Amino acid-based glass, its method of manufacture and its use

Abstract

The present invention discloses a biodegradable glass based on amino acids, peptides and their derivatives, and the manufacturing method and use thereof, in which the main raw material of the glass is one or more combinations of amino acids, peptides and their derivatives or their salts. Compared with conventional glasses, the glass of the present invention has obvious advantages such as high biocompatibility, biodegradability, 3D printability, compostability, etc., and its manufacturing process is simple and eco-friendly, and can effectively avoid the impact of conventional glasses on the ecological environment. It is widely applied in the fields of medicine, building materials, chemical industry, food, electronics, national defense, etc., including but not limited to tissue engineering, tooth / bone repair, drug release, cell / protein isolation and storage, optical fiber communication, coating layer, precision instrument, etc.

Description

[Technical field]

[0001] The present invention relates to a glass material, its manufacturing method and its use, in particular to an amino acid-based bio-molecular glass, its manufacturing method and its use, and relates to the field of novel materials. [Background technology]

[0002] Glass is generally made from inorganic minerals such as silica and calcium carbonate as its main raw materials, and is one of the most commonly used materials in daily life. Glass is almost indecomposable under natural conditions, and is also easily broken, so glass has a significant impact on the environment and ecology in terms of pollution, hazards, and durability.

[0003] Conventionally, several kinds of glass materials, products and their manufacturing methods have been disclosed, for example, a manufacturing method of silicate glass, silicate glass and silica raw material for silicate glass have been disclosed (WO2015 / 129495 JA 2015.09.03). Glass products using β-quartz or β-spodumene solid solution as the main raw material have been disclosed (WO2005 / 058766 EN 2005.06.30). Lithium silicate glass ceramics and lithium silicate glasses containing divalent metal oxides have been disclosed (WO2013 / 053864 DE 2013.04.18).

[0004] In 1969, Bioglass, invented by LL Hench of the University of Florida, is made up of 45% Na 2 O, 25% CaO, 25% SiO 2 and 5% P 2 O 5 and exemplary compositions and uses of bioglass (also known as bioactive glass) have been disclosed (US4478904A, US6338751B1, US7569105B2).

[0005] The glass materials and products disclosed above have in common that the raw materials are all inorganic minerals. Up until now, no amino acid-based biomolecular glass material and its manufacturing method have been disclosed.

[0006] Amino acids are the basic units that make up proteins, and peptides are compounds formed by linking two or more amino acids together through peptide bonds. Amino acids and peptides are important components of living organisms, and play an extremely important role in the information transmission, metabolism, disease, aging, and other aspects of living organisms. Amino acid-based biomolecules have extremely high biocompatibility, have a clear metabolic mechanism within living organisms, and are biodegradable. Surprisingly, the present inventors have found that biodegradable glass that has a glassy structure at room temperature can be obtained by producing amino acids, peptides, and their derivatives through a specific manufacturing process, and the present invention is based on this very concept. Based on the amino acid-based biomolecular glass discovered by the present invention, it is expected that it will be widely applied as a new material in the fields of medicine, building materials, the chemical industry, food, electronics, national defense, and other fields. Summary of the Invention [Problem to be solved by the invention]

[0007] The primary objective of the present invention is to provide an amino acid-based biomolecular glass and a manufacturing method thereof, which is eco-friendly, highly biocompatible, biodegradable, 3D printable, compostable, and has a simple manufacturing process, making it eco-friendly. [Means for solving the problem]

[0008] In a first aspect, the amino acid-based glass described above is characterized in that the main raw material is an amino acid, peptide, or derivative thereof represented by formula (1), and the content of the main raw material in the glass is 70 wt% or more, preferably 80 wt% or more, and more preferably 90 wt% or more; [ka] The amino acids include glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, and pyrrolysine; The peptide is a molecule formed by condensing n amino acids through peptide bonds, where n is greater than or equal to 2, and preferably, 2≦n≦10; The derivative is an amino acid or peptide having protecting groups for the amino group (P1) and the carboxy group (P2), The protecting groups at P1 are Trt, Boc, Fmoc, Cbz / Z, Allyl, C 2 -C 18 protecting groups at P2 include, but are not limited to, OFm, Otbu, OBzl, OAll, OMe, OEt; P1 and P2 are characterized in that one of them is protected or both are protected simultaneously.

