition components and no redundant impurities, avoids hidden skin allergy caused by complex components of the natural extract or residual impurities such as solvents, heavy metals and the like caused by the industrial extraction process, and greatly reduces the risk of toxic and side effects on human bodies. Compared with natural extract, the polypeptide composition has small addition amount in cosmetic or skin external medicine preparation, and can promote skin microcirculation.
Detailed Description
The endpoints and any values of the ranges disclosed herein are not limited to the precise range or value, and are understood to encompass values approaching those ranges or values. For numerical ranges, one or more new numerical ranges may be found between the endpoints of each range, between the endpoint of each range and the individual point value, and between the individual point value, in combination with each other, and are to be considered as specifically disclosed herein. The invention is further illustrated with reference to the following examples.
Example 1.
A polypeptide composition for promoting skin microcirculation comprises carnosine and palmitoyl pentapeptide-4. The polypeptide composition can be applied to skin surface to promote skin microcirculation, ensure skin nutrition supply, and relieve skin discomfort symptoms.
Carnosine (alanyl-histidine) is a dipeptide composed of beta-alanine and histidine, and has a strong antioxidant ability, and is capable of stably protecting cell membranes, especially as a water-soluble radical scavenger, and is capable of preventing peroxidation of cell membranes. Compared with other biological antioxidants such as VE and VC, the carnosine has stronger antioxidant capacity, so that the skin aging caused by free radicals can be delayed. In addition, carnosine is helpful for repairing skin tissue, and has therapeutic and prophylactic effects on skin allergy caused by ultraviolet rays.
Palmitoyl pentapeptide refers to a derivative of pentapeptide composed of five amino acids in sequence, i.e., palmitoyl-Lys-Thr-Lys-Ser (abbreviated as Pal-KTTKS), which is composed of five amino acids lysine-threonine-lysine-serine (Lys-Thr-Lys-Ser). KTTKS is the shortest fragment of collagen precursor I, released during collagen dissolution, and can stimulate synthesis of collagen I, III and fibronectin in human fibroblasts, and the original KTTKS polypeptide is palmitoylated to increase bioavailability and enhance its ability to penetrate the stratum corneum.
Unless otherwise specified, each component in the polypeptide composition of the present invention is commercially available.
In the polypeptide composition provided by the invention, the mass ratio of carnosine to palmitoyl pentapeptide-4 is (1:4) - (4:1), preferably 1:1. The effective dosage range of the polypeptide composition is 10 mu g/mL-2000 mu g/mL. The effective dosage range is converted into percentage, and is 0.001wt% to 0.2wt%. Namely, the addition amount of the polypeptide composition in the preparation is only 0.001-0.2 wt%, and the addition amount in the cosmetic formula or the pharmaceutical formula is quite low, so that the production economic benefit of the preparation can be improved.
The mechanism of promoting skin microcirculation by the polypeptide composition of the invention is as follows:
(1) The skin microcirculation is closely related to the state of vasomotor blood vessels. The skin blood flow is regulated by sympathetic vasomotor nerves which release norepinephrine, interact with postsynaptic α1 and α2 receptors of cutaneous arterial and arteriovenous short-circuit branches, and sympathetic vasomotor nerves which release cholinergic neurotransmitters acting on muscarinic receptors of cutaneous blood vessels, which act synergistically to regulate the cutaneous microvascular vasomotor state. Acetylcholine, an important cholinergic neurotransmitter involved in nerve signaling in humans, has a close relationship with neural network construction, neural information communication, and neural density distribution. Therefore, the acetylcholine can regulate and control the vasodilation of the micro-blood vessels and regulate the blood flow velocity, thereby achieving the effect of improving the skin microcirculation. The invention combines carnosine and palmitoyl pentapeptide-4 for use, can effectively inhibit the activity of acetylcholinesterase in skin, and reduce the hydrolysis of acetylcholines, thereby increasing the content of acetylcholines in skin. More acetylcholine is involved in reflex regulation of sympathetic vasomotor nerves and sympathetic vasomotor nerves in the skin, so that the microvessel vasodilation can be effectively regulated, the microvessel blood flow speed can be regulated, the skin microcirculation can be promoted, and the skin can be kept healthy.
(2) Factors that influence the physiological response of capillary blood flow velocity also have clotting effects. Thrombin acts directly on the last step of the blood coagulation process to promote the conversion of soluble fibrinogen in the blood plasma into insoluble fibrin, thereby achieving the purpose of quick-acting hemostasis. Other effects of thrombin on the blood coagulation system include the induction of platelet aggregation, secondary release reactions, and the like. Therefore, the carnosine and the palmitoyl pentapeptide-4 are compounded and used, so that the activity of thrombin can be effectively inhibited, the conversion of soluble fibrinogen in blood plasma is prevented, the reaction of inducing platelet aggregation, secondary release and the like is prevented, the blood capillaries of the skin are kept smooth, the normal flow of blood flow is ensured, the microcirculation of the skin is effectively promoted, and the skin is kept healthy.
