WO2022089287A1 - 用于皮肤表面的仿生胶原溶液的制备方法和使用方法 - Google Patents

用于皮肤表面的仿生胶原溶液的制备方法和使用方法 Download PDF

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Publication number
WO2022089287A1
WO2022089287A1 PCT/CN2021/125186 CN2021125186W WO2022089287A1 WO 2022089287 A1 WO2022089287 A1 WO 2022089287A1 CN 2021125186 W CN2021125186 W CN 2021125186W WO 2022089287 A1 WO2022089287 A1 WO 2022089287A1
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solution
collagen
skin surface
collagen solution
biomimetic
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PCT/CN2021/125186
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English (en)
French (fr)
Chinese (zh)
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杜明春
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杜明春
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Priority to KR1020227046111A priority Critical patent/KR20230018468A/ko
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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
    • A61K8/65—Collagen; Gelatin; Keratin; Derivatives or degradation products thereof
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/20—Halogens; Compounds thereof
    • 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
    • A61K8/19—Cosmetics or similar toiletry preparations characterised by the composition containing inorganic ingredients
    • A61K8/24—Phosphorous; Compounds thereof
    • 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
    • A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
    • A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
    • 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
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • A61Q19/08—Anti-ageing preparations

Definitions

  • the invention relates to a biological material and a method for preparing and using the same, in particular to a method for preparing and using a biomimetic collagen solution on the skin surface.
  • collagen In skin tissue, collagen is one of the components of the supporting structure of the dermis. Its mesh structure provides protection and elasticity for the skin, and a large amount of water, extracellular matrix and functional cells are distributed between the fibers. An important biochemical reaction site, providing moisture and nutrients to the epidermis.
  • the diffusion coefficient of the molecule is inversely proportional to the square root or cube root of the molecular weight. The larger the molecular weight, the larger the molecular volume and the smaller the diffusion coefficient. Therefore, it is difficult for collagen molecules with relative molecular mass ranging from about 2kD to 300kD to diffuse into the dermis through the stratum corneum, and be absorbed by the skin tissue to exert its repair and regeneration effect.
  • collagen molecules can only be absorbed through skin appendages such as hair follicles, sebaceous glands and sweat glands.
  • skin appendages such as hair follicles, sebaceous glands and sweat glands.
  • the total area of hair follicles, sweat glands and sebaceous glands is less than 1% of the total surface area of the skin, so the absorption of collagen molecules by hair follicles, sweat glands and sebaceous glands is also very small.
  • the skin is an organ mainly for excretion, and the efficiency of passive diffusion is obviously not too high.
  • the conventional method is to reduce the molecular weight of collagen molecules to use collagen peptides of small molecular weight.
  • collagen peptides are made of collagen or gelatin after being degraded by protease, and their biological activity is poor; and due to their small molecular weight, collagen peptides are easily degraded in the body and easily digested and absorbed by skin tissue, so the skin The repair effect is limited.
  • the effect of promoting collagen absorption can also be achieved by means of the functions of introduction instruments (conductivity, ultrasonic introduction, radio frequency introduction, microcrystal, microneedle introduction, etc.).
  • introduction instruments conductivity, ultrasonic introduction, radio frequency introduction, microcrystal, microneedle introduction, etc.
  • long-term disordered use of the instrument can cause certain damage to the skin.
  • complexity of the operation is not conducive to large-scale promotion and use.
  • the present invention develops a biomimetic collagen solution for use on the skin surface from a biomimetic perspective: (1) the collagen raw material selects type I, type III or type V collagen specific to skin tissue; (2) Add simulated body fluid components, adjust the pH value of the solution, and simulate the microenvironment of skin tissue; (3) Add linking molecules to promote the absorption of collagen molecules in skin tissue (especially the dermis).
  • the developed low-concentration biomimetic collagen solution is applied on the skin surface by smearing, spraying or immersion.
