CN115463111A - Composite material with three-layer core-shell structure, preparation method thereof and calcium supplement preparation - Google Patents
Composite material with three-layer core-shell structure, preparation method thereof and calcium supplement preparation Download PDFInfo
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Abstract
The invention belongs to the technical field of new materials, and particularly relates to a composite material with a three-layer core-shell structure, a preparation method of the composite material and a calcium supplement preparation. The composite material has a three-layer core-shell structure, wherein: the core layer is nano calcium carbonate, the middle layer is flavan-3-ol polymer, and the outer shell layer is polypeptide; the flavan-3-ol polymer is a bridge bond and is combined with nano calcium carbonate and polypeptide. The invention utilizes a large amount of phenolic hydroxyl and benzene rings contained in the flavan-3-ol polymer, and the phenolic hydroxyl exists mainly in the form of catechol and biphenyltriol, and can form a bridge bond between the nano calcium carbonate and the polypeptide to effectively improve the bonding of the polypeptide on the surface of the nano calcium carbonate, thereby promoting the absorption effect of calcium ions and improving the bone density enhancing capability of the nano calcium carbonate. When the composite material prepared by the invention is used as a calcium supplement preparation, the mechanical property and mechanical property of bones can be obviously improved, and the composite material has a good calcium supplement effect.
Description
Technical Field
The invention belongs to the technical field of new materials, particularly relates to a pharmaceutical preparation, and particularly relates to a composite material with a three-layer core-shell structure, a preparation method thereof and a calcium supplement preparation.
Background
With the increase of aging degree of population, patients with osteoporosis in middle-aged and elderly people are also increasing gradually, and bone problems caused by insufficient calcium intake and accelerated loss are more prominent, so that a heavy burden is brought to the society. At present, the calcium preparation plays an important role when the intake of dietary calcium is generally insufficient, and can effectively prevent and treat various acute and chronic bone diseases. Calcium supplement preparations on the market at present mainly comprise three types of products according to types: inorganic calcium salts, organic acid calcium salts and organic calcium salts.
The inorganic calcium salt mainly comprises calcium carbonate, calcium hydrophosphate, calcium hydroxide, calcium chloride and the like, and the calcium supplement has stronger stimulation effect on people with less gastric acid secretion or gastric acid secretion disorder, and is easy to cause uncomfortable symptoms such as constipation, calculus and the like after being taken for a long time, so the calcium supplement cannot be used blindly and needs to be selected according to specific people. The organic acid calcium salt is a product prepared by a series of reactions between organic acid and inorganic calcium salt, such as calcium gluconate, calcium lactate, calcium pyruvate, calcium citrate, calcium acetate and the like, and the calcium supplement has the defects that the calcium content is lower, and a certain effect of improving the bone density can be achieved by taking a large amount of the calcium supplement. The organic calcium salt is also called chelated calcium, which means that amino acid or polypeptide is chelated with calcium ions through ionic bond, coordinate bond or adsorption to generate amino acid chelated calcium or polypeptide chelated calcium, and although the polypeptide is favorable for promoting calcium absorption, the polypeptide capable of being chelated on the calcium surface is limited (as shown in fig. 1). Therefore, the function of polypeptide in polypeptide chelated calcium for promoting calcium absorption is not obvious, and the dosage of taking chelated calcium is still larger under the condition of the same calcium content.
Therefore, there is a need to develop a new material for calcium supplement, which is more beneficial to promote calcium absorption, has better calcium supplement effect, and is suitable for long-term administration.
Disclosure of Invention
The invention provides a composite material with a three-layer core-shell structure, a preparation method thereof and a calcium supplement preparation, which are used for solving one or more technical problems in the prior art and providing at least one beneficial choice or creation condition.
To overcome the above technical problems, a first aspect of the present invention provides a composite material.
Specifically, the composite material has a three-layer core-shell structure, wherein: the core layer is nano calcium carbonate, the middle layer is flavan-3-ol polymer, and the outer shell layer is polypeptide; the flavan-3-ol polymer is a bridge bond which is used for jointing the nano calcium carbonate and the polypeptide.