[0009] The derivatives further include molecules similar to the backbone of the above amino acid or peptide molecules or their derivative molecular structures, isomers and salts thereof.

[0010] In a second aspect, the amino acid-based glass described above is characterized in that it is made entirely from the amino acids, peptides and derivatives thereof described above.

[0011] In a third aspect, the amino acid-based glass described above may be made from a single type of molecule or a combination of two or more types of molecules, The single type of molecule includes a single type of amino acid molecule, a single type of peptide molecule, a single type of amino acid derivative, or a single type of peptide derivative; The combinations are characterized by including a combination of amino acid molecules, a combination of peptide molecules, a combination of amino acid derivative molecules, a combination of peptide molecule derivatives, a combination of amino acid molecules and peptide molecules, a combination of amino acids and amino acid derivatives, a combination of amino acids and peptide derivatives, a combination of peptides and amino acid derivative molecules, a combination of peptides and peptide derivatives, a combination of amino acid derivatives and peptide derivatives, a combination of amino acids, peptides and amino acid derivatives, a combination of amino acids, peptides and peptide derivatives, a combination of amino acids, amino acid derivatives and peptide derivatives, a combination of amino acids, peptides and peptide derivatives, a combination of amino acids, amino acid derivatives and peptide derivatives, or a combination of amino acids, peptides, amino acid derivatives and peptide derivatives.

[0012] In a fourth aspect, the amino acid-based glass described above may further contain, in addition to the main raw material described above, an auxiliary raw material, which contains one or a mixture of two or more selected from a clarifier, a flux, an opacifier, and a colorant.

[0013] However, the ratio of the auxiliary material is 0 to 5 wt%, preferably 0 to 1 wt%, The fining agent includes one or a mixture of two or more of antimony oxide, sodium nitrate, ammonium nitrate, sodium sulfate, calcium sulfate, sodium chloride, and ammonium chloride; The flux is one or a mixture of two or more of sodium carbonate, potassium carbonate, sodium carbonate, and potassium nitrate; The opacifying agent is one or a mixture of two or more of cryolite, sodium silicofluoride, and tin phosphide; The colorants are metal compounds of transition elements such as cobalt, manganese, nickel, iron, and copper.

[0014] In a fifth aspect, a method for producing amino acid-based glass includes the steps of heating the above-mentioned raw materials to a temperature higher than the melting point temperature under an inert gas atmosphere and maintaining the temperature for a certain period of time, then cooling the raw materials to below room temperature, and transferring the cooled sample to an annealing furnace for annealing.

[0015] In one preferred embodiment of the present invention, the melting point temperature (T m ) refers to a temperature that is 5 to 200 K higher than the melting point temperature, preferably a temperature that is 10 to 50 K higher than the melting point temperature, and the temperature retention time is 5 min to 1 hour, preferably 15 to 30 minutes.

[0016] In one preferred embodiment of the present invention, the annealing temperature is the glass transition temperature (T g ) is 20 to 100K lower than the glass transition temperature (T g ) and the annealing treatment time is 5 min to 3 h, preferably 15 min to 1 h.

[0017] In one embodiment of the present invention, the amino acid-based glass described above is a single-molecule glass, and includes the following manufacturing steps: (1) A certain mass of amino acid, peptide or derivative powder is weighed out and placed in a mortar and ground uniformly, and then transferred to a crucible. (2) The crucible containing the raw materials from step (1) is left in a heating device under an inert gas atmosphere. (3) The device of step (2) is subjected to a heat treatment, and S 1 The crucible was heated from room temperature to M 1 The temperature is raised to T 1 Time keeping warm processing, However, S 1 1~50K min -1 and preferably 2 to 10K min -1 and M 1 T m The temperature is 5 to 200 K higher than T m The temperature is 10 to 50 K higher than T 1 The time is 5 min to 1 h, and preferably 15 to 30 min. (4) The apparatus of step (3) is subjected to a temperature reduction treatment, and S 2 The crucible was cooled at a rate of M 2 The temperature is lowered to However, S 21~100K min -1 and preferably 50 to 100K min -1 and M 2 is 273.15K (ice water mixture temperature) or 293.15~298.15K (room temperature). (5) The sample from step (4) is heated to a temperature of M 3 The annealing furnace was moved to T 3 The glass is then annealed for 24 hours. However, M 3 T g The temperature is 20 to 100 K lower than T g The temperature is 20 to 50 K lower than that of T 3 The time is 5 min to 3 h, preferably 15 min to 1 h.

