CN111420023A - Compound containing type I collagen and hyaluronic acid, preparation and use thereof - Google Patents
Compound containing type I collagen and hyaluronic acid, preparation and use thereof Download PDFInfo
- Publication number
- CN111420023A CN111420023A CN202010362763.6A CN202010362763A CN111420023A CN 111420023 A CN111420023 A CN 111420023A CN 202010362763 A CN202010362763 A CN 202010362763A CN 111420023 A CN111420023 A CN 111420023A
- Authority
- CN
- China
- Prior art keywords
- collagen
- concentration
- type
- hyaluronic acid
- complex
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Abstract
The invention provides a compound containing type I collagen and hyaluronic acid, which is characterized by comprising the type I collagen, the hyaluronic acid and a balancing substance; wherein the balance substance comprises NaH2PO4‑Na2HPO4A system, a Tris-HCl system, a Tris-maleic acid system or a HEPES system, and comprising NaCl and/or KCl; the pH of the complex is 6-8, and the concentration of NaCl and/or KCl is 0.2-0.9 wt%. The invention also provides a preparation method of the compound. In the physiological pH value range of the compound, the type I collagen and the hyaluronic acid can be mutually dissolved in a wider range of proportion, and the compound has a stable system and can not generate precipitation or denaturation for a long time; and the osmotic pressure and the tension of the compound are both suitable for physiological systems. The compound provided by the invention can effectively promote epidermal cells to secrete collagen fibers, inhibit inflammation and effectively promote skin tissue repair. The preparation method of the compound containing the type I collagen and the hyaluronic acid is simple, low in cost and easy for large-scale production.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to a compound containing type I collagen and hyaluronic acid, a preparation method of the compound, application of the compound in preparing a medicament for repairing skin injury, or a cosmetic for repairing skin injury.
Background
Skin damage is the loss and loss of structure and function of skin tissue caused by multiple factors, both internal and external. Skin lesions can be divided into mild lesions and severe lesions. In general, minor injuries heal themselves, but heavier injuries do not work well by themselves.
The metabolic balance of cells is the basis of skin tissue remodeling and repair, and the exogenous addition of the active monomer can improve the microenvironment of damaged skin tissues and promote the anabolism of nutrients required by the metabolism of the skin tissues, and is very important for accelerating the skin regeneration and repair process.
Collagen and Hyaluronic Acid (HA) are the most important cell-secreting matrix components in skin tissue. Collagen in natural skin tissue forms a fiber network, hyaluronic acid is inlaid and integrated into a tissue structure and endowed with physiological functions, biological effects are cooperatively exerted, and cell migration, differentiation and proliferation metabolic activities are promoted. The collagen, hyaluronic acid and other important extracellular matrix components are optimized and recombined through physicochemical properties, so that the collagen/hyaluronic acid composite is very suitable for skin repair and regeneration under a microenvironment required by local healing of the skin.
HA exists in vivo in its acid form, whereas existing extraction methods are generally obtained in the form of its salts due to process limitations; collagen and HA in a salt form are oppositely charged, and are easy to form polymers in a liquid state to generate precipitates, so that the research and the application of the collagen-HA bionic composite repair material are greatly limited. In order to expand the application of the collagen-HA bionic composite repair material, the method reported in the prior patent literature comprises the steps of designing and using the collagen-HA bionic composite repair material in a separated mode (201310099817.4); the two are dissolved and mixed by physical or chemical methods, such as removing sodium salt in HA by electrochemical treatment (200910041033.X), but the process is more complicated; the modified thinning HA and the collagen are self-crosslinked to form a hydrogel three-dimensional scaffold (201711462799.6), and the functional activity of the collagen is influenced after the modification.
Further, the isoelectric point of collagen is about ph7.4, and collagen is unstable and easily precipitated when the solution is near neutral. However, the neutral environment is the pH most suitable for metabolism in the cell.
Disclosure of Invention
Aiming at the main problems in the prior art, the invention provides a compound for dissolving type I collagen and hyaluronic acid and maintaining the activity of the collagen and the hyaluronic acid, and the compound is simple to prepare, low in cost and stable in system.
Accordingly, in one aspect, the present invention provides a complex comprising type I collagen and hyaluronic acid, wherein the complex comprises type I collagen, hyaluronic acid and a balancing substance; wherein the balancing substance comprises NaH2PO4-Na2HPO4A system, a Tris-HCl system, a Tris-maleic acid system or a HEPES system, andincluding NaCl and/or KCl; the pH of the complex is 6-8.
In another aspect, the invention provides the use of the complex in the manufacture of a medicament for the repair of skin damage; or a cosmetic for repairing skin damage using the complex.
In another aspect, the present invention provides a method for preparing a complex comprising type I collagen and hyaluronic acid, wherein the method comprises the steps of:
a. preparing a balance substance: adding NaH to water2PO4-Na2HPO4Substances of the system, substances of the Tris-HCl system, substances of the Tris-maleic acid system or substances of the HEPES system, and NaCl and/or KCl;
b. adding type I collagen and hyaluronic acid to the balance solution to obtain a complex containing type I collagen and hyaluronic acid, wherein the pH of the complex is 6-8.