The nano calcium carbonate has the characteristics of low cost, safety, good biocompatibility, pH sensitivity and slow biodegradability, and is often used as a drug nano carrier in biomedical research. Meanwhile, the nano calcium carbonate can be efficiently internalized by M cells through endocytosis, so that intracellular Ca is generated 2+ The level is obviously increased, and the nano calcium carbonate particles can induce osteoblast differentiation and have a certain promotion effect on osteoblast proliferation. The polypeptide is effective in promoting bone mineral elements such as calcium, phosphorus, zinc, etc. absorption and deposition in bone, and promoting activity of bone cells. Therefore, theoretically, the polypeptide can form a coordination compound with calcium ions through coordination reaction, which is also the reaction basis of the synthesis process of a large number of 'polypeptide chelated calcium' and 'amino acid chelated calcium'. Therefore, the applicant directly reacts fish glue polypeptide and nano calcium carbonate, and finds that no obvious polypeptide layer is observed on the surface of the nano calcium carbonate (see comparative example 1 and figure 1). Meanwhile, after the applicant hydrolyzes the fish glue polypeptide-nano calcium carbonate product prepared in the comparative example 1,the content of free amino acids in the product is detected by using HPLC (high performance liquid chromatography), and the content of the amino acids in the product is also lower, namely only 0.27mg/g (see table 6), so that the polypeptide chelated calcium prepared by directly using the fish gelatin polypeptide and the nano calcium carbonate is further illustrated, and the conjugation effect of the polypeptide and the calcium is not ideal.
Based on the structure, the invention takes nano calcium carbonate as a core layer, flavan-3-ol polymer as a middle layer and polypeptide as a shell layer, and takes the flavan-3-ol polymer as a bridge bond for connecting the nano calcium carbonate and the polypeptide to form the composite material with a three-layer core-shell structure. The research finds that: the flavan-3-ol polymer is used for carrying out surface modification on the nano calcium carbonate, and then the polypeptide is connected, compared with the direct reaction of the polypeptide and the nano calcium carbonate, the surface bonding of the polypeptide on the nano calcium carbonate can be more effectively improved, so that the absorption effect of calcium ions can be more favorably promoted, and the bone density enhancing capability of the nano calcium carbonate can be improved.
The reason for this is mainly that the flavan-3-ol polymer is a natural product having a large number of phenolic hydroxyl groups and widely distributed in roots, stems, leaves, and fruits of plants. The research finds that the flavan-3-ol polymer contains a large amount of phenolic hydroxyl and benzene rings, and the phenolic hydroxyl is mainly in the forms of catechol and biphenol, so that a coordination compound can be formed with metal ions at the same time and combined with the polypeptide. The specific reaction process is as follows:
(1) Coordination reaction of flavan-3-ol polymer and metal ion
The flavan-3-ol polymer has a large number of ortho phenolic hydroxyl groups, and after the ortho phenolic hydroxyl groups are dissociated, the ortho phenolic hydroxyl groups can be bonded with most metal ions in an ionic bond mode to finally form a coordination compound, and the reaction process is as follows:
wherein: me n+ Represents a metal ion.
(2) Conjugation of flavan-3-ol polymers to polypeptides
The flavan-3-ol polymer has a large number of phenolic hydroxyl groups (hydrophilic) and a large number of benzene rings (hydrophobic). The phenolic hydroxyl can form hydrogen bonds with amino (glutamic acid, aspartic acid) and carboxyl (lysine and hydroxylysine) side bonds on polypeptide molecules; the benzene ring can form hydrophobic force with hydrophobic amino acid. This manner of hydrogen bond-hydrophobic interaction provides for the secure association of flavan-3-ol polymers with a large number of polypeptides, the reaction scheme of which is shown in FIG. 9.
The present invention utilizes the chemical reaction characteristics of flavan-3-ol polymer and makes use of the flavan-3-ol polymer to form bridge bond between nano calcium carbonate and polypeptide so as to make nano calcium carbonate and polypeptide possess excellent joint effect.
As a further improvement of the scheme, the composite material has the average particle size of 110-230nm, and the small-particle-size composite material is more favorable for improving the absorption of calcium ions.
As a further improvement of the scheme, the content of amino acid in the composite material is 33.89 +/-0.11-104.21 +/-1.00 mg/g, and the high content of amino acid is more beneficial to supplementing collagen and improving the mechanical property and mechanical property of bones.
In a further improvement of the above aspect, the flavan-3-ol polymer is at least one selected from the group consisting of tea flavan-3-ol polymer, grape seed flavan-3-ol polymer, hop flavan-3-ol polymer, apple flavan-3-ol polymer, and cocoa flavan-3-ol polymer.
The molecular structure characteristics of the flavan-3-ol polymer are shown in figure 2, wherein: FIG. 2-A is a polymer of tea flavan-3-ol 13 A CNMR map; FIG. 2-B shows flavan-3-ol polymers from apple 13 A CNMR map; FIG. 2-C is a view of a cocoa flavan-3-ol polymer 13 A CNMR map; FIG. 2-D is a view of a polymer of grape seed flavan-3-ols 13 A CNMR map; FIG. 2-E is of a polymer of hop flavan-3-ols 13 A CNMR map; FIG. 2-F is the flavan-3-ol C skeleton designation. By making reference to FIG. 2 13 CNMR signals were assigned and it was found that these flavan-3-ol polymers have a similar C6-C3-C6 structural skeleton (FIG. 2-F) characteristic of flavan-3-ols, and the results of the assignment of each C signal are shown in Table 1.