[0018] In the case of glass made of a mixture of two or more kinds of molecules, the following improved process (1 o )~(5 o ) or the following step (6 o )~(8 o ). (1 o ) Powder of each component is weighed out, placed in a mortar and ground uniformly, and then transferred to a different crucible. (2 o ) Follow steps (2) to (3). (3 o ) The above molten components are mixed in a given ratio in the same crucible and appropriately stirred to make them homogenous, the mixing ratio being preferably 1:1:... (4 o ) process (3 o The mixture obtained in step M 1 T under temperature s Keep warm for a period of time; (5 o ) Follow steps (4) to (5). (6 o ) The powders of each component are weighed out and mixed uniformly in a predetermined ratio by stirring, the mixing ratio being preferably 1:1:... (7 o) The homogeneously mixed powder is placed in a mortar and ground uniformly, and then transferred to a crucible. (8 o ) Follow steps (2) to (5).

[0019] In a sixth aspect, a method for producing an amino acid-based glass is characterized in that an auxiliary material is added in addition to a main material, and the method includes the following steps: (1) The main raw materials and auxiliary raw materials are weighed out, mixed in the specified ratio, stirred uniformly, and transferred to a crucible. (2) Follow steps (2) to (5) of the fifth embodiment.

[0020] In the seventh embodiment, the T m and T g is measured by standard differential scanning calorimetry (DSC) methods.

[0021] The DSC heating rate is preferably 10K min -1 The temperature is plotted on the horizontal axis and the heat flow on the vertical axis, and a curve is drawn. The initial and final temperatures of the sample are measured, and the midpoint between the initial and final temperatures is designated as T m Let us assume that.

[0022] T m After heating to a temperature 20 K higher than the above, the temperature is kept at 40° C. for 10 min.

[0023] The DSC temperature drop rate is preferably 10K min -1 The temperature is lowered to 273.15K and then the temperature is kept at 273.15K for 10 minutes.

[0024] The second heating is performed, and the heating rate of the DSC is preferably 10K min -1 A curve was drawn with temperature as the horizontal axis and heat flow as the vertical axis, and the initial and final temperatures of the glass transition temperature were recorded by extrapolating the tangent line. The midpoint between the initial and final temperatures was determined as T g Let us assume that.

[0025] The amino acid-based glass is produced by the method described above.

[0026] In an eighth aspect, the amino acid-based glass and its manufacturing method of the present invention have the following advantages and beneficial effects. (1) The amino acid-based glass of the present invention has properties such as hardness, brittleness, transparency, and light transmission, and has a hardness in the range of 420 to 550 HV, preferably in the range of 500 to 550 HV, and a transparency in the range of 30% to 91%, preferably in the range of 80% to 91%. (2) The amino acid based glass of the present invention has a good glass forming ability (GFA), and the fragility index (m) of the amino acid based glass is in the range of 10-100, preferably 10-50. (3) The amino acid-based glass of the present invention is environmentally friendly and has high biocompatibility and biodegradability. (4) The amino acid-based glass of the present invention can be produced by a simple process, has high repeatability, and is ecological and environmentally friendly. (5) The amino acid-based glasses of the present invention can be used for additive manufacturing (3D printing). (6) The amino acid-based glass of the present invention is compostable, significantly reducing the damage to the ecological environment that conventional glasses cause.

[0027] In a ninth aspect, the amino acid-based glass of the present invention can be used in the fields of medicine, building materials, chemical industry, food, electronics, national defense, etc., including, but not limited to, tissue engineering, tooth / bone repair, drug release, cell / protein isolation and storage, fiber communication, coating layers, precision instruments, etc.