  • the invention provides an aqueous solution of biomimetic collagen and a preparation method and use method thereof.
  • step (2) under low temperature conditions, the collagen solution obtained in step (1) is slowly added to simulate body fluid components in the stirring process to fully dissolve;
  • the pH value of the collagen solution obtained in step (2) is adjusted to be greater than or equal to 4 but less than or equal to 10 by an alkaline solution or an acidic solution to form a homogeneous solution;
  • the linking molecule solution is added to the collagen solution obtained in step (3) and the preparation is completed after stirring evenly. After the preparation is completed, the biomimetic collagen solution is stored under low temperature conditions.
  • the range of low temperature conditions in step (2), step (3) and step (4) is greater than or equal to 0°C but less than or equal to 10°C; the solid collagen material is selected from type I, type III
  • the pH value of the collagen solution is adjusted to be greater than or equal to 6 but less than or equal to 8 through an alkaline solution or an acidic solution.
  • type I, type III or type V collagen is a type of collagen unique to skin tissue.
  • the collagen solution is prepared as far as possible according to the content of different types of collagen in the skin tissue, but in order to facilitate the concentration of collagen molecules Flow, the collagen solution is finally a dilute solution, and the total concentration of all types of collagen is greater than or equal to 0.0001 wt.% but less than or equal to 0.1 wt.%.
  • the acidic solution in step (1) and step (3) is at least one of hydrochloric acid, nitric acid, sulfuric acid, phosphoric acid, tartaric acid, citric acid, oxalic acid, acetic acid and formic acid ;
  • Described alkaline solution in described step (3) comprises triethylamine, tetramethylethylenediamine, pyridine, piperidine, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, ammoniacal liquor, phosphoric acid
  • At least one of disodium hydrogen and sodium bicarbonate; the concentration of the acidic solution and the alkaline solution is greater than or equal to 0.01M but less than 10M.
  • the acidic solution in the step (1) is added to fully dissolve the solid collagen material.
  • the addition of the acidic solution is a trace addition, and does not significantly change the concentration of the collagen solution, so long as the collagen is dissolved to form a homogeneous solution.
  • adding an alkaline solution or an acidic solution in the step (3) is to adjust the pH value of the collagen solution.
  • the addition of the acidic solution or the alkaline solution is a micro-addition, which does not significantly change the concentration of the collagen solution, as long as the solution reaches a preset pH value and forms a homogeneous solution.
  • the simulated body fluid components include Na + , K + , Mg 2+ , Ca 2+ , Cl - , HCO 3 - , HPO 4 2- , SO 4 2- , CO 3 2- , PO 4 One or a combination of two or more of 3- and H 2 PO 4 - .
  • the purpose of adding simulated body fluid components is to adapt the ionic environment of the collagen solution to the microenvironment in the skin tissue.
  • the addition of simulated body fluid components is a small amount, and does not significantly change the concentration of collagen solution therein.
  • the final ion concentration of each ion in the biomimetic collagen solution for the skin surface was in the range of 0.1-500 mM, and the final total ion concentration was in the range of 0.1-1000 mM.
  • the linking molecules are isothiocyanates, isocyanates, acyl azides, N-hydroxysuccinimide esters (NHS esters), sulfonyl chlorides, aldehydes, epoxides, aryl halides , one or more mixtures of imide ester, carbodiimide, acid anhydride, fluorophenyl ester, proanthocyanidin and genipin.
  • the linker molecules are added to enhance the absorption of collagen molecules into the skin tissue. The addition of the linker molecule solution did not significantly change the concentration of the collagen solution therein, and the final concentration of the linker molecules in the biomimetic collagen solution for skin surface was 0.0001 wt.% or more but 10 wt.% or less.
  • the final concentration of the linking molecule in the biomimetic collagen solution for skin surface is greater than or equal to 0.0001 wt.% but less than or equal to 1 wt.%.
  • the final concentration of the linking molecule in the biomimetic collagen solution for skin surface is greater than or equal to 0.0001 wt.% but less than or equal to 0.1 wt.%.
  • the final concentration of the linking molecules in the biomimetic collagen solution for skin surface is greater than or equal to 0.001 wt.% but less than or equal to 0.01 wt.%.
  • biomimetic collagen solution for a skin surface