Example 2.
A polypeptide composition for promoting skin microcirculation comprising the components of example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:4. Wherein carnosine can be selected from Chinese rong-zhen organism (product number RZ-19)032609 with a content of 99% or more) or German Dexin (Symrise)The palmitoyl pentapeptide-4 can be selected from Sichuan Hibiscus Sabdariffae (product No. LS289, product No. 98) or Meihua Pelargonium (product No. MH-041401, product No. 99%). Those skilled in the art can choose the relevant commercial products according to actual needs, and the present embodiment is not limited to the example. The carnosine of this example is Decine Germany (Symrise) (-je)>The content is more than or equal to 99.5 percent), and the palmitoyl pentapeptide-4 is selected from Chinese Meihai (product No. MH-041401, the content is more than or equal to 99 percent).
Example 3.
A polypeptide composition for promoting skin microcirculation comprising the components of example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 3:7. The sources of carnosine and palmitoyl pentapeptide-4 of this example were the same as in example 2.
Example 4.
A polypeptide composition for promoting skin microcirculation comprising the components of example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 4:6. The sources of carnosine and palmitoyl pentapeptide-4 of this example were the same as in example 2.
Example 5.
A polypeptide composition for promoting skin microcirculation comprising the components as in example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:1. The sources of carnosine and palmitoyl pentapeptide-4 of this example were the same as in example 2.
Example 6.
A polypeptide composition for promoting skin microcirculation comprising the components of the polypeptide composition as in example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 6:4. The sources of carnosine and palmitoyl pentapeptide-4 of this example were the same as in example 2.
Example 7.
A polypeptide composition for promoting skin microcirculation comprising the components of the polypeptide composition as in example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 7:3. The sources of carnosine and palmitoyl pentapeptide-4 of this example were the same as in example 2.
Example 8.
A polypeptide composition for promoting skin microcirculation comprising the components as in example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 4:1. The sources of carnosine and palmitoyl pentapeptide-4 of this example were the same as in example 2.
Comparative example 1.
A polypeptide composition for promoting skin microcirculation comprising the components as in example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:9. The carnosine of this comparative example was selected from German Dexin (Symrise)The content is more than or equal to 99.5 percent), and the palmitoyl pentapeptide-4 is selected from Chinese Meihai (product No. MH-041401, the content is more than or equal to 99 percent).
Comparative example 2.
A polypeptide composition for promoting skin microcirculation comprising the components as in example 1, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 9:1. The carnosine of this comparative example was selected from German Dexin (Symrise)The content is more than or equal to 99.5 percent), and the palmitoyl pentapeptide-4 is selected from Chinese Meihai (product No. MH-041401, the content is more than or equal to 99 percent).
Example 9.
In vivo efficacy evaluation experiment of polypeptide composition for promoting skin microcirculation
1 purpose of experiment
In vivo studies were performed in nude mice, and the promotion of the polypeptide composition on skin microcirculation was verified by measuring the blood perfusion amount and skin red value of the skin of the nude mice after administration, thereby determining the preferred range and the optimal mass ratio of carnosine and palmitoyl pentapeptide-4 in the polypeptide composition.
2 Experimental methods
2.1 preparation for experiments
2.1.1 use in this experimentIs selected from German Dexin (Symrise)The content is more than or equal to 99.5 percent), and the palmitoyl pentapeptide-4 is selected from Chinese Meihai (product No. MH-041401, the content is more than or equal to 99 percent).
2.1.2 the mass ratios of carnosine and palmitoyl pentapeptide-4 according to examples 2 to 8 and comparative examples 1 and 2 were prepared by weighing 9 sets of polypeptide compositions, respectively, and then preparing a 9 sets of polypeptide solutions with a mass percentage of 0.2wt% with 50% propylene glycol for use. Corresponding to the composition ratio of the 9 sets of polypeptide solutions, the 9 sets of solutions were numbered as example 2, example 3, example 4, example 5, example 6, example 7, example 8, comparative example 1 and comparative example 2, respectively. The amounts of carnosine and palmitoyl pentapeptide-4 used in the examples 2 to 8 and comparative examples 1 and 2 may be any amounts as long as they satisfy the requirements of the experiment. Table 1 provides a combination of the amounts used for 9 sets of polypeptide compositions.
In addition, a carnosine solution with a mass percentage of 0.2wt% was prepared using 50% propylene glycol, and a palmitoyl pentapeptide-4 solution with a mass percentage of 0.2wt% was prepared using 50% propylene glycol, for comparison as polypeptide compositions and individual components in the compositions.