Table 1: process for preparing flavan-3-ol polymer from different plant sources 13 CNMR signal attribution
| Plant and method for producing the same | C4 | C3 | C2 | C6 | C8 |
| Tea | 26.1 | 70.0 | 77.9 | 99.7 | 107.2 |
| Apple (apple) | 37.0 | 72.9 | 76.6 | 96.5 | 97.9 |
| Cocoa | 36.9 | 72.2 | 76.4 | 96.6 | 100.5 |
| Grape seed | 37.0 | 72.5 | 76.7 | 96.4 | 100.8 |
| Hop flower | 56.0 | 70.7 | 77.2 | 102.3 | 97.9 |
| Plant and method for producing the same | C4-a | C2’ | C5’ | C6’ | C1’ |
| Tea | 110.6 | 115.1 | 116.5 | 121.1 | 130.6 |
| Apple (Malus pumila) | 100.5 | 115.9 | 116.7 | 118.8 | 131.9 |
| Cocoa | 112.8 | 115.7 | 116.7 | 118.0 | 131.9 |
| Grape seed | 102.7 | 115.7 | 116.7 | 118.5 | 131.8 |
| Hop flower | 107.6 | 115.3 | 116.2 | 119.4 | 132.6 |
| Plant and method for producing the same | C3’ | C4’ | C8a | C7 | C5 |
| Tea | 133.0 | 139.2 | 156.2 | 156.2 | 156.4 |
| Apple (apple) | 132.4 | 144.8 | 154.5 | 155.4 | 156.4 |
| Cocoa | 132.4 | 144.8 | 154.4 | 155.3 | 155.7 |
| Grape seed | 132.4 | 144.8 | 154.5 | 155.4 | 155.7 |
| Hop flower | 132.6 | 145.9 | 155.1 | 156.7 | 156.7 |
Meanwhile, the structure unit types of the flavan-3-ol polymers were analyzed by matrix assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF MS), and the molecular structural features of these flavan-3-ol polymers were further determined, with the results shown in fig. 3. Wherein: FIG. 3-A is a MALDI-TOF MS spectrum of a tea flavan-3-ol polymer; FIG. 3-B is a MALDI-TOF MS spectrum of apple flavan-3-ol polymer; FIG. 3-C is a MALDI-TOF MS spectrum of cocoa flavan-3-ol polymer; FIG. 3-D is a MALDI-TOF MS spectrum of a grape seed flavan-3-ol polymer; FIG. 3-E is a MALDI-TOF MS spectrum of hop flavan-3-ol polymers.
As can be seen from fig. 3: the tea flavan-3-ol polymer shows ion peaks at m/z =2050u, 2338u, 2625u, 2912u, 3200u, 3486u and 3774u, and the peaks are equally spaced at 288u, indicating that the tea flavan-3-ol polymer is a flavan-3-ol polymer having (epi) catechin as a structural unit. The mass number difference of the apple flavan-3-ol polymer in m/z =2049u, 2338u, 2625u, 2913u, 3199u, 3490u and 3791u, and the interval between the peaks is about 288u shows that the apple flavan-3-ol polymer is flavan-3-ol polymer with (epi) catechin (288 u) as a structural unit. The cocoa flavan-3-ol polymer has ion peaks at m/z =601u, 753u, 889u, 1041u, 1177u, 1329u, 1464u, 1617u, 1753u, 1905u, 2041u and 2193u, and the difference in mass number of 152u between the peaks indicates that the cocoa polyphenol is a flavan-3-ol polymer with (epi) gallocatechin (152u +152u = 304u) as a structural unit. The grape seed flavan-3-ol polymer has ion peaks at m/z =601u, 753u, 889u, 1041u, 1177u, 1329u, 1464u, 1617u, 1753u, 1905u, 2041u and 2193u, and the mass number difference of 288u is separated between the peaks, so that the grape seed flavan-3-ol polymer has a highly similar molecular structure and is a flavan-3-ol polymer taking (epi) gallocatechin (152u +152u =304 u) as a structural unit. Hop polyphenols are flavan-3-ol polymers with (epi) catechin (288 u) as a structural unit, which are characterized in that the hop polyphenols have ion peaks at m/z =889u, 1177u, 1465u, 1753u and 2041u, and the mass number difference of the interval 288u among the peaks. By 13 The typical structural formula of these flavan-3-ol polymers can be inferred from the results of CNMR and MALDI-TOF MS tests as follows:
from the typical structural formula of the above flavan-3-ol polymer, it is known that: these flavan-3-ol polymers have a large number of phenolic hydroxyl groups and benzene rings, and the phenolic hydroxyl groups are mainly present in the form of catechol and biphenyltriol.