The compound containing the type I collagen and the hyaluronic acid provided by the invention has the advantages that the type I collagen and the hyaluronic acid can be mutually dissolved in any proportion within the range of physiological pH value, the system is stable, and no precipitate can be generated after long-time placement; also in a preferred manner, the osmotic pressure and tonicity of the complex are both adapted to the physiological system.
The compound containing the type I collagen and the HA, provided by the invention, can effectively promote epidermal cells to secrete collagen fibers and matrixes, inhibit inflammation allergy and resist aging of active ingredients, regulate and control the metabolic activity of cells, and can effectively promote skin tissue repair and restore blood circulation.
The preparation method of the compound containing the type I collagen and the hyaluronic acid is very simple, low in cost and easy for large-scale production.
Drawings
FIG. 1: SDS-PAGE electrophoretograms of the type I collagen prepared in example 1 and type I collagen supplied by Sigma;
FIG. 2: characteristic absorption peaks of type i collagen prepared in example 1;
FIG. 3A: characteristic absorption peak of the mixed solution prepared in comparative example 1; FIG. 3B: characteristic absorption peak of gel liquid prepared in example 2;
FIG. 4A: characteristic absorption peak of the mixed solution prepared in comparative example 2; FIG. 4B: characteristic absorption peak of gel liquid prepared in example 3;
FIG. 5A: characteristic absorption peak of the mixed solution prepared in comparative example 3; FIG. 5B: characteristic absorption peak of gel liquid prepared in example 4;
FIG. 6A is a diagram showing the mRNA expression of Col1- α 1 in a control group, a group added with CI and HA, and a group added with CI, HA and SAC, FIG. 6B is a diagram showing the mRNA expression of Col17- α 1 in a control group, a group added with CI and HA, and a group added with CI, HA and SAC, FIG. 6C is a diagram showing the mRNA expression of iNOS in a control group, a group added with CI and HA, and a group added with CI, HA and SAC, FIG. 6D is a diagram showing the mRNA expression of L IF in a control group, a group added with CI and HA, and a group added with CI, HA and SAC, and FIG. 6E is a diagram showing the mRNA expression of MMP-1 in a control group, a group added with CI and HA, and a group added with CI;
fig. 7A is a view of the condition of the face after laser treatment of acne before treatment with a human-like collagen repair dressing; FIG. 7B is a view of the face at 2.5 days after application of the human-like collagen repair dressing; FIG. 7C is a view showing the condition of the face at 0.5 day after application of the gel liquid of the present invention; FIG. 7D is a view showing the condition of the face 1.5 days after applying the gel liquid of the present invention; FIG. 7E shows the condition of the face after applying the gel liquid of the present invention for 2.5 days;
FIG. 8A shows acne conditions prior to use of the gel of the present invention; FIG. 8B shows acne conditions at 2.5 days using gel solutions of the present invention;
FIG. 9A shows the scar before application of the gel of the present invention; FIG. 9B shows the state of scars at 2 weeks of application of the gel solution of the present invention.
Detailed Description
The invention provides a compound containing type I collagen and hyaluronic acid, which is characterized by comprising the type I collagen, the hyaluronic acid and a balancing substance; wherein the balancing substance comprises NaH2PO4-Na2HPO4A system, a Tris-HCl system, a Tris-maleic acid system or a HEPES system, and comprising NaCl and/or KCl; the pH of the complex is 6-8.
To obtain isotonicity, the concentration of NaCl and/or KCl is preferably 0.2-0.9% by weight.
In the complex provided by the present invention, the type I collagen and the hyaluronic acid are mutually soluble in a wide range of proportions, and therefore, the weight proportion thereof is not particularly limited.
In order to more closely approximate the composition of type I collagen and hyaluronic acid in cartilage tissue, preferably, the weight ratio of type I collagen to hyaluronic acid is 1-20: 10-1; more preferably 1 to 5: 5-1.
The concentration of type I collagen and hyaluronic acid is not particularly limited, but in order to effectively supplement type I collagen and hyaluronic acid, preferably, the concentration of type I collagen is 0.5 to 8mg/ml, preferably 1 to 5 mg/ml; the concentration of hyaluronic acid is 0.1-8mg/ml, more preferably 0.5-5 mg/ml.
In order to provide a complex that more closely approximates a physiological system, in a preferred embodiment of the invention, the balancing substance comprises NaH2PO4-Na2HPO4System and NaCl; wherein, in the complex, NaH2PO4In a concentration of 0.04-0.7 wt% and Na2HPO4The concentration of (A) is 0.1-0.9 wt%, and the concentration of NaCl is 0.3-0.8 wt%; preferably, NaH2PO4Has a concentration of 0.08-0.64 wt% NaH2PO4The concentration of (A) is 0.2-0.8 wt%, and the concentration of NaCl is 0.4-0.5 wt%.