2.2 Experimental grouping
The experiments were divided into a blank group and a drug group. The blank group is a nude mouse group coated with 50% propylene glycol, and the drug group is 11 nude mouse groups coated with 11 groups of polypeptide solutions (see experiment 2.1.2).
2.3 Experimental procedure
72 nude mice were randomly divided into 12 groups of 6 mice, and after 1 week of adaptive feeding, the other groups except for the blank group were each coated with polypeptide solution (2.1.2) on the backs of the nude mice, 200 μl each time, once daily for 7 days. The blood perfusion amount of the skin of nude mice was measured using a laser Doppler blood flow meter (PeriFlux 5000, sweden) and the skin red value was measured using a color difference meter (Konikoku Meidad CM-26d, japan) at day 0 and 1h after day 7 of administration.
3 results of experiments
3.1 Effect of polypeptide compositions at different concentrations on blood perfusion levels and skin Red values in nude mice skin
The vascular perfusion and skin redness are important indicators reflecting microvascular function. The blood vessel perfusion volume can be reflected by detecting the movement of red blood cells in capillaries in the tissue by using a laser Doppler instrument. The measured perfusion rate of blood flow varies greatly, depending on the degree of expansion and contraction of the microvasculature. The higher the value of the blood perfusion volume, the more frequent the microvascular expansion and contraction, and the better the skin microcirculation effect. Blood vessels and heme exist in the dermal papilla layer of the skin, and the state of the blood vessels and heme in the skin can be known by detecting the red value of the skin surface through a color difference meter, and the higher the red value of the skin is, the faster the blood vessels microcirculation in the skin is.
Table 1 Effect of polypeptide compositions on skin blood perfusion and skin redness of nude mice
The increase in blood perfusion and skin red after 7 days was calculated according to the following formula:
increase = (day 7 value-day 0 value)/(day 0 value×100%
Skin blood perfusion amount data are shown in table 1, and it is clear from the data that the polypeptide compositions of examples 2 to 8 and comparative examples 1 and 2 of the present invention can increase blood perfusion amount and increase skin red value after being applied to the skin of nude mice. The blank group is not smeared with polypeptide solution, the blood perfusion quantity is increased negatively, the increase of the skin red value is not more than 1%, and the skin red value can be considered to be not increased. As can be seen from comparison of the data of the blank group and the administration group, the polypeptide composition containing carnosine and palmitoyl pentapeptide-4 can increase the blood perfusion quantity of skin, improve the red value of skin and improve the microcirculation capacity of skin after being applied.
In addition, as can be seen from the data in Table 1, the mass ratio of carnosine to palmitoyl pentapeptide-4 in the polypeptide composition was (1:4) - (4:1), the rise of blood perfusion amount was as high as 4.34% -12.50%, and the rise of skin red value was as high as 4.18% -8.84%. The polypeptide compositions of examples 2 to 8 of the present invention have an effect of remarkably promoting skin microcirculation. The optimal mass ratio of carnosine to palmitoyl pentapeptide-4 of the polypeptide composition of the present invention is 1:1. The mass ratio of carnosine and palmitoyl pentapeptide-4 of comparative examples 1 and 2 was not within the mass ratio range of the present invention, and the improvement amplitude of the blood perfusion amount and the skin red value was small, and the effect of promoting skin microcirculation of comparative examples 1 and 2 was not as good as that of the present invention.
3.2 Effect of polypeptide composition and individual polypeptide on blood perfusion amount and skin Red value of nude mice skin at equivalent concentration
Example 2 with the lowest blood perfusion increase and example 8 with the lowest skin red increase after 7 days were compared with the polypeptide alone and the results are shown in Table 2.
Table 2 Effect of polypeptide compositions on blood perfusion levels and skin redness values in nude mice compared to the polypeptide alone
From the data in Table 2, the 7-day rise in blood perfusion performance was superior for the groups of example 2 and example 8 than for the carnosine alone and palmitoyl pentapeptide-4 group. The 7-day rise in skin redness performance of the groups of example 2 and example 8 was superior to that of the carnosine and palmitoyl pentapeptide-4 alone. The polypeptide composition provided by the invention has better effect on promoting skin microcirculation compared with the effect of independently using carnosine or palmitoyl pentapeptide-4 after being compounded and used.
Example 10.
Efficacy evaluation experiment of polypeptide composition for increasing skin acetylcholine content
1 purpose of experiment
In vivo studies were performed in nude mice used in this experiment to verify the increasing effect of polypeptide compositions of different concentrations on skin acetylcholine content at optimal mass ratios of carnosine and palmitoyl pentapeptide-4.