  • the biomimetic collagen solution being the biomimetic collagen solution for a skin surface according to any one of the preceding embodiments. prepared by the method of preparation.
  • the biomimetic collagen solution is applied to the skin surface by one or more combinations of self-smearing, spraying, and immersion. .
  • the embodiments of the present invention are proposed solutions from the perspective of bionics for the problem that collagen molecules are difficult to absorb through the skin.
  • the embodiments of the present invention are mainly optimized as follows: (1) According to the type of collagen molecules contained in the skin tissue, Select type I, type III or type V collagen, prepare collagen solution according to the content of different types of collagen in the skin tissue, and match the composition of the solution with the skin tissue as much as possible; (2) According to the composition and content of ions in the body fluid and the pH environment , adding simulated body fluid components to the solution, by regulating the ionic components and ionic strength, and further regulating the pH value, so that the collagen solution matches the microenvironment of the skin tissue; (3) Compared with the conventional method, the collagen molecule is directly combined with the skin tissue.
  • the method for realizing the absorption of collagen molecules adds connecting molecule components in the collagen solution, and the connecting molecules can react with the collagen molecules in the collagen solution and the collagen components in the skin tissue at the same time, thereby combining the collagen molecules in the skin tissue,
  • the high-efficiency reaction of linking molecules can improve the absorption rate of collagen molecules in skin tissue.
  • the storage time of the collagen solution after adding the linking molecule is greater than or equal to 0 min but less than or equal to 60 min, so as not to affect its use effect.
  • the concentration of the collagen solution is greater than or equal to 0.0001 wt.% but less than or equal to 0.1 wt.%.
  • the choice of low-concentration collagen solution is conducive to the flow transmission of collagen molecules and the absorption of collagen molecules in skin tissue.
  • the solution environment in the biomimetic collagen solution of the present invention is closer to the microenvironment of the skin tissue, and its biocompatibility is better than that of the conventional collagen solution, which is more conducive to the absorption of collagen molecules into the skin tissue (especially in the dermis);
  • the role of molecules in skin tissue can delay the degradation of collagen molecules, exert its biological activity, and promote skin tissue repair and regeneration.
  • FIG. 1 is a graph showing the effect of subcutaneous absorption of collagen molecules labeled by fluorescein isothiocyanate (FITC) fluorescent staining in a biomimetic collagen solution according to an embodiment of the present invention
  • FIG. 1A is a sample of Example 1
  • FIG. 1B is a sample of Example 2
  • Figure 1C is a sample of Example 3
  • Figure 1D is a sample of Example 4
  • Figure 1E is a sample of Comparative Example 1
  • Figure 1F is a sample of Comparative Example 2
  • FIG. 2 is an effect diagram of live/dead cell staining in a biomimetic collagen solution according to an embodiment of the present invention
  • FIG. 2A is the sample of Example 1
  • FIG. 2B is the sample of Example 2
  • FIG. 2C is the sample of Example 3
  • FIG. 2D It is a sample of Example 4
  • Figure 2E is a sample of Comparative Example 1
  • Figure 2F is a sample of Comparative Example 2);
  • FIG. 3 is an effect diagram of HE staining (hematoxylin-eosin staining) of biomimetic collagen solution implanted in rats according to an embodiment of the present invention
  • FIG. 3A is the sample of Example 1
  • FIG. 3B is the sample of Example 2
  • Figure 3C is a sample of Example 3
  • Figure 3D is a sample of Example 4
  • Figure 3E is a sample of Comparative Example 1
  • Figure 3F is a sample of Comparative Example 2
  • a preparation method for a biomimetic collagen solution on a skin surface wherein, the steps are sequentially included:
  • the pH value of the collagen solution obtained in step (2) was adjusted to 7.2 by 0.01M NaOH solution or 0.01M acetic acid solution to form a homogeneous solution;
  • a method of using a biomimetic collagen solution for skin surface the biomimetic collagen solution is prepared according to the above preparation method, and the using method includes: 10 minutes (min) after the biomimetic collagen solution is prepared, evenly smearing it On the pre-repaired skin surface, the skin surface was washed after 2 hours (h).
  • a preparation method for a biomimetic collagen solution on a skin surface wherein, the steps are sequentially included:
  • step (3) at 2°C, adjust the pH value of the collagen solution obtained in step (2) to 10 by 0.2M KOH solution or 0.1M ammonia solution to form a homogeneous solution;