In order to further improve the stability of the compound containing the type I collagen and the hyaluronic acid, the balancing substance further contains one or more of glucose, 1, 3-propanediol and Tween 80.
In a preferred embodiment, the balancing substance comprises glucose, 1,3 propanediol and tween 80; preferably, the concentration of glucose is 0.1-10 wt%, preferably 1-5 wt%; the concentration of the 1, 3-propanediol is 0.5-3 wt%, preferably 0.5-2 wt%; the concentration of tween 80 is 0.1 to 1 wt.%, preferably 0.1 to 0.5 wt.%.
The inventor finds that in the compound containing the type I collagen and the hyaluronic acid, the balancing substance not only can provide the pH value under the physiological environment, but also HAs the functions of solubilization and dissolution assistance, and is beneficial to enabling the type I collagen and the HA to be mutually soluble in any proportion; meanwhile, the isotonic and osmotic pressure of liquid can be effectively maintained, and the method is very suitable for the direct application of a physiological system.
In order to further improve the repair effect of the skin, the inventor of the present application has studied a large number of traditional Chinese medicine components, and has unexpectedly found that when the salvia miltiorrhiza bunge extract is added to the compound containing the type I collagen and the hyaluronic acid, the compound can protect and improve the growth microenvironment of chondrocytes, has multiple regulation effects of stimulating the physiological metabolic secretion activity of cells, regulating and controlling the activity of signal pathways, promoting the regeneration of epidermal cells, inhibiting the expression of cell apoptosis key factor iNOS caused by activating and damaging inflammatory genes, inhibiting the expression of interleukin L IF gene participating in mediating inflammatory response and stimulating the synthesis of acute inflammatory protein, and the like, thereby further improving the repair effect and simultaneously effectively improving inflammation and allergic response.
Therefore, the compound containing the type I collagen and the hyaluronic acid also contains the salvia miltiorrhiza extract.
In order to further improve the repairing effect, the content of the active ingredients in the salvia miltiorrhiza bunge extract is 50-99 wt%, preferably 60-90 wt%.
In order to further improve the healing effect, the concentration of the active ingredient is 3-200. mu.g/ml, preferably 7-100. mu.g/ml, more preferably 10-50. mu.g/ml.
In order to further maintain the activity of the effective components of the salvia miltiorrhiza and make the medicine slowly release, the salvia miltiorrhiza extract exists in the compound in the form of microcapsules. The microcapsule can be prepared by the prior art, preferably, the microcapsule is prepared by coating water-soluble materials such as chitosan, gelatin, alginate and methylcellulose as capsule wall materials, wherein the capsule core is Saviae Miltiorrhizae radix extract. The microcapsule can overcome the problem that water-soluble effective components of Saviae Miltiorrhizae radix are easy to absorb moisture and have reduced activity, and has sustained release effect.
Preferably, the salvia miltiorrhiza extract is a water-soluble extract.
Preferably, the compound also contains gel matrix auxiliary materials; preferably, the gel base adjuvant is present at a concentration of 0.1 to 3% by weight. The gel base includes, but is not limited to, one or more of cellulose derivatives, carbomers, alginates, tragacanth and gelatin.
The compound provided by the invention can be used for preparing a medicine for repairing skin injury; or a cosmetic for repairing skin damage using the complex.
The skin lesions include: trauma from various external factors: for example, skin damage caused by burns, scalds, frostbites, sunburn, cuts, and the like; pressure sores, e.g., bedsores, protective article pressure injuries; scars; skin allergies, e.g., seasonal skin allergies; red and swollen; acne; flushing; the laser treats the red swelling and inflammation after the operation.
The invention also provides a drug compound for repairing damaged skin, which comprises the compound containing the type I collagen and the hyaluronic acid. The pharmaceutical composition may also include other components, such as antibiotics, as the case requires. The pharmaceutical complex may also include a pharmaceutically acceptable carrier.
The pharmaceutically acceptable carrier may be, for example, a filler, a fragrance, a flavoring agent, a coloring agent, a wetting agent, an excipient, a surfactant.
The pharmaceutical compositions provided by the present invention may be prepared according to methods known in the art and formulated into any dosage form suitable for human or animal use.
The content of the collagen I-and hyaluronic acid-containing complex provided by the present invention in the pharmaceutical complex is usually 0.1-95 wt%, or may be adjusted by those skilled in the art according to different applications.
In the drug compound provided by the invention, the drug compound can be a gel, a dressing (for example, a non-woven fabric or a dressing pad is used as a support) and the like.
The invention also provides the application of the drug compound as an injection or as a tissue engineering implant material. The invention also provides a cosmetic for repairing damaged skin, which can be facial cleanser, cream, emulsion, facial mask (which can be a facial mask containing non-woven fabrics or cotton fibers or a facial mask without non-woven fabrics), an application material and the like.