2 Experimental methods
2.1 preparation for experiments
2.1.1 carnosine used in the experiment was selected from De-carnosine (Symrise) in GermanyThe content is more than or equal to 99.5 percent), and the palmitoyl pentapeptide-4 is selected from Chinese Meihai (product No. MH-041401, the content is more than or equal to 99 percent).
2.1.2 polypeptide compositions of the invention were formulated with 50% propylene glycol in polypeptide solutions of 0.01wt%,0.05wt%,0.1wt%,0.2wt%,0.3wt%,0.4wt%,0.5wt% and 1wt% in the order ACh 1,ACh 2,ACh 3,ACh 4,ACh 5,ACh 6,ACh 7 and ACh 8. In the polypeptide composition of the experiment, the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:1. In addition, a carnosine solution with a mass percentage of 0.2wt% was prepared using 50% propylene glycol, and a palmitoyl pentapeptide-4 solution with a mass percentage of 0.2wt% was prepared using 50% propylene glycol, for comparison as polypeptide compositions and individual components in the compositions.
2.2 Experimental grouping
The experiments were divided into a blank group and a drug group. The blank group is a nude mice group coated with 50% propylene glycol, and the drug group is 10 nude mice groups coated with 10 groups of polypeptide solutions (this example 2.1.2) respectively.
After the 66 nude mice are randomly divided into 11 groups, 6 nude mice are adaptively fed for 1 week, polypeptide solution is smeared on the backs of the nude mice except for a blank group (see experiment 2.1.2), 200 mu L of each nude mice are administrated once daily for 7 days continuously. After the experiment, the back skin of the nude mice was taken, and the acetylcholine content was tested using an Elisa kit (E0912 Ra, product number: E0912 Ra) from the rat acetylcholine (ACh) ELISA kit, WUYOUR commercial Co., ltd.).
3 acetylcholine content determination
3.1 principle of experiment
Coating ACh antibody on 96-well microwell plate to obtain solid phase carrier, sequentially adding standard substance and sample into microwell, wherein ACh is combined with antibody connected to the solid phase carrier, washing plate, adding biotinylated ACh antibody, washing unbound biotinylated antibody, adding HRP-labeled avidin, thoroughly washing again, and adding substrate (TMB) for color development. TMB is converted to blue under the catalysis of peroxidases and to a final yellow color under the action of acids. The shade of color and ACh in the sample were positively correlated. The absorbance (o.d. value) was measured at a wavelength of 450nm using an enzyme-labeled instrument, and the sample concentration was calculated.
3.2 sample collection
The skin tissue of the back of the nude mice is crushed and homogenized, the mixture is centrifuged for 20 minutes at 1000 Xg, and the supernatant is taken for detection.
3.3 preparation of reagents
3.3.1 all reagents and samples were equilibrated slowly to room temperature (18-25 ℃) prior to use.
3.3.2 standard (lyophilized product): each bottle of the standard was diluted to 1mL with the standard diluent, covered, and left to stand at room temperature for about 10 minutes while repeating inversion/rubbing to aid dissolution at a concentration of 200nmol/L. EP tubes of 7 diluted standards were prepared, 50. Mu.L of a standard diluent was added to each EP tube, and the mixture was diluted to 200nmol/L,100nmol/L,50nmol/L,25nmol/L,12.5nmol/L,6.25nmol/L,3.12nmol/L, and the standard diluent (0 nmol/L) was directly used as a blank well.
3.3.3 detection diluent A and detection diluent B: 6mL of the concentrated test solutions A and B were diluted to 12mL with 6mL of deionized water, and 2-fold dilution was performed.
3.3.4 detection solution A and detection solution B: before use, the diluent A or B is respectively detected and diluted and mixed according to the ratio of 1:100.
3.3.5 concentrated wash: 20mL of the concentrated wash was diluted to 600mL with 580mL of deionized water and 30-fold dilution was performed.
3.3.6 substrate solution: the required volume of TMB was aspirated with a sterilized pipette tip into another clean container for use.
3.4 procedure
3.4.1 sample addition: and respectively arranging a standard hole, a sample hole to be tested and a blank hole. A standard well 7-well was set, and 100. Mu.L of standards of different concentrations were added sequentially (see experiment 3.3.2). 100 mu L of standard diluent is added to the blank hole, 100 mu L of sample to be detected is added to the Yu Kongjia, the ELISA plate is added with a coating film, and the incubation is carried out for 2 hours at 37 ℃.
3.4.2 the liquid was discarded and dried without washing.
3.4.3 100. Mu.L of working solution A was added to each well (see experiment 3.3.4), and the ELISA plate was covered with the coating and incubated at 37℃for 1 hour.
3.4.4 discarding the liquid in the wells, washing each well with 400. Mu.L of washing liquid, soaking for 1-2 minutes, spin-drying, and repeating washing the plate 3 times. After the first washing, the washing liquid in the holes is completely dried.