As a further improvement of the above scheme, the polypeptide is a fish gelatin polypeptide, and the fish gelatin polypeptide is at least one selected from the group consisting of red-mouth-swimming fish gelatin polypeptide, spotted maigre gelatin polypeptide, kynurenin polypeptide and pyracantha twill gelatin polypeptide. The molecular weight of the polypeptides is less than 20KDa, and the polypeptides are small molecular peptides and have good calcium absorption promoting effect.
In a second aspect of the invention, a method of making a composite material is provided.
Specifically, the preparation method of the composite material is used for preparing the composite material, and comprises the following steps:
(1) Dispersing nano calcium carbonate into water, adding flavan-3-ol polymer, stirring for reaction, and washing by adopting a first solvent to obtain nano calcium carbonate loaded with flavan-3-ol polymer;
(2) Dispersing the nano calcium carbonate loaded with the flavan-3-ol polymer prepared in the step (1) in the first solvent, adding the polypeptide, and then washing by using the first solvent to obtain the composite material.
As a further improvement of the above scheme, the mass ratio of the nano calcium carbonate and the flavan-3-ol polymer is 1: (1-200); the mass ratio of the nanometer calcium carbonate loaded with the flavan-3-ol polymer to the polypeptide is 1: (1-30).
As a further improvement of the above scheme, the preparation method of the composite material comprises the following steps:
(1) Dispersing 1 part by mass of nano calcium carbonate in 5-2000 parts by mass of water, adding 1-200 parts by mass of flavan-3-ol polymer, stirring for reaction for 20-120min, and then washing by adopting a first solvent to obtain nano calcium carbonate loaded with the flavan-3-ol polymer;
(2) And (2) taking 1 part by mass of the nanometer calcium carbonate loaded with the flavan-3-ol polymer prepared in the step (1) to fully disperse in 1-400 parts by mass of a first solvent, adding 1-30 parts by mass of polypeptide, and washing by adopting the first solvent to obtain the composite material.
As a further improvement of the above scheme, the preparation process of the nano calcium carbonate comprises the following steps:
dissolving 1 part by mass of calcium chloride in 50-1500 parts by mass of a second solvent to obtain a calcium chloride solution; adding 0.2-3.8 parts by mass of surfactant into 10 parts by mass of the calcium chloride solution, and performing ultrasonic treatment to obtain a modified calcium chloride solution;
dissolving 1 part by mass of carbonate in 10-1200 parts by mass of a third solvent to obtain a carbonate solution;
and (2) dropwise adding 1-150 parts by mass of the carbonate solution into the modified calcium chloride solution, placing the modified calcium chloride solution in a microwave field, stirring, centrifuging, collecting precipitate, washing with a fourth solvent, and heating and drying at the temperature of 750-850 ℃ to obtain the nano calcium carbonate.
Preferably, the process parameters of the ultrasonic treatment are as follows: the frequency is 10-30KHz, the power is 100-140W, and the processing time is 20-40min.
Preferably, the process parameters of the microwave field are as follows: the frequency is 2000-3000MHz, the power is 80-120W, the temperature is 20-30 ℃, and the processing time is 12-90min.
Preferably, the centrifugal treatment process parameters are as follows: the centrifugal force is 7000-9000g, the temperature is 0-20 deg.C, and the time is 20-40min.
Preferably, the surfactant is selected from at least one of sodium dodecyl benzene sulfonate, sodium fatty alcohol ether sulfate and secondary sodium alkyl sulfonate.
Preferably, the carbonate is at least one selected from sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate.
Preferably, the first solvent and the fourth solvent are selected from at least one of methanol, acetone, ethanol, and acetonitrile.
Further preferably, the first solvent is at least one selected from the group consisting of a 20wt% aqueous methanol solution, a 5wt% aqueous acetone solution, a 30wt% aqueous ethanol solution, and a 20wt% aqueous acetonitrile solution.
Preferably, the second solvent is at least one selected from the group consisting of ethylene glycol, polyethylene glycol (abbreviation: PEG) -200, PEG-400, PEG-600, PEG-1450, PEG-3350, PEG-4000, and PEG-8000.