The content of the collagen type I and hyaluronic acid-containing complex provided by the present invention in the cosmetic is usually 0.1 to 95% by weight, or may be adjusted accordingly by those skilled in the art according to various applications.
The present invention also provides a method for preparing a complex comprising type I collagen and hyaluronic acid, wherein the method comprises the steps of:
a. preparing a balance substance: adding NaH to water2PO4-Na2HPO4Substances of the system, substances of the Tris-HCl system, substances of the Tris-maleic acid system or substances of the HEPES system, and NaCl and/or KCl;
b. adding type I collagen and hyaluronic acid to the balance solution to obtain a complex containing type I collagen and hyaluronic acid, wherein the pH of the complex is 6-8;
in a preferred embodiment, the concentration of NaCl and/or KCl is 0.2-0.9% by weight.
In a preferred embodiment, the weight ratio of type I collagen to hyaluronic acid in the prepared complex containing type I collagen and hyaluronic acid is not particularly limited, and is preferably 1 to 10: 10-1; more preferably 1 to 5: 5-1.
In a preferred embodiment, the concentration of type I collagen in the prepared complex comprising type I collagen and hyaluronic acid is 0.5-8mg/ml, preferably 1-5 mg/ml; the concentration of hyaluronic acid is 0.1-8mg/ml, preferably 0.5-5 mg/ml.
In a preferred embodiment of the invention, the balancing substance comprises NaH2PO4-Na2HPO4System and NaCl; and in the prepared compound containing type I collagen and hyaluronic acid, NaH2PO4In a concentration of 0.04-0.7 wt% and Na2HPO4The concentration of (A) is 0.1-0.9 wt%, and the concentration of NaCl is 0.3-0.8 wt%; preferably, NaH2PO4In a concentration of 0.08-0.5 wt%, NaH2PO4The concentration of (A) is 0.3-0.8 wt%, and the concentration of NaCl is 0.4-0.5 wt%.
In a preferred embodiment of the present invention, the balancing substance further comprises one or more of glucose, 1, 3-propanediol and tween 80.
In a preferred embodiment, in the prepared complex comprising type I collagen and hyaluronic acid, the balancing substance comprises glucose, 1, 3-propanediol and tween 80; preferably, the concentration of glucose is 0.1-10 wt%, preferably 1-5 wt%; the concentration of the 1, 3-propanediol is 0.5-3mg/ml, preferably 0.5-2 mg/ml; the concentration of the Tween 80 is 0.1-1mg/ml, preferably 0.1-0.5 mg/ml.
In a preferred embodiment, the method for preparing a complex containing type I collagen and hyaluronic acid according to the present invention further comprises adding the microcapsule encapsulating the salvia miltiorrhiza extract to the complex containing type I collagen and hyaluronic acid obtained in step b.
The microcapsules can be prepared by techniques known in the art, preferably by spray drying; chitosan is preferably used as the capsule wall material.
Both type I collagen and hyaluronic acid are commercially available.
Examples
Example 1: preparation of collagen and detection of physicochemical properties
Pretreatment: chopping tendon of cattle, cleaning, washing with normal saline, encapsulating, and processing with Co60And (6) sterilizing. The remaining steps are performed under sterile conditions.
Preparing high-purity type I collagen solution by adding appropriate amount of 0.5M acetic acid into beef tendon, adding pepsin (1 g pepsin is added into 20g beef tendon), performing enzymolysis at 6 deg.C for 24-48 hr, stopping enzymolysis with 15 mmol/L EDTA, centrifuging, and collecting supernatant as type I collagen solution, which is performed at 4 deg.C.
And (3) purification: adding collagen solution and 10% NaCl according to the volume of 1:1 for salting out, and standing overnight. And centrifuging to obtain a precipitate, dissolving the precipitate with 0.5M acetic acid, and dialyzing the solution in deionized water to pH 5 to obtain a high-purity type I collagen solution (not less than 10 mg/ml).
Standard control product SigmaI collagen product C9301, weighing 0.6mg, adding 0.5M acetic acid 120 μ L, shaking slowly to dissolve, making into 5mg/ml solution, and adding 10 μ L into the balance solution.
The quality detection of I-type collagen (refer to the method for detecting hybrid protein in appendix B of YY0954-2015 standard in Chinese medical industry). A Tris-glycine discontinuous separation system is adopted to prepare 6% separation gel and 5% concentrated gel, 10mg/ml of I-type collagen solution and 10. mu.l of Sigma standard control solution are taken, 10. mu.l of each I-type collagen solution and 10. mu.l of Sigma standard control solution are added into 90. mu. L double distilled water for dilution, 2X L oaddingbuffer is added in proportion for mixing, boiling water bath is carried out for 10min, 12000Xg and 5min of collagen are centrifuged to take supernatant fluid 15. mu. L for SDS-PAGE electrophoresis, the conditions are 60V, 20min, 120V and 1h 25min (instrument model: Bio-Rad and PowerPac Universal), the gel is dyed by using Coomassie brilliant blue R-250 dyeing solution, and scanning gel imaging (Umax, Power L ook and 2100X L-USB) is carried out to obtain high-purity characteristic I, wherein the left of a molecular weight standard substance, the left channel is prepared I of the above mentioned collagen, and the right channel is I.