3.4.5 100. Mu.L of working solution for detecting B was added to each well (see experiment 3.3.4), and the ELISA plate was covered with the coating and incubated at 37℃for 30 minutes.
3.4.6 discarding the liquid in the holes, spin-drying, and washing the plate 5 times, wherein the method is the same as that of the experiment step 3.4.4.
3.4.7 adding 90 mu L of substrate solution to each hole, adding a coating film to an ELISA plate, and developing color at 37 ℃ for 25 minutes in a dark place. When the front 3-4 holes of the standard holes have obvious gradient blue, the gradient blue of the rear 3-4 holes is not obvious, and the method can be terminated.
3.4.8 50. Mu.L of stop solution was added to each well to stop the reaction, at which time the blue color turned yellow immediately.
3.4.9 after ensuring that the bottom of the microplate was free of water droplets and air bubbles in the wells, the optical density (o.d. value) of each well was measured immediately with an microplate reader at a wavelength of 450 nm.
4 experimental results
4.1 Effect of polypeptide compositions of different concentrations on acetylcholine content
Because the acetylcholine participates in the reflex regulation of the sympatholytic nerve and the sympatholytic nerve, the microvessel diastole can be effectively regulated, thereby regulating the microvessel blood flow speed and promoting the skin microcirculation. Therefore, the content of the acetylcholine in the skin is improved, and the microcirculation effect of the skin can be improved. The results of the acetylcholine content test are shown in Table 3.
TABLE 3 acetylcholine content of different mass percent groups
| Group of | Mass concentration percentage (wt%) | Acetylcholine content (pg/mL) | Amplification of |
| Blank control | 0 | 64.33 | 0.00％ |
| ACh 1 | 0.01 | 75.85 | 17.91％ |
| ACh 2 | 0.05 | 91.43 | 42.13％ |
| ACh 3 | 0.1 | 109.65 | 70.45％ |
| ACh 4 | 0.2 | 145.31 | 125.88％ |
| ACh 5 | 0.3 | 125.64 | 95.31％ |
| ACh 6 | 0.4 | 106.44 | 65.46％ |
| ACh 7 | 0.5 | 88.67 | 37.84％ |
| ACh 8 | 1 | 79.20 | 23.12％ |
The increase in acetylcholine content of each group was calculated according to the following formula:
ACh X group acetylcholine content increase= (ACh X group acetylcholine content-blank group acetylcholine content)/(blank group acetylcholine content X100%)
Wherein x=1, 2,3,4,5,6,7,8.
As can be seen from the data in table 3, the bare mice in the blank group were not treated with the polypeptide composition of the present invention, and their acetylcholine content was the acetylcholine content in the skin of the bare mice themselves, which is the lowest value of the acetylcholine content in each group. The groups ACh 1 to ACh 8 each had different concentrations of polypeptide composition and an acetylcholine content of 17.91% to 125.88% increase. Wherein, in the low concentration section (0 wt% -0.2 wt%) of the polypeptide composition, the content of acetylcholine and the mass concentration percentage of the polypeptide composition are positively correlated. When the mass concentration percentage of the polypeptide composition is higher than 0.2wt%, the content of acetylcholine in the skin of nude mice is significantly reduced. It is illustrated that the content of acetylcholine in the skin is highest when the polypeptide composition of the invention is present in the formulation at a mass concentration of 0.2wt%. Further, it is stated that the polypeptide composition of the present invention should not be present in an amount exceeding 0.2wt% in the formulation in order to maximize the acetylcholine content of the skin.
4.2 Effect of polypeptide composition and individual polypeptide on acetylcholine content at equivalent concentration
TABLE 4 influence of groups of polypeptide compositions and groups of individual polypeptides on acetylcholine content
| Group of | Mass concentration percentage (wt%) | Acetylcholine content (pg/mL) | Amplification of |
| Blank control | 0 | 64.33 | 0.00％ |
| ACh 4 | 0.2 | 145.31 | 125.88％ |
| Carnosine (carnosine) | 0.2 | 115.74 | 79.92％ |
| Palmitoyl pentapeptide-4 | 0.2 | 111.03 | 72.59％ |
From the data in Table 4, it is clear that the increase in acetylcholine content in the skin of nude mice in the group of polypeptide compositions is significantly higher than in the carnosine group or palmitoyl pentapeptide-4 group at the same concentration. It is explained that the effect of the polypeptide composition of the present invention on promoting the increase of the acetylcholine content in the skin is better than that of the carnosine or palmitoyl pentapeptide-4 alone after the carnosine and palmitoyl pentapeptide-4 are compounded, and further it is confirmed that the effect of the polypeptide composition of example 9 of the present invention on promoting the microcirculation of the skin is better than that of the carnosine or palmitoyl pentapeptide-4 alone.