  • a method of using a biomimetic collagen solution for skin surface the biomimetic collagen solution is prepared according to the above preparation method, and the using method includes: after the biomimetic collagen solution is prepared for 60 minutes, uniformly spraying it on pre-repaired skin surface, and the skin surface was washed after 1 h.
  • a preparation method for a biomimetic collagen solution on a skin surface wherein, the steps are sequentially included:
  • the pH value of the collagen solution obtained in step (2) is adjusted to 4 by 1M formic acid solution or 0.2M phosphoric acid solution to form a homogeneous solution;
  • a method for using a biomimetic collagen solution for skin surface the biomimetic collagen solution is prepared according to the above preparation method, and the using method comprises: immersing the pre-repaired skin surface in the solution 0 min after the biomimetic collagen solution is prepared , the skin surface was washed after 3 h.
  • a method for preparing a biomimetic collagen solution on a skin surface comprising the steps of:
  • the pH value of the collagen solution obtained in step (2) is adjusted to 6 by 0.01M pyridine solution or 2M tartaric acid solution to form a homogeneous solution;
  • a method for using a biomimetic collagen solution for skin surface the biomimetic collagen solution is prepared according to the above-mentioned preparation method, and the using method comprises: after preparing the biomimetic collagen solution for 30 minutes, spraying it evenly and then smearing it on The skin surface was pre-repaired, and the skin surface was washed after 2 hours.
  • Comparative Example 1 a preparation method for a collagen solution on the skin surface and a method for using the same, comprising the following steps in turn:
  • the collagen solution is applied to the skin surface by spraying.
  • Comparative Example 2 a preparation method for a collagen solution on the skin surface and a method for using the same, wherein the following steps are included in sequence:
  • the collagen solution is applied to the surface of the skin by smearing.
  • Collagen solutions were prepared according to the preparation methods in Examples 1-4 and Comparative Examples 1-2, and 1 mL and 6 ⁇ 10 5 rat skin fibroblasts were taken respectively (Shanghai Cell Bank, Chinese Academy of Sciences)
  • the cells were mixed to form collagen hydrogel-encapsulated cells at 37°C for three-dimensional culture experiments.
  • the medium was high glucose DMEM (HyClone) medium containing 10% (v/v%) fetal bovine serum, 1% streptomycin and penicillin, and the medium was changed once a day.
  • the temperature of the incubator (STERI 371, Thermo Electron Corporation) was set at 37°C and humidified air containing 5% (v/v%) CO 2 .
  • the cells in the hydrogel were stained with live/dead cells, and the staining solution was 2mmol/L calcein-AM (calcein acetoxymethyl ester solution, Sigma) (used to stain live cells and emit green fluorescence) ) and 2 mmol/L EthD-1 solution (ethidium bromide dimer 1, Sigma) (used to stain dead cells, emit red fluorescence), observe the samples on A1 confocal microscope (Nikon), green excitation light The wavelength is 488 nm, and the wavelength of the red excitation light is 562 nm. Live/dead cell staining in collagen hydrogels is shown in Figure 2.
  • the binding effect test shows that, compared with Comparative Example 1-2, the collagen solution in Comparative Example 1-2 is a strongly acidic solution, which is not conducive to the use of the collagen solution on the skin surface;
  • the solution is neutral and can be adjusted according to different skins, which is more suitable for the microenvironment of the skin surface;
  • Examples 1-4 add ionic components similar to those of body fluids, so that the ionic strength and permeability of the collagen solution are comparable to those of the skin.
  • the microenvironment is closer, which is conducive to the transmission of collagen molecules; in Examples 1-4, connecting molecules are added, which can realize the combination of collagen molecules and collagen components in the dermis during the process of collagen molecules entering the dermis, which is beneficial to the collagen molecules in the solution.
  • Layer enrichment and absorption; collagen solutions in Examples 1-4 are more favorable for cell growth and fusion with in vivo tissues.

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PCT/CN2021/125186 2020-10-26 2021-10-21 用于皮肤表面的仿生胶原溶液的制备方法和使用方法 WO2022089287A1 (zh)

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CN112402289A (zh) * 2020-10-26 2021-02-26 杜明春 一种用于皮肤表面的仿生胶原溶液及其制备方法和使用方法
CN112354013B (zh) * 2020-10-26 2022-10-18 杜明春 一种仿生胶原水溶液及其制备方法和使用方法
CN115845134A (zh) * 2022-12-26 2023-03-28 深圳钧兴生物科技有限公司 一种可注射胶原材料及其制备方法

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