[0028] In a tenth embodiment, the amino acid-based glass of the present invention is capable of dissolving drug molecules during the melting process, and preferably the drug molecules are short half-life drug molecules and / or insoluble drug molecules.

[0029] The drug molecules include tumor chemotherapy drug molecules, imaging agent molecules, antipyretic analgesic and anti-inflammatory molecules, single-component compounds of traditional Chinese medicines, immunomodulators, and mixtures of any one or more of them.

[0030] Chemotherapy drug molecules include any one or mixtures of two or more of pemetrexed, fluorouracil, doxorubicin, paclitaxel, docetaxel, vincristine, cisplatin, tamoxifen, megestrol, goserelin, and the like.

[0031] Contrast agent molecules include barium sulfate, iodine preparations (sodium iodide, gastrografin, iotalamate meglumine, ioxaglic acid, iohexol, iopromide, iopamiron, iotrolan, iodized poppy seed oil, iophendilate), 18 This includes any one or mixture of two or more of FDG, Gd-DTPA, Mn-DPDP, SPIO and similar substances.

[0032] Antipyretic, analgesic and anti-inflammatory molecules include aspirin, brufen, p-acetaminophenol, idomethicin, nimesulide, rofecoxib, celecoxib and the like, or mixtures of any one or more of these analogs.

[0033] The single component compound molecule of the herbal medicine includes any one or mixture of two or more of curcumin, nobiletin, triptolide, Scutellaria Root, Coriolus versicolor polysaccharides, and their analogs.

[0034] Immunomodulators include any one or mixtures of two or more of the following: glycoproteins, pidotimod, thymosin alpha 1, muramyl dipeptide, interferon gamma, interleukin-2, levamisole, and the like.

[0035] Other examples include drugs requiring sustained release, such as insulin, paliperidone, nifedipine, ranitidine hydrochloride, and mixtures of any one or more of these analogues.

[0036] It can be used as a subcutaneous embedding agent, an oral agent, or a tissue engineering scaffold material, and preferably, the raw material is a biologically active amino acid, peptide, or derivative thereof, and is characterized by realizing localized, sustained release of a drug as the amino acid-based glass biodegrades.

[0037] In an eleventh embodiment, the amino acid-based glass of the present invention performs a function by dissolving other functional agents during the melting process or applying them to the surface of the glass material in the form of a coating layer, and the functional agents include, but are not limited to, conductive agents, germicides / anticorrosive agents, and radiation protection agents.

[0038] Conductive agents include any one or more of the following: indium tin oxide, graphite, polyacetylene, and the like.

[0039] The germicide / anticorrosion agents include nanosilver, chlorine formulations, peroxides, organosulfur, organobromine and nitrogen-sulfur containing heterocyclic compounds and the like, or mixtures of any one or more of these.

[0040] Radiation protectants include any one or more of the following: melanin, polyimide, and the like.

[0041] In a twelfth aspect, the amino acid-based glass of the present invention may be prepared by dissolving a drug or functional preparation in a melting process using a powder co-melting method, or by dissolving a drug or functional preparation in a good solvent in advance, blending the drug or functional preparation with the molten amino acid-based glass, and then removing the solvent; The content of the drug molecule is 0.01 to 25 wt%, preferably 0.1 to 1 wt%, The content of the functional molecule is characterized by being 0.01 to 5 wt %, and preferably 0.1 to 1 wt %. [Brief description of the drawings]