The invention combines carnosine and palmitoyl pentapeptide-4 for use, can effectively inhibit the activity of acetylcholinesterase in skin, and reduce the hydrolysis of acetylcholines, thereby increasing the content of acetylcholines in skin. More acetylcholine is involved in reflex regulation of sympathetic vasomotor nerves and sympathetic vasomotor nerves in the skin, so that the microvessel vasodilation can be effectively regulated, the microvessel blood flow speed can be regulated, the skin microcirculation can be promoted, and the skin can be kept healthy.
Example 11.
Efficacy evaluation experiment of polypeptide composition for inhibiting thrombin Activity
1 purpose of experiment
Adverse environmental factors can cause free radical build-up in the skin. The free radicals induce oxidative hemolysis of red blood cells and damage the wall structure of blood vessels, thereby activating blood platelets in blood vessels and promoting the conversion of prothrombin into thrombin. The increase of thrombin activity in skin blood vessels induces the enhancement of platelet aggregation, and simultaneously thrombin catalyzes the decomposition of fibrinogen into fibrin to promote blood coagulation, so that the blood flow rate is further slowed down and is detained, the blood flow rate is slowed down, the blood volume in blood vessels is increased and the oxygen consumption is increased, therefore, the inhibition rate of the polypeptide composition on the thrombin activity is measured, and the effect of the composition on improving skin microcirculation can be reflected.
The basic principle of the experiment is that the action substrate (fibrinogen) of the enzyme is uniformly distributed on an agar plate, enzyme solution is added into plate-like holes for diffusion reaction, and the enzyme and the substrate undergo hydrolysis reaction in the diffusion process, so that the fibrinogen is hydrolyzed into fibrin, and crosslinking occurs to form milky precipitate. The diameter of the white precipitation ring is positively correlated with the enzyme activity.
2 Experimental methods
2.1 preparation for experiments
2.1.1 carnosine used in the experiment was selected from De-carnosine (Symrise) in GermanyThe content is more than or equal to 99.5 percent), and the palmitoyl pentapeptide-4 is selected from Chinese Meihai (product No. MH-041401, the content is more than or equal to 99 percent).
2.1.2A polypeptide composition of the present invention was dissolved in 0.05mol/L PBS and diluted to 1. Mu.g/mL, 2.5. Mu.g/mL, 5. Mu.g/mL, 10. Mu.g/mL, 15. Mu.g/mL, 20. Mu.g/mL, 50. Mu.g/mL and 100. Mu.g/mL polypeptide solutions, numbered Prothrombin 1,Prothrombin 2,Prothrombin 3,Prothrombin 4,Prothrombin 5,Prothrombin 6,Prothrombin 7 and Prothrombin 8, respectively. In the polypeptide composition of the experiment, the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:1. In addition, a carnosine solution at a concentration of 10. Mu.g/mL was prepared using a 0.05mol/L PBS solution, and a palmitoyl pentapeptide-4 solution at a concentration of 10. Mu.g/mL was prepared using a 0.05mol/L PBS solution, for comparison as polypeptide compositions and individual components in the compositions.
2.2 Experimental grouping
The experiments were divided into a blank group and a drug group. Wherein, the blank group is a PBS solution of 0.05mol/L, and the drug group is a polypeptide solution of 10 groups (example 2.1.2).
2.3 Experimental procedure
Fibrinogen plate preparation: cooling 2% agarose solution to 50-60 ℃, mixing with 0.1% fibrinogen in a volume ratio of 1:1, pouring the mixture into a plate with a thickness of about 2mm, cooling to obtain a fibrinogen plate, punching holes at a distance of 1.6cm, and a pore diameter of about 4mm.
Preparation of thrombin standard curve: the thrombin standard substances diluted by 28U/mL, 14U/mL, 7U/mL, 3.5U/mL and 1.75U/mL are added with 20 mu L of sample in each hole of the plate hole, and the mixture is sealed and then subjected to constant-temperature diffusion reaction at 37 ℃ for 8-10 hours. And measuring the diameter of the precipitation ring of each reaction hole, drawing a standard curve by taking the diameter of the precipitation ring of each thrombin standard substance reaction hole as an ordinate and the thrombin activity as an abscissa, and carrying out equation regression calculation.
Determination of sample inhibition thrombin activity: mixing each drug group sample with 0.05mol/L PBS solution at a volume ratio of 1:1, taking 20 mu L sample holes after mixing with 7U/mL thrombin at a volume ratio of 1:1, adding 20 mu L thrombin and 3.5U/mL thrombin into blank control holes, sealing, performing constant-temperature diffusion reaction at 37 ℃ for 8-10 h, and measuring the diameter of a precipitation ring of each reaction hole.