A2 mu L sample is taken and scanned by an ultramicro nucleic acid protein detector (Nanodrop 2000), the wavelength is 200nm-800nm, the readings of the characteristic peaks 217 and 230nm of collagen are 1.592 and 1.397 respectively (shown in figure 2), and the characteristic requirements of the type I collagen are met.
Type I collagen prepared in example 1 was used and subsequent experiments were performed.
Example 2: preparation of a Complex of the present application (pH 6)
a. Preparation of the balance (90 ml): adding NaH into deionized water2PO40.643g，Na2HPO40.189 g; NaCl 0.47g, glucose 0.1g, 1,3 propylene glycol 0.5ml, Tween 800.1 ml.
b. 10mg/ml type I collagen liquid is measured and 10ml is obtained.
HA 800mg dissolved in 40ml of the equilibrium material formulated in a, HA concentration 20 mg/ml.
d. Mixing steps a, b, c to obtain 100ml of a complex containing type I collagen and HA, pH 6, NaH of the complex2PO4Is about 0.643 wt%, Na2HPO4The concentration of (A) is about 0.189% by weight, the concentration of NaCl is about 0.47% by weight, the concentration of glucose is about 0.1% by weight, the concentration of 1, 3-propanediol is 0.5ml/ml, the concentration of Tween-80 is 0.1ml/ml, the concentration of type I collagen isThe degree was 1mg/ml and the HA concentration was 8 mg/ml.
Example 3: preparation of complexes of the present application (pH 7)
a. Preparation of the balance (70ml) material: adding NaH into deionized water2PO40.322g，Na2HPO40.566g, NaCl 0.45g, glucose 2g, 1,3 propanediol 1.5ml, Tween 800.5 ml.
b. 30ml of 10mg/ml type I collagen solution is measured.
HA 200mg dissolved in 20ml of the equilibrium material formulated in a, HA concentration 10 mg/ml.
d. Mixing the steps a, b and c to obtain 100ml of a complex containing type I collagen and hyaluronic acid, the pH of the complex being 7, NaH2PO4Is about 0.322 wt%; na (Na)2HPO4About 0.566 wt%, NaCl about 0.44 wt%, glucose about 5 wt%, 1, 3-propanediol about 1.5ml/ml, Tween-80 about 0.5ml/ml, hyaluronic acid about 2mg/ml, and type I collagen about 3 mg/ml.
Example 4: preparation of complexes of the present application (pH8)
a. Preparation of the balance (20 ml): adding NaH into deionized water2PO4The concentration of (A) is 0.04 g; na (Na)2HPO40.897 g; NaCl 0.42g, glucose 4g, 1,3 propylene glycol 3ml, Tween 800.98 ml.
b. 80ml of I type collagen solution with the concentration of 10mg/ml is measured.
HA 50mg dissolved in 5ml of the equilibrium material formulated in a, HA concentration 10 mg/ml.
d. Mixing the steps a, b and c to obtain 100ml of a complex containing type I collagen and hyaluronic acid, the pH of the complex being 8, NaH2PO4Is about 0.04 wt%; na (Na)2HPO4Is about 0.897 wt%; NaCl concentration of about 0.42 wt%, glucose concentration of about 4 wt%, 1,3 propylene glycol concentration of 3ml/ml, Tween 80 concentration of 0.98ml/ml, hyaluronic acid concentration of 0.5mg/ml, type I collagen concentration of 8 mg/ml.
Comparative example 1: preparing a mixture of low concentration collagen and HA
A collagen type I solution was prepared in a concentration of 2mg/ml by the method of example 1.
HA solution was prepared in PBS at 16mg/ml, pH 6.
Mixing the solutions prepared in the steps a and b in a ratio of 1:1, namely mixing the hyaluronic acid with the final concentration of 8
mg/ml and 1mg/ml of type I collagen were added to obtain a mixture (with precipitate formed) containing type I collagen and hyaluronic acid, and the pH of the mixture was 6.
Comparative example 2: preparing mixed solution of collagen and HA with medium concentration
A high concentration type I collagen solution was prepared at a concentration of 6mg/ml by the method of example 1.
HA solution was prepared in PBS at a concentration of 4 mg/ml.
And (c) mixing the solutions prepared in the steps (a) and (b) in a ratio of 1:1, namely adding the mixed solution according to the conditions that the final concentration of the hyaluronic acid is 2mg/ml and the concentration of the type I collagen is 3mg/ml to obtain a mixed solution (with precipitate generation) containing the type I collagen and the hyaluronic acid, wherein the pH of the mixed solution is 7.