Further preferably, the second solvent is at least one selected from the group consisting of ethylene glycol, PEG-200 (40 wt% aqueous solution), PEG-400 (40 wt% aqueous solution), PEG-600 (40 wt% aqueous solution), PEG-1450 (40 wt% aqueous solution), PEG-3350 (40 wt% aqueous solution), PEG-4000 (20 wt% aqueous solution), PEG-8000 (10 wt% aqueous solution).
Preferably, the third solvent is selected from at least one of polybutylene succinate (abbreviation: PBS) buffer and 3- (N-morpholine) propanesulfonic acid (abbreviation: MOPS) buffer.
Further preferably, the third solvent is at least one selected from the group consisting of PBS buffer (0.8M) and MOPS buffer (1.0M).
A third aspect of the invention provides a use of a composite material.
In particular to a calcium supplement preparation, which contains the composite material.
Compared with the prior art, the technical scheme of the invention at least has the following technical effects or advantages:
the composite material has a three-layer core-shell structure, wherein: the nano calcium carbonate is a core layer, the flavan-3-ol polymer is a middle layer, and the polypeptide is a shell layer; the flavan-3-ol polymer contains a large amount of phenolic hydroxyl and benzene rings, and the phenolic hydroxyl mainly exists in the forms of catechol and biphenyltriol, so that a bridge bond can be formed between the nano calcium carbonate and the polypeptide to connect the nano calcium carbonate and the polypeptide, so that the bonding of the polypeptide on the surface of the nano calcium carbonate is effectively improved, the absorption effect of calcium ions is promoted, and the bone density enhancing capability of the nano calcium carbonate is improved. The particle size of the composite material prepared by the invention is 110-230nm, and the content of amino acid is 33.89 +/-0.11-104.21 +/-1.00 mg/g; when used as a calcium supplement preparation, the calcium supplement preparation can obviously improve the mechanical property and mechanical property of bones and has good calcium supplement effect.
Drawings
FIG. 1 is a TEM image of the nano calcium carbonate-fish gelatin polypeptide prepared in comparative example 1;
FIG. 2 is of flavan-3-ol polymers 13 CNMR map and flavan-3-ol C skeleton label;
FIG. 3 is a MALDI-TOF MS spectrum of flavan-3-ol polymers;
fig. 4 is TEM image of nano calcium carbonate-flavan-3-ol polymer-fish gelatin polypeptide prepared in example 1;
FIG. 5 is the XRD pattern of the nano calcium carbonate-flavan-3-ol polymer-fish gelatin polypeptide prepared in example 1;
FIG. 6 is the synthesis reaction path and corresponding SEM image and TEM-element spectrum analysis result for preparing nano calcium carbonate-flavan-3-ol polymer-fish glue polypeptide in example 1;
FIG. 7 is a graph of biomechanical properties of rat femurs that were dosed with samples of example 1 and comparative examples 1-4;
FIG. 8 is a Micro-CT examination of rat femurs dosed with samples of example 1 and comparative examples 1-4;
FIG. 9 shows a schematic representation of the binding reaction of flavan-3-ol polymers to polypeptides.
Detailed Description
The present invention is specifically described below with reference to examples in order to facilitate understanding of the present invention by those skilled in the art. It should be particularly noted that the examples are given solely for the purpose of illustration and are not to be construed as limitations on the scope of the invention, as non-essential improvements and modifications to the invention may occur to those skilled in the art, which fall within the scope of the invention as defined by the appended claims. Meanwhile, the raw materials mentioned below are not specified and are all commercial products; the process steps or preparation methods not mentioned in detail are all process steps or preparation methods known to the person skilled in the art.
Example 1
A composite material having a three-layer core-shell structure, wherein: the core layer is nano calcium carbonate, the middle layer is tea flavan-3-ol polymer, and the shell layer is red-mouth swimming fish glue polypeptide; the tea flavan-3-ol polymer is a bridge bond, and is combined with nano calcium carbonate and red-mouth-carrying fish glue polypeptide.