3 results of experiments
TABLE 5 diameter of reaction well precipitation ring for different concentration groups
3.1 Effect of polypeptide compositions at different concentrations on thrombin Activity
(1) Comparison of the blank group with other group data
The size of the precipitation ring is positively correlated with the enzyme activity, namely, the smaller the diameter of the precipitation ring is, the lower the thrombin activity is, and the higher the inhibition efficiency of the corresponding additive on thrombin is. The effects of each drug group on inhibition of thrombin activity are shown in Table 5. The data show that the diameter of the precipitation circle is the largest, the thrombin activity is the highest, and the coagulation response is the strongest in the blank group without the polypeptide composition added. When the coagulation reaction occurs in the skin microcirculation process, the blood flow is not smooth, and the skin microcirculation is finally hindered. The diameter of the reaction hole precipitation ring of each medicine group is smaller than that of a blank control group, which indicates that the polypeptide composition can effectively inhibit the activity of thrombin and slow down the speed of coagulation reaction. When the coagulation reaction occurs in the skin microcirculation process, the coagulation process is slowed down, and the blood flow in the blood vessel is kept smooth, so that the effect of promoting the skin microcirculation is achieved.
(2) Comparison of data for different concentration groups in a group of polypeptide compositions
The decrease in diameter of the reaction well precipitation ring for each group of thrombin was calculated according to the following formula:
the diameter of the reaction well precipitation ring of Prothrombin Y group decreased by = (reaction well precipitation ring diameter value of blank control group-reaction well precipitation ring diameter value of Prothrombin Y group)/(reaction well precipitation ring diameter value of blank control group × 100%)
Wherein x=1, 2,3,4,5,6,7,8.
As is clear from the data in Table 5, the values of the diameter of the reaction well precipitated circles in the low concentration zone of the polypeptide composition of the present invention were not significantly different from those of the blank group, indicating that the inhibition effect of the polypeptide composition on thrombin was not significant in the range of the addition concentration of 0. Mu.g/mL to 10. Mu.g/mL, and the inhibition effect of thrombin was not effectively inhibited, and the blood vessel was kept smooth, and therefore, the polypeptide composition did not have the effect of promoting skin microcirculation. Starting from the data of the Prothrombin 4 group, the smaller the diameter value of the reaction well precipitation circle, the more the concentration of the polypeptide composition, the more the decrease in the amplitude from 0.12% to 13.23%, demonstrating that thrombin activity can be significantly inhibited when the polypeptide composition is added to the formulation at a concentration of 10 μg/mL. When the coagulation reaction occurs in the skin microcirculation process, the coagulation process is slowed down, the blood flow in the blood vessel is kept smooth, and the effect of promoting the skin microcirculation is finally achieved.
3.2 Effect of polypeptide composition and individual Polypeptides on thrombin Activity at equivalent concentrations
Table 6 diameter of reaction well precipitation ring for polypeptide composition group and individual polypeptide group
From the data in Table 6, it can be seen that the thrombin activity test was performed using the same concentration of the polypeptide composition solution, carnosine solution and palmitoyl pentapeptide-4 solution, and that the diameter of the reaction pore precipitation ring of the polypeptide composition group was significantly smaller than that of the blank group, carnosine group and palmitoyl pentapeptide-4 group. Since thrombin activity is proportional to the diameter of the reaction well precipitation circle, the results in Table 6 demonstrate that the polypeptide composition of the present invention has better effect on inhibiting thrombin activity than the carnosine group or the palmitoyl pentapeptide-4 group after the carnosine and palmitoyl pentapeptide-4 are compounded, and further confirm the conclusion that the polypeptide composition of example 9 of the present invention has better effect on promoting skin microcirculation than carnosine or palmitoyl pentapeptide-4 alone.
The carnosine and palmitoyl pentapeptide-4 are compounded and used, so that the activity of thrombin can be effectively inhibited, the conversion of soluble fibrinogen in blood plasma is prevented, the reaction of inducing platelet aggregation, secondary release and the like is prevented, the blood capillaries of the skin are kept smooth, the normal flow of blood flow is ensured, the microcirculation of the skin is effectively promoted, and the skin is kept healthy.
The experimental results of examples 10 and 11 show that the polypeptide composition for promoting skin microcirculation of the present invention has the lowest effective concentration of 10 mug/mL and the highest effective concentration of 0.2wt%, and in the concentration interval, the polypeptide composition can raise the acetylcholine content of skin, promote the expansion and contraction of skin microvascular, inhibit the activity of thrombin in blood vessel, slow down the coagulation process and maintain the blood flow in blood vessel smooth, so as to promote skin microcirculation. After unifying the units of the effective dosage ranges, the effective dosage range of the polypeptide composition of the invention is 10 mug/mL-2000 mug/mL or 0.001wt% to 0.2wt%.
Example 12.