Comparative example 3: preparation of high concentration of collagen and HA mixture (pH8)
A high concentration type I collagen solution was prepared in the same manner as in example 1 at a concentration of 16 mg/ml.
HA solution was prepared in PBS at a concentration of 1 mg/ml.
And (c) mixing the solutions prepared in the steps (a) and (b) in a ratio of 1:1, namely adding the mixed solution according to the final concentration of 0.5mg/ml of hyaluronic acid and the concentration of 8mg/ml of type I collagen to obtain a mixed solution (with precipitate generation) containing the type I collagen and the hyaluronic acid, wherein the pH of the mixed solution is 8.
Physical property test 1: detection of type I collagen Stable compatibility with HA (pH 6)
The compound prepared in example 2 and the low concentration mixed solution prepared in comparative example 1 were centrifuged at 12000Xg at 4 ℃ for 10min, and the supernatant was aspirated for further use. Respectively taking 2 mul of samples for detection, continuously scanning by using an ultramicro nucleic acid protein detector (Nanodrop 2000) with the wavelength of 200nm-800nm, reading the characteristic peak 230nm of the type I collagen, and finding out that the characteristic peak in the supernatant of the mixed solution basically disappears at 230 nm; the characteristic peaks of the composite gel liquid before and after centrifugation have no significant change (figure 3).
The hydroxyproline method is used for measuring the collagen concentration (refer to the collagen detection method in the appendix A of the Chinese medical industry standard YY 0954-2015): the operation is carried out according to the specification of Nanjing kit for detecting constructed hydroxyproline (A030-2-1). Sucking 0.25ml of centrifugal supernatant of the two samples processed in the step a, adding 0.5ml of hydrolysate in the kit, uniformly mixing, and hydrolyzing in a boiling water bath for 20 min; the pH was adjusted to 65, the supernatant was centrifuged according to the procedure, absorbance was measured at a wavelength of 550nm, and the absorbance was compared with a standard to calculate the type I collagen content (Table 1).
The method for determining the content of the sodium hyaluronate by the glucuronic acid method (refer to the method in the appendix A of the YY0308-2004 standard of the Chinese medical industry): and (b) sucking 200 mu l of each of the centrifugal supernatant and the glucuronic acid standard solution of the two samples treated in the step a, putting the centrifugal supernatant and the glucuronic acid standard solution in an ice water bath, slowly adding 1ml of precooled 0.025M sodium tetraborate sulfuric acid, shaking up, boiling in a boiling water bath for 20min, taking out, cooling to room temperature, adding 40 mu l of precooled 0.1% carbazole ethanol solution, fully shaking up, and placing at room temperature for 2 h. The absorbance of each standard tube and sample tube at 550nm was measured with a spectrophotometer. The content of glucuronic acid in the sample tube is calculated by using a standard curve, and the mass concentration of sodium hyaluronate in the sample is converted according to a formula (table 1).
The results of the concentration measurement of collagen and HA show that the HA and collagen concentration are obviously reduced after the mixed solution group is centrifuged compared with that before the mixed solution group is centrifuged; but the HA and collagen concentrations of the compound prepared in seawater 2 have no significant difference before and after centrifugation, which shows that the balancing substance of the invention HAs good stability and the function of promoting intermiscibility.
TABLE 1 detection analysis of pH 6 Low concentration type I collagen and HA Stable compatibility test protein
Note: significant differences
Physical property test 2: detection of type I collagen Stable compatibility with HA (pH 7)
The compound prepared in example 3 and the medium-concentration mixed solution prepared in comparative example 2 were centrifuged at 12000Xg at 4 ℃ for 10min, and the supernatant was aspirated for use. Respectively taking 2 mul of samples for detection, continuously scanning by using an ultramicro nucleic acid protein detector (Nanodrop 2000) with the wavelength of 200nm-800nm, reading the characteristic peak 230nm of the type I collagen, and finding that the characteristic peak 230nm in the supernatant of the mixed solution basically disappears; while the characteristic peaks of the complexes of the invention did not change significantly before and after centrifugation (fig. 4).
The remaining steps are identical to those of b-d in performance test 1, and the results show that the balancing substance according to the invention (pH 7) has good stability and a phase-solubility-promoting effect (Table 2).
TABLE 2 detection analysis of collagen type I at moderate concentration in pH7 and HA Stable compatibility test protein
Note: significant differences
Physical property test 3: detection of type I collagen Stable compatibility with HA (pH8)
The compound prepared in example 4 and the high concentration mixed solution prepared in comparative example 3 were centrifuged at 12000Xg at 4 ℃ for 10min, and the supernatant was aspirated for use. Respectively taking 2 mul of samples for detection, continuously scanning by using an ultramicro nucleic acid protein detector (Nanodrop 2000) with the wavelength of 200nm-800nm, reading the characteristic peak 230nm of the type I collagen, and finding that the characteristic peak 230nm in the supernatant of the mixed solution basically disappears; while the characteristic peaks of the complexes of the invention did not change significantly before and after centrifugation (fig. 5).