A method of making a composite material comprising the steps of:
(1) Dissolving 1 part by mass of calcium chloride in 50 parts by mass of ethylene glycol to obtain a calcium chloride solution;
(2) Dissolving 1 part by mass of sodium carbonate in 10 parts by mass of PBS (0.8M) buffer solution to obtain a sodium carbonate solution;
(3) Mixing 10 parts by mass of the calcium chloride solution prepared in the step (1) with 0.2 part by mass of sodium dodecyl benzene sulfonate, and treating for 30min in an ultrasonic field with the power of 20KHz and 120W; then dropwise adding 1 part by mass of the sodium carbonate solution prepared in the step (2), placing the solution in a microwave field with power of 100W and 25 ℃ of 2450MHz for stirring reaction for 12min, carrying out centrifugal treatment for 30min under the conditions of centrifugal force 1000g and 0 ℃, collecting precipitates, washing the precipitates for 3 times by using methanol, transferring the precipitates to a muffle furnace with the temperature of 800 ℃, and heating and drying the precipitates to obtain nano calcium carbonate;
(4) Dispersing 1 part by mass of the nano calcium carbonate prepared in the step (3) in 5 parts by mass of water, adding 1 part by mass of tea flavan-3-ol polymer, and stirring for reacting for 20min; then washing with 20wt% methanol water solution, and obtaining nano calcium carbonate with flavan-3-ol polymer loaded on the surface after washing;
(5) And (3) fully dispersing 1 part by mass of the nano calcium carbonate loaded with the flavan-3-ol polymer on the surface prepared in the step (4) in 1 part by mass of 20wt% methanol aqueous solution, adding 5 parts by mass of red-mouth-carrying fish gelatin polypeptide, and washing by using 20wt% methanol aqueous solution to obtain the nano calcium carbonate-flavan-3-ol polymer-fish gelatin polypeptide composite material.
The TEM image of the nano calcium carbonate-flavan-3-ol polymer-fish glue polypeptide composite material prepared in example 1 is shown in FIG. 4, and the synthesis reaction path, the corresponding SEM image and the TEM-element energy spectrum analysis result are shown in FIG. 6. As can be seen from FIGS. 4 and 6, the outermost layer of the composite material prepared in example 1 had a distinct polypeptide layer, with the intermediate linker moiety being a flavan-3-ol polymer; in the prepared composite material, the mass ratio of calcium element is 21.08%, the mass ratio of nitrogen element is 1.88%, the mass ratio of oxygen element is 25.18%, and the mass ratio of carbon element is 43.09%.
Examples 2 to 15
Examples 2-15 differ from example 1 in that: the preparation process parameters of the composite material, and the specific selection and dosage of each raw material are different, and are specifically shown in tables 2-3.
Table 2: preparation conditions of Nano calcium carbonate of examples 2 to 15
Table 3: preparation conditions of the composites of examples 2 to 15
Comparative example 1
A method of making a composite material comprising the steps of:
(1) Dissolving 1 part by mass of calcium chloride in 50 parts by mass of ethylene glycol to obtain a calcium chloride solution;
(2) Dissolving 1 part by mass of sodium carbonate in 10 parts by mass of PBS (0.8M) buffer solution to obtain a sodium carbonate solution;
(3) Mixing 10 parts by mass of the calcium chloride solution prepared in the step (1) with 0.2 part by mass of sodium dodecyl benzene sulfonate, and treating for 30min in an ultrasonic field with the power of 20KHz and 120W; then dropwise adding 1 part by mass of the sodium carbonate solution prepared in the step (2), placing the solution in a microwave field with power of 100W and 25 ℃ of 2450MHz for stirring reaction for 12min, carrying out centrifugal treatment for 30min under the conditions of centrifugal force 1000g and 0 ℃, collecting precipitates, washing the precipitates for 3 times by using methanol, transferring the precipitates to a muffle furnace with the temperature of 800 ℃, and heating and drying the precipitates to obtain nano calcium carbonate;
(4) And (3) fully dispersing 1 part by mass of the nano calcium carbonate prepared in the step (3) in 1 part by mass of a 20wt% methanol aqueous solution, adding 5 parts by mass of red-mouth-carrying fish glue polypeptide, and washing by using the 20wt% methanol aqueous solution to obtain the nano calcium carbonate-fish glue polypeptide composite material of the comparative example.
Comparative example 1 differs from example 1 only in that: comparative example 1 Fish gelatin polypeptide and Nano calcium carbonate were reacted directly without the addition of tea flavan-3-ol Polymer.
The TEM image of the nano calcium carbonate-fish glue polypeptide composite material prepared in comparative example 1 is shown in fig. 1, and it can be seen from fig. 1 that no obvious polypeptide layer is observed on the surface of the nano calcium carbonate.
Comparative example 2
Comparative example 2 is the nano calcium carbonate prepared in example 1.
Comparative example 3
Comparative example 3 is a commercially available calcium carbonate.
Comparative example 4
Comparative example 4 is a blank water.
Performance test
1. Particle size and diffraction peak position
The diffraction peak positions of the nano calcium carbonate-flavan-3-ol polymer-fish glue polypeptide composite material samples prepared in the examples 1 to 15 were analyzed by XRD, wherein: the XRD pattern of the sample of example 1 is shown in FIG. 5, and it can be seen from FIG. 5 that the diffraction peaks of the sample show the crystal plane structure consistent with the vaterite crystal plane; the particle size (average particle diameter) of the sample was measured by Dynamic Light Scattering (DLS), and the measurement results are shown in table 4.