The present example discloses the use of a polypeptide composition according to any one of examples 1 to 11 for promoting skin microcirculation in the preparation of a cosmetic for promoting skin microcirculation.
The polypeptide composition consists of carnosine and palmitoyl pentapeptide-4, has high compatibility with various cosmetic raw materials, and is suitable for preparing cosmetics in various dosage forms. These cosmetic formulations include facial cleansers, lotions, emulsions, essences, creams, masks and the like. The color cosmetic product which stays on the face of a human body for a long time can be used as one of skin care components, not only can meet the beautifying face requirements of people, but also can improve the content of acetylcholine in the skin, simultaneously inhibit the activity of thrombin, achieve the effect of promoting the microcirculation of the skin, increase the nutrition supply of the skin and keep the skin healthy.
The polypeptide composition has definite components, can promote skin microcirculation, has small addition amount and has no toxic or side effect.
Example 13.
The present embodiment discloses the use of the polypeptide composition for promoting skin microcirculation as in any one of examples 1 to 11 for the preparation of a skin external preparation for promoting skin microcirculation.
The polypeptide composition consists of carnosine and palmitoyl pentapeptide-4, has high compatibility with various medicine auxiliary materials, and is suitable for preparing medicines in various dosage forms. Such pharmaceutical dosage forms include sprays, gels, creams or topical patches and the like. The polypeptide composition for promoting skin microcirculation is applied to the treatment of skin diseases caused by skin microcirculation disturbance, can improve the content of acetylcholine in skin, inhibit thrombin activity, achieve the effect of promoting skin microcirculation, relieve skin discomfort symptoms and restore skin to health.
The polypeptide composition has definite components, can promote skin microcirculation, has small addition amount and has no toxic or side effect.
Finally, it should be noted that the above embodiments are only for illustrating the technical solution of the present invention and not for limiting the scope of the present invention, and although the present invention has been described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the technical solution of the present invention without departing from the spirit and scope of the technical solution of the present invention.
Claims (10)
1. Use of a polypeptide composition consisting of carnosine and palmitoyl pentapeptide-4 in a mass ratio of (1:4) - (4:1) for the preparation of a skin microcirculation promoter.
2. The use according to claim 1, characterized in that: the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:1.
3. The use according to claim 1, characterized in that: the effective dosage range is 10 mug/mL-2000 mug/mL.
4. A use according to any one of claims 1 to 3, characterized in that: the skin microcirculation promoter promotes skin microcirculation by increasing the content of skin acetylcholine; or alternatively
The skin microcirculation promoter promotes skin microcirculation by inhibiting thrombin activity; or alternatively
The skin microcirculation promoter promotes skin microcirculation by increasing the content of skin acetylcholine while inhibiting thrombin activity.
5. Use of a polypeptide composition in the preparation of a cosmetic or skin external preparation for promoting skin microcirculation; the polypeptide composition consists of carnosine and palmitoyl pentapeptide-4, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is (1:4) - (4:1);
the cosmetic is a facial cleanser, a toning lotion, an emulsion, an essence, cream or a facial mask;
the skin external medicine is spray, gel, cream or local patch.
6. The use according to claim 5, wherein the mass ratio of carnosine to palmitoyl pentapeptide-4 is 1:1.
7. The use according to claim 5, wherein the effective dose of the polypeptide composition is in the range of 10 μg/mL to 2000 μg/mL.
8. The use according to any one of claims 5 to 7, wherein the cosmetic or dermatological topical drug increases the skin acetylcholine content.
9. The use according to any one of claims 5 to 7, wherein the cosmetic or dermatological topical drug inhibits thrombin activity.
10. The use according to any one of claims 5 to 7, wherein the cosmetic or dermatological topical drug increases the skin acetylcholine content while inhibiting thrombin activity.
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Citations (3)
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| CN101721340A (en) * | 2009-10-23 | 2010-06-09 | 无限极（中国）有限公司 | Cosmetic composition for delaying skin aging |
| CN110279608A (en) * | 2019-08-06 | 2019-09-27 | 无限极（中国）有限公司 | With the peptide composition and its nano liposomes that delay eye part skin aging function and cosmetics |
| CN111603428A (en) * | 2020-06-04 | 2020-09-01 | 陶兴仲 | Whitening and freckle-removing plant type essence, preparation method and use method |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101721340A (en) * | 2009-10-23 | 2010-06-09 | 无限极（中国）有限公司 | Cosmetic composition for delaying skin aging |
| CN110279608A (en) * | 2019-08-06 | 2019-09-27 | 无限极（中国）有限公司 | With the peptide composition and its nano liposomes that delay eye part skin aging function and cosmetics |
| CN111603428A (en) * | 2020-06-04 | 2020-09-01 | 陶兴仲 | Whitening and freckle-removing plant type essence, preparation method and use method |
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