The remaining steps are identical to those of b-d in performance test 1, and the results show that the balancing substance according to the invention (pH8) has good stability and a phase-solubility-promoting effect (Table 3).
TABLE 3 detection analysis of pH8 high concentration type I collagen and HA Stable compatibility test protein
Note: significant differences
Physical property test 4: detection of storage stability of type I collagen and HA complex
After the compound (pH 7) of the type I collagen and the HA prepared in the performance test 2 is stored for 12 weeks, the concentration of the collagen is determined by a hydroxyproline method, and the content of the sodium hyaluronate is determined by a glucuronic acid method, so that the content and the pH of the type I collagen and the HA are not changed after the compound is placed for 12 weeks, and the balance substance HAs good stability.
TABLE 4 pH7 collagen type I and HA gel liquid storage 12 weeks stability experiment
And (5) performance test: effect of complexes of the invention on epidermal cell phenotype
Type I collagen coated plates: the type I collagen complex (pH 7) prepared in example 3 was added to a 24-well plate in an amount of 0.3ml per well, and dried in an incubator at 37 ℃ for 2 days to form a film. DMEM-F12 medium (1 ml) was added just before use to balance for use.
Epidermal cell (human keratinocytes, Hacat cell line) phenotype regulation experiment:
the experimental components are as follows: three groups of untreated control group, collagen type I (CI) + HA treated group, and collagen type I (CI) + HA + Salvia miltiorrhiza extract (Salvia miltiorrhiza active components, SAC) treated group. The Hacat cells were seeded in 24-well plates, wherein the cells of type I Collagen (CI) + HA treated group, and type I Collagen (CI) + HA + SAC treated group were seeded in 24-well plates coated with the above type I collagen; the cell inoculation density is 3 ten thousand per well, MEM culture medium containing 10% serum and 1% double antibody is added, the Saviae Miltiorrhizae radix extract is dissolved with PBS, and the amount of salvianolic acid B effective concentration is preferably 20 μ g/ml; three samples were tested at 37 ℃ and 5% CO2Incubated under conditions for 24 hours.
The results of quantitative fluorescence qPCR detection, analysis and test of 5 genes respectively include Col1- α, Col17- α, iNOS, L IF and MMP-1, GAPDH detection is used as an internal reference gene for expression quantity difference analysis (FIG. 6) shows that ① expression of forward phenotype gene Col1- α 1 promoting cell proliferation and differentiation is remarkably up-regulated and different from a control group, wherein the group of type I Collagen (CI) + HA and type I Collagen (CI) + HA + SAC group shows that the expression of Col1- α is remarkably up-regulated and different from a control group, wherein the group of type I Collagen (CI) + HA + SAC shows that the group of type I) + HA and type I + SAC mediates adhesion of keratinocytes and basement membrane, and the group of intracellular and external connection, the gene Col17 for relieving skin aging as a bridge of intracellular and extracellular connections, the group and the group of type I (HA) + and HA) + HA are remarkably down-regulated, and the group I + HA + collagen (CI + HA + binding, and the expression of the intracellular and extracellular connection, and intracellular and extracellular connection, the expression of the gene interaction between the extracellular connection, the intracellular and skin aging-relieving collagen (SAC + collagen + HA + collagen + HA + collagen (CI + HA) shows that the intracellular connection, the.
The following experiments will examine the effects of the composition of the present invention containing type I collagen and hyaluronic acid on the improvement of redness, swelling, acne, scars, etc
The gels used in the following experiments were prepared by the following method: 99% by weight of the gel obtained in example 3 were mixed homogeneously with 1% by weight of hydroxymethylpropylcellulose.
Performance test 6:
enrollment subject cases (1 volunteer): acne is a patient whose face has symptoms of redness, swelling, inflammation and allergy on the day after the operation of laser treatment.
The experimental process comprises the following steps: on the evening of the day when acne is treated by laser, facial skin is cleaned by running water in a conventional method and is wiped dry. A proper amount of 'human-like collagen repair dressing' (Xian giant bio-gene technology, Inc.) is extruded and evenly smeared on the skin of an affected part once in the morning and at night, the use is carried out for 2.5 days, and a patient feels that the red removing and anti-inflammatory effects are not obvious, as shown in figures 7A and 7B. FIG. 7A front face condition with "human-like collagen repair dressing" applied; FIG. 7B is the facial condition 2.5 days after the "human-like collagen repair dressing" was applied;
the patient is then coated with the gel solution of the present invention in the same manner as the "human-like collagen repair dressing" is used. FIG. 7C shows the facial condition of the patient at 0.5 day using the gel solution of the present invention, and FIG. 7D shows the facial condition of the patient at 1.5 days using the gel solution of the present invention; FIG. 7D shows the condition of the face after 2.5 days using the gel solution of the present invention. The results show that: the gel liquid can obviously eliminate red swelling and inflammation after laser surgery.
Performance test 7:
enrollment subject cases (10 volunteers): adolescent acne, comedo, papule, pustule, and red swelling of the face.
The using method comprises the following steps: the facial skin is cleaned by running water and wiped dry by a conventional method. The gel liquid of the invention is evenly smeared on the skin of the affected part once in the morning and at night. Acne was significantly reduced after 1 day of use in all volunteers. After 2.5 days of use, the effect is very significant. FIG. 8A is a graph of acne condition in one of the patients prior to use of the gel solution of the present invention; FIG. 8B shows acne condition at 2.5 days using gel of the present invention.
Performance test 8:
case of selected observation object (1 name): the laser on the hand removes nevus, and hyperplastic scars are formed for 4 months after the operation.
The using method comprises the following steps: the cleaning solution washes hands and dries. The gel liquid of the invention is evenly smeared on the skin of the affected part 1 time a day. FIG. 9A shows the scar before application of the gel of the present invention; FIG. 9B shows the state of scars at 2 weeks of application of the gel solution of the present invention. The results show that: the gel liquid can obviously reduce scars, and the originally convex granulation tissues are changed into flat ones, so that the pigmentation is obviously reduced.
Performance test 9:
enrollment observations situation (20 volunteers): when the mask, goggles and other protective articles are worn for a long time, the face is damaged by pressure, or allergic manifestations such as red swelling, pimple or itching appear.
The using method comprises the following steps: before sleeping, the face skin is cleaned by running water and dried. The gel liquid of the invention is evenly applied to the skin of the affected part. The next morning, all volunteers had a clear disappearance of red, papular or itchy symptoms.
Claims (10)
1. A complex comprising type I collagen and hyaluronic acid, wherein the complex comprises type I collagen, hyaluronic acid and a balancing substance; wherein the balancing substance comprises NaH2PO4-Na2HPO4A system, a Tris-HCl system, a Tris-maleic acid system or a HEPES system, and comprising NaCl and/or KCl; the pH of the complex is 6-8; preferably, the concentration of NaCl and/or KCl is 0.2-0.9% by weight.
2. The compound of claim 1, wherein the weight ratio of type I collagen to hyaluronic acid is 1-20: 10-1; preferably, the concentration of the type I collagen is 0.5-8mg/ml, and the concentration of the hyaluronic acid is 0.1-8 mg/ml; more preferably, the concentration of the type I collagen is 1-5mg/ml and the concentration of the hyaluronic acid is 0.5-5 mg/ml.
3. The composite of claim 1, wherein the balancing substance comprises NaH2PO4-Na2HPO4System and NaCl; wherein, in the complex, NaH2PO4In a concentration of 0.04-0.7 wt% and Na2HPO4The concentration of (A) is 0.1-0.9 wt%, and the concentration of NaCl is 0.3-0.8 wt%; preferably, NaH2PO4Has a concentration of 0.08-0.64 wt% NaH2PO4The concentration of (A) is 0.2-0.8 wt%, and the concentration of NaCl is 0.4-0.5 wt%.
4. The complex according to any one of claims 1 to 3, wherein the balancing substance further comprises one or more of glucose, 1,3 propanediol, and Tween 80; preferably, the balancing substance comprises glucose, 1,3 propanediol and tween 80; preferably, the concentration of the glucose is 0.1-10 wt%, the concentration of the 1, 3-propanediol is 0.5-3ml/ml, and the concentration of the tween 80 is 0.1-1 ml/ml.
5. The compound of claim 4, wherein the compound is further comprises Salvia miltiorrhiza extract; preferably, the content of the active ingredient in the salvia miltiorrhiza extract is 50 to 99 weight percent, preferably 60 to 90 weight percent.
6. The complex according to claim 5, wherein the concentration of the active ingredient is 7-100 μ g/ml; preferably, the salvia miltiorrhiza extract is present in the complex in the form of microcapsules.
7. The composition of any one of claims 1-6, wherein the composition further comprises a gel matrix adjuvant; preferably, the gel base adjuvant is present at a concentration of 0.1 to 3% by weight.
8. Use of a complex according to any one of claims 1 to 7 in the manufacture of a medicament for the repair of skin lesions; or a cosmetic for repairing skin damage using the complex.
9. The use of claim 8, wherein the skin injury comprises trauma, skin irritation, redness, acne, flushing, and scar repair.
10. A method of preparing a complex comprising type I collagen and hyaluronic acid according to claim 1, comprising the steps of:
a. preparing a balance substance: adding NaH to water2PO4-Na2HPO4Substances of the system, substances of the Tris-HCl system, substances of the Tris-maleic acid system or substances of the HEPES system, and NaCl and/or KCl;
b. adding type I collagen and hyaluronic acid to the balance solution to obtain a complex containing type I collagen and hyaluronic acid, wherein the pH of the complex is 6-8; preferably, the concentration of NaCl and/or KCl is 0.2-0.9% by weight.
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