Table 4: average particle size and XRD diffraction peaks for samples of examples 1-15
2. Amino acid content
The samples obtained in examples 1 to 15 and comparative example 1 were analyzed by acid degradation-HPLC to measure the amino acid content therein, and the results are shown in Table 5.
Table 5: amino acid content in samples prepared in examples 1-15 and comparative example 1
| Sample (I) | Total content of amino acids (mg/g) |
| Example 1 | 33.89±0.11 |
| Example 2 | 44.26±1.24 |
| Example 3 | 53.18±3.12 |
| Example 4 | 55.21±1.28 |
| Example 5 | 56.73±0.11 |
| Example 6 | 63.22±0.41 |
| Example 7 | 61.45±0.33 |
| Example 8 | 66.81±0.47 |
| Example 9 | 72.64±0.35 |
| Example 10 | 83.11±2.71 |
| Example 11 | 89.68±1.99 |
| Example 12 | 94.04±1.63 |
| Example 13 | 100.08±2.56 |
| Example 14 | 100.02±1.42 |
| Example 15 | 104.21±1.00 |
| Comparative example 1 | 0.27±0.00 |
As can be seen from Table 5, the amino acid content in the nano calcium carbonate-flavan-3-ol polymer-fish glue polypeptide composite materials prepared in examples 1-15 is 33.89 +/-0.11-104.21 +/-1.00 mg/g, which is far higher than that in the fish glue polypeptide-nano calcium carbonate prepared in comparative example 1 by 0.27mg/g. Therefore, the flavan-3-ol polymer is used as a bridge bond to connect the nano calcium carbonate and the polypeptide, so that the bonding effect of the polypeptide on the surface of the nano calcium carbonate can be effectively improved.
In addition, the specific content of each amino acid in example 1 and comparative example 1 is shown in table 6 below.
Table 6: specific content of amino acids in the samples prepared in example 1 and comparative example 1
Calcium supplement effect experiment:
taking the samples prepared in the example 1 and the comparative examples 1-4 as calcium supplement preparations, carrying out gavage treatment on SD rats of 12 weeks for 8 weeks, wherein the gavage amount is 300mg/kg body weight/day, once a day, and carrying out femoral biomechanical test and femoral Micro-CT analysis on the SD rats after the gavage is finished, wherein the specific method comprises the following steps:
(1) Femoral biomechanical testing
And taking the degreased and dried left femur, and testing the biomechanical property of the rat femur by adopting a three-point bending mode of a universal testing machine. Setting the downward advancing speed of a central pressure head of the universal testing machine to be 1mm/min according to a standard bending mechanical property experiment method YB/T5349-2014; the span was set at 10mm until the bone broke, and the indenter displacement and the change in pressure during the process were recorded, and the mechanical property test results are shown in fig. 7 and table 7.
Table 7: physical and mechanical properties of femurs of rats of samples of gavage example 1 and comparative examples 1 to 4
| Sample (I) | Maximum load (N) | Flexural modulus (MPa) | Flexural Strength (MPa) |
| Example 1 | 82.02±0.23 a | 555.0±28.30 a | 61.2±4.25 a |
| Comparative example 1 | 49.39±5.57 b | 384.5±23.30 c | 27.7±0.85 c |
| Comparative example 2 | 95.32±1.63 a | 547.0±15.60 ab | 50.35±4.31 ab |
| Comparative example 3 | 83.70±6.37 a | 442.5±43.10 bc | 31.60±2.96 c |
| Comparative example 4 | 63.14±0.32 b | 426.5±0.71 c | 46.22±4.40 b |
(2) Micro-CT analysis of femurs
Taking a freshly stripped right femur, cleaning, fixing for 1 week by 4% paraformaldehyde solution, performing three-dimensional reconstruction scanning on a femoral metaphysis by using a Micro-CT system, selecting a cancellous bone area of the femur in an observation area, and calculating the bone density (BMD, g/cm) of the area 3 ) And bone microstructure parameters: bone volume fraction (BV/TV,%), trabecular number (Tb.N, 1/mm), and results are shown in FIG. 8 and Table 8.