[0042] [Figure 1] FIG. 1 is a photograph of the Ac-Lys glass produced in Example 1 at room temperature, which can be processed into glass beads or a glass coating layer. [Diagram 2]FIG. 2 is a DSC-TGA diagram of the Ac-Lys glass prepared in Example 1. At its melting temperature Tm=536.70K, no significant weight loss was observed, indicating that Ac-Lys did not decompose when melted at high temperatures. [Diagram 3] FIG. 3 is a DSC diagram of the Ac-Lys glass produced in Example 1, which has a glass transition temperature Tg=295.10K. [Figure 4] FIG. 4 shows the nuclear magnetic resonance hydrogen spectrum of the Z-Phe-Phe glass produced in Example 2. Compared to the Z-Phe-Phe raw material, the peaks did not change significantly, indicating that the chemical composition of the peptide raw material molecule did not change after undergoing heat melting and annealing treatment. [Diagram 5] FIG. 5 shows that the optical transparency of the Z-Phe-Phe glass produced in Example 2 is comparable to that of commercially available glasses. [Figure 6] FIG. 6 is a DSC spectrum of the Z-Phe-Phe glass produced in Example 2, which has a glass transition temperature Tg=320.75K. [Figure 7] FIG. 7 shows polarized microscope photographs of the Boc-Gly powder and the Boc-Gly glass prepared in Example 3, which demonstrate that the glass formed is amorphous. [Figure 8] FIG. 8 shows the biocompatibility measurement results of the Boc-Gly glass produced in Example 3. The above-mentioned glass was processed into a square coated layer with a width of 2 cm, and 3T3 cells were co-incubated with it, and the activity of the measurement cells was measured by the MTT method. [Figure 9] FIG. 9 shows the results of measuring the mechanical properties of the Boc-Ala glass produced in Example 4. [Figure 10] FIG. 10 is a biodegradation curve of the Boc-Ala glass prepared in Example 4 in compost soil samples, with the initial mass of the glass sample being 42.58 mg. [Figure 11] FIG. 11 shows the performance measurement results of the mixed glass produced in Example 5. [Figure 12]FIG. 12 shows the decomposition status of the mixed glass prepared in Example 5 in the artificial gastric juice (according to the preparation method of the Chinese Pharmacopoeia). [Figure 13] Figure 13 shows the weight change of mice after intragastric injection of the mixed glass prepared in Example 5. The period of intragastric injection of mice is 5 days / time, the mass is 5 mg kg-1, the observation period is 30 days, and the number of intragastric injections is 5 times in total. [Figure 14] 14 shows a pattern printed by a 3D printing device using the mixed glass produced in Example 6. The mixed powder was placed in a cartridge of the 3D printing device and the heating temperature was set to 450K. [Figure 15] FIG. 15 shows the decomposition state of the mixed glass produced in Example 6 after it was embedded in the body of an animal mouse model. [Figure 16] FIG. 16 shows the time-dependent biodegradation state of the amino acid-based glass carrying insulin produced in Example 7 after it was subcutaneously embedded in the body of a mouse. [Figure 17] FIG. 17 shows the blood glucose change of diabetic mice after the insulin-loaded amino acid-based glass prepared in Example 7 was orally injected into the stomach of the mice. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0043] The technical solutions of the present invention are described in detail below through examples, but the scope of the protection of the present invention is not limited thereto.

[0044] Example 1 The process for producing lysine-based glass includes the following steps: (1) 20 mg of N-acetyl-L-lysine (Ac-Lys) powder is weighed out and placed in a mortar and ground uniformly, and then transferred to a crucible. (2) The crucible containing the Ac-Lys powder in step (1) was heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) Heat treatment is performed on the device in step (2) for 10K min -1The crucible is heated from room temperature to 600 K at a heating rate of 1000 K and kept at this temperature for 10 min. (4) The apparatus in step (3) is cooled down to 10K min -1 The crucible is cooled to 273.15K at a rate of 0.05°C. (5) The sample from step (4) is transferred into an annealing furnace at a temperature of 283.15 K and is subjected to constant temperature treatment for 20 minutes to perform glass annealing treatment, thereby obtaining an Ac-Lys glass.

[0045] FIG. 1 is a photograph of the Ac-Lys glass produced in Example 1 at room temperature, which can be processed into glass beads or glass coating layers.

[0046] FIG. 2 is a DSC-TGA diagram of the Ac-Lys glass produced in Example 1, and its melting temperature T m = 536.70 K, and no significant weight loss was observed at the melting temperature, revealing that Ac-Lys did not decompose when melted at high temperatures.

[0047] FIG. 3 is a DSC diagram of the Ac-Lys glass produced in Example 1, and its glass transition temperature is T g =295.10K.

[0048] Example 2 The method for preparing phenylalanine-based peptide glasses includes the following steps. (1) 50 mg of benzyloxycarbonyl-phenylalanyl-phenylalanyl (Z-Phe-Phe) powder is weighed out and placed in a mortar and ground uniformly, and then transferred to a crucible. (2) The crucible containing the Z-Phe-Phe powder in step (1) was heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) The device from step (2) is subjected to a heat treatment at 40K min -1 The crucible is heated from room temperature to 500 K at a heating rate of 0.15° C. and kept at this temperature for 20 min. (4) The apparatus in step (3) is subjected to a temperature-reducing treatment for 50K min -1The crucible is cooled to 273.15K at a rate of 0.05°C. (5) The sample from step (4) is transferred into an annealing furnace at a temperature of 283.15 K and isothermally treated for 10 minutes to perform glass annealing treatment, thereby obtaining Z-Phe-Phe glass.

[0049] FIG. 4 shows the nuclear magnetic resonance hydrogen spectrum of the Z-Phe-Phe glass produced in Example 2. Compared to the Z-Phe-Phe raw material, the peaks did not change significantly, indicating that the chemical composition of the peptide raw material molecule did not change after undergoing thermal melting and annealing treatment.

[0050] FIG. 5 shows the optical transparency of the Z-Phe-Phe glass produced in Example 2, which is comparable to commercially available glasses.

[0051] FIG. 6 shows the DSC spectrum of the Z-Phe-Phe glass produced in Example 2, and shows that its glass transition temperature is T g =320.75K.

[0052] Example 3 The process for producing glycine-based glass includes the following steps: (1) 30 mg of N-tert-butoxycarbonyl-L-glycine (Boc-Gly) powder is weighed out and placed in a mortar and ground uniformly, and then transferred to a crucible. (2) The crucible containing Boc-Gly in step (1) was heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) Heat treatment is performed on the device in step (2) for 10K min -1 The crucible is heated from room temperature to 600 K at a heating rate of 1000 K and kept at this temperature for 30 min. (4) The apparatus in step (3) is cooled down to 10K min -1 The crucible is cooled to 273.15K at a rate of 0.05°C. (5) The sample from step (4) is transferred to an annealing furnace at a temperature of 283.15 K and isothermally treated for 30 minutes to perform glass annealing treatment, thereby obtaining a Boc-Gly glass.

[0053] FIG. 7 shows polarized microscope photographs of the Boc-Gly powder and the Boc-Gly glass prepared in Example 3, which demonstrate that the glass formed is amorphous.

[0054] Figure 8 shows the biocompatibility test results of the Boc-Gly glass prepared in Example 3. The glass was processed into a square coating layer with a width of 2 cm, and 3T3 cells were co-incubated with it, and the activity of the cells was measured by the MTT method. Note that the glass prepared in Example 3 does not dissolve in a neutral aqueous solution.

[0055] Example 4 The method for making alanine-based glasses includes the following steps: (1) 20 mg of N-tert-butoxycarbonyl-L-alanine (Boc-Ala) powder is weighed out and placed in a mortar and ground uniformly, and then transferred to a crucible. (2) The crucible containing the Boc-Ala powder in step (1) was heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) Heat treatment is performed on the device in step (2) for 5K min -1 The crucible is heated from room temperature to 650K at a heating rate of 0.15°C and kept at this temperature for 5 minutes. (4) The apparatus in step (3) is cooled to 20K min -1 The crucible is cooled to 273.15K at a rate of 0.05°C. (5) The sample from step (4) is transferred to an annealing furnace at a temperature of 283.15 K and isothermally treated for 10 minutes to perform glass annealing treatment, thereby obtaining a Boc-Ala glass.

[0056] FIG. 9 shows the results of measuring the mechanical properties of the Boc-Ala glass produced in Example 4.

[0057] FIG. 10 is a biodegradation curve of the Boc-Ala glass prepared in Example 4 in compost soil samples, with the initial mass of the glass sample being 42.58 mg.

[0058] Example 5 The method for producing glasses based on phenylalanine and glutamic acid includes the following steps: (1) 10 mg of L-phenylalanine ethyl ester powder (Phe-OEt) and 10 mg of N-tert-butoxycarbonyl-L-dimethyl glutamate (Boc-Glu-dME) powder are weighed out and placed in a mortar and ground uniformly. 0.1 wt% copper sulfate powder is added, and the mixture is ground uniformly and then transferred to a crucible. (2) The crucible containing the mixed amino acids in step (1) is heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) Heat treatment is performed on the device in step (2) for 10K min -1 The crucible is heated from room temperature to 550 K at a heating rate of 0.15° C. and kept at this temperature for 10 min. (4) The apparatus in step (3) is cooled down to 10K min -1 The crucible is cooled to 273.15K at a rate of 0.05°C. (5) The sample from step (4) is transferred to an annealing furnace at a temperature of 283.15 K and isothermally treated for 10 minutes to perform glass annealing treatment, thereby obtaining a mixed glass of Phe-OEt / Boc-Glu-dME.

[0059] FIG. 11 shows the performance measurement results of the mixed glass produced in Example 5.

[0060] FIG. 12 shows the decomposition status of the mixed glass prepared in Example 5 in the artificial gastric juice (according to the preparation method of the Chinese Pharmacopoeia).

[0061] 13 shows the change in mouse body weight after intragastric injection of the mixed glass prepared in Example 5. The period of intragastric injection of the mouse was 5 days / time, and the mass was 5 mg kg -1 The observation period was 30 days, and the number of intragastric injections was 5 in total.

[0062] Example 6 The method for producing glasses based on active peptides and amino acid derivatives includes the following steps. (1) 10 mg of immunologically active peptide Val-Gln-Pro-Ile-Pro-Tyr powder and 10 mg of N-tert-butoxycarbonyl-L-arginine methyl ester (Boc-L-Arg-OMe) powder were weighed out and placed in a mortar and ground uniformly, and then transferred to a crucible. (2) The crucible containing the mixed powder in step (1) is heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) Heat treatment is performed on the device in step (2) for 10K min -1 The crucible is heated from room temperature to 450K at a heating rate of 0.15°C and kept at this temperature for 20 minutes. (4) The apparatus in step (3) is cooled down to 10K min -1 The crucible is cooled to 273.15K at a rate of 0.05°C. (5) The sample from step (4) is transferred to an annealing furnace at a temperature of 283.15 K and is subjected to constant temperature treatment for 10 minutes to perform glass annealing treatment, thereby obtaining a mixed glass.

[0063] 14 shows a pattern printed by a 3D printing device using the mixed glass produced in Example 6. The mixed powder is placed in the cartridge of the 3D printing device and the heating temperature is set to 450K.

[0064] FIG. 15 shows the decomposition state of the mixed glass produced in Example 6 after it was embedded in the body of an animal mouse model.

[0065] Example 7 The method for making insulin-loaded amino acid-based glass includes the following steps. (1) 50 mg of a powder of the immunologically active peptide Val-Gln-Pro-Ile-Pro-Tyr is weighed out and placed in a mortar and ground uniformly, and then transferred into a crucible. (2) The crucible containing the mixed powder in step (1) is heated with N 2 The mixture is left in a heating device under atmospheric conditions. (3) Heat treatment is performed on the device in step (2) for 10K min -1The crucible is heated from room temperature to 450K at a heating rate of 1000K, kept at this temperature for 10 minutes, and then cooled to 330K. (4) 5 mg of insulin powder is weighed out and placed in a mortar and ground uniformly. Then, it is transferred to the crucible from step (3), stirred uniformly, and kept at this temperature for 10 minutes to dissolve it. (5) The apparatus of step (4) is subjected to a temperature-lowering treatment at 20K min -1 The crucible is cooled to 273.15K at a rate of 0.05°C. (6) The sample from step (5) is transferred to an annealing furnace at a temperature of 273.15 K and is subjected to constant temperature treatment for 20 minutes to perform glass annealing treatment, thereby obtaining an amino acid-based glass loaded with insulin.

[0066] FIG. 16 shows the time-dependent biodegradation state of the amino acid-based glass carrying insulin produced in Example 7 after being subcutaneously embedded in the body of a mouse.

[0067] FIG. 17 shows the blood glucose change of diabetic mice after the insulin-loaded amino acid-based glass prepared in Example 7 was orally injected into the stomach of the mice.

Claims

1. An amino acid-based bio-molecular glass, the main raw material being one or a combination of two or more of the amino acids, peptides, and derivatives thereof or salts thereof represented by formula (1), the content of the main raw material in the bio-molecular glass being 70 wt % or more, and the transparency of the bio-molecular glass being 30% or more; 【Chemistry 1】 the amino acid is one or a combination of two or more selected from the group consisting of glycine, alanine, valine, leucine, isoleucine, methionine, proline, tryptophan, serine, tyrosine, cysteine, phenylalanine, asparagine, glutamine, threonine, aspartic acid, glutamic acid, lysine, arginine, histidine, selenocysteine, and pyrrolysine; The peptide refers to a molecule formed by condensing n amino acids by peptide bonds, where n is ≧2; The amino acid or peptide derivative refers to an amino acid or peptide having a protecting group on the amino group P1 and / or the carboxy group P2, However, the protecting group on the amino group P1 is Trt, Boc, Fmoc, Cbz / Z, Allyl, C ２ -C １８ one or a combination of two or more selected from the group consisting of an acyl group, a benzoyl group, and a naphthoyl group; the protecting group on the carboxy group P2 is any one or a combination of two or more selected from the group consisting of OFm, Otbu, OBzl, OAll, OMe, and OEt; The amino acid-based biomolecular glass, wherein one or both of the amino group P1 and the carboxy group P2 are protected.

2. 2. The amino acid-based biomolecular glass according to claim 1, characterized in that the content of said main raw material in said biomolecular glass is 80 wt % or more.

3. 2. The amino acid-based biomolecular glass according to claim 1, characterized in that the content of said main raw material in said biomolecular glass is 90 wt % or more.

4. 2. The amino acid-based biomolecular glass according to claim 1, wherein n satisfies 2≦n≦10.

5. 5. The amino acid-based biomolecular glass according to claim 1, wherein all of the biomolecular glass is made from the amino acids, peptides and derivatives thereof.

6. The biomolecular glass is made of a single type of molecule or a combination of two or more types of molecules: the single type of molecule is a single type of amino acid molecule, a single type of peptide molecule, a single type of amino acid derivative, or a single type of peptide derivative; The amino acid-based biomolecular glass according to any one of claims 1 to 5, characterized in that the combinations include a combination of amino acid molecules, a combination of peptide molecules, a combination of amino acid derivative molecules, a combination of peptide molecule derivatives, a combination of amino acid molecules and peptide molecules, a combination of amino acids and amino acid derivatives, a combination of amino acids and peptide derivatives, a combination of peptides and amino acid derivative molecules, a combination of peptides and peptide derivatives, a combination of amino acids, peptides and amino acid derivatives, a combination of amino acids, peptides and peptide derivatives, a combination of amino acids, amino acids, peptides and peptide derivatives, a combination of amino acids, amino acid derivatives and peptide derivatives, or a combination of amino acids, peptides, amino acid derivatives and peptide derivatives.

7. The amino acid-based biological molecular glass according to any one of claims 1 to 4, further comprising an auxiliary material, the auxiliary material being one or a mixture of two or more selected from the group consisting of clarifiers, fluxes, opacifiers, and colorants.

8. The amino acid-based biomolecular glass according to any one of claims 1 to 7, characterized in that the hardness of the biomolecular glass is in the range of 420 to 550 HV.

9. 8. The amino acid-based biomolecular glass according to claim 1, characterized in that the brittleness index (m) of the biomolecular glass is in the range of 10-100.

10. The method for producing the amino acid-based biomolecular glass according to any one of claims 1 to 9, further comprising: heating the raw material to a melting point (T ｍ ) and then maintaining the temperature for a certain period of time, followed by lowering the temperature to room temperature or below, and transferring the cooled sample to an annealing furnace for annealing.

11. The manufacturing method according to claim 10, characterized in that the temperature higher than the melting point temperature is a temperature 5 to 200 K higher than the melting point temperature, and the heat retention time is 5 min to 1 h.

12. The annealing temperature is the glass transition temperature (T ｇ 12