Table 8: rat bone Density Performance of samples from lavage example 1 and comparative examples 1-4
| Sample(s) | Bone volume fraction BV/TV (%) | Number of trabeculae (Tb.N) |
| Example 1 | 23.44 | 2.48 |
| Comparative example 1 | 20.14 | 2.30 |
| Comparative example 2 | 19.78 | 2.39 |
| Comparative example 3 | 19.13 | 1.80 |
| Comparative example 4 | 16.63 | 1.86 |
As can be seen from fig. 7 and 8 and tables 7 and 8, the physical and mechanical properties of the femur of the gavage rat obtained by using the sample of example 1 are significantly better than those of the other samples, and the load force is the largest under the same displacement condition, indicating that the femur is the most "firm". Micro-CT is utilized to find that the bone volume fraction and the number of trabeculae of the rat are obviously larger than those of other samples after the samples in the example 1 are perfused, which indicates that the sample in the example 1 has stronger calcium supplement effect than calcium carbonate, nano calcium carbonate and calcium gluconate.
It will be obvious to those skilled in the art that many simple derivations or substitutions can be made without inventive effort without departing from the inventive concept. Therefore, simple modifications to the present invention by those skilled in the art according to the present disclosure should be within the scope of the present invention. The above embodiments are preferred embodiments of the present invention, and all similar processes and equivalent variations to those of the present invention should fall within the scope of the present invention.
Claims (10)
1. A composite material having a three-layer core-shell structure, wherein: the core layer is nano calcium carbonate, the middle layer is flavan-3-ol polymer, and the outer shell layer is polypeptide; the flavan-3-ol polymer is a bridge bond which is used for jointing the nano calcium carbonate and the polypeptide.
2. The composite material of claim 1, wherein the composite material has an average particle size of 110-230nm.
3. The composite material according to claim 1, wherein the composite material has an amino acid content of 33.89 ± 0.11-104.21 ± 1.00mg/g.
4. The composite material of claim 1, wherein the flavan-3-ol polymer is selected from at least one of tea flavan-3-ol polymer, grape seed flavan-3-ol polymer, hop flavan-3-ol polymer, apple flavan-3-ol polymer, cocoa flavan-3-ol polymer.
5. The composite material of claim 1, wherein the polypeptide is a isinglass polypeptide selected from at least one of cimicifuga guttifera, nibea albiflora, kynurenin, and echinocandin twill.
6. A method for preparing a composite material, characterized in that it is used for preparing a composite material according to any one of claims 1 to 5, comprising the following steps:
(1) Dispersing nano calcium carbonate into water, adding flavan-3-ol polymer, stirring for reaction, and washing by adopting a first solvent to obtain nano calcium carbonate loaded with flavan-3-ol polymer;
(2) Dispersing the nano calcium carbonate loaded with the flavan-3-ol polymer prepared in the step (1) in the first solvent, adding the polypeptide, and then washing by using the first solvent to obtain the composite material.
7. The method according to claim 6, wherein the mass ratio of the nano calcium carbonate to the flavan-3-ol polymer is 1: (1-200); the mass ratio of the nanometer calcium carbonate loaded with the flavan-3-ol polymer to the polypeptide is 1: (1-30).
8. The method for preparing the composite material according to claim 6, wherein the preparation process of the nano calcium carbonate comprises the following steps:
dissolving 1 part by mass of calcium chloride in 50-1500 parts by mass of a second solvent to obtain a calcium chloride solution; adding 0.2-3.8 parts by mass of surfactant into 10 parts by mass of the calcium chloride solution, and performing ultrasonic treatment to obtain a modified calcium chloride solution;
dissolving 1 part by mass of carbonate in 10-1200 parts by mass of a third solvent to obtain a carbonate solution;
and (2) dropwise adding 1-150 parts by mass of the carbonate solution into the modified calcium chloride solution, placing the modified calcium chloride solution in a microwave field, stirring, centrifuging, collecting precipitate, washing with a fourth solvent, and heating and drying at the temperature of 750-850 ℃ to obtain the nano calcium carbonate.
9. The method for preparing the composite material according to claim 8, wherein the surfactant is selected from at least one of sodium dodecylbenzene sulfonate, sodium fatty alcohol ether sulfate, and sodium secondary alkyl sulfonate;
the carbonate is selected from at least one of sodium carbonate, sodium bicarbonate, potassium carbonate and potassium bicarbonate;
the first solvent and the fourth solvent are both selected from at least one of methanol, acetone, ethanol and acetonitrile;
the second solvent is at least one selected from ethylene glycol, polyethylene glycol-200, polyethylene glycol-400, polyethylene glycol-600, polyethylene glycol-1450, polyethylene glycol-3350, polyethylene glycol-4000 and polyethylene glycol-8000;
the third solvent is at least one selected from polybutylene succinate buffer solution and 3- (N-morpholine) propanesulfonic acid buffer solution.
10. A calcium supplement preparation comprising the composite material according to any one of claims 1 to 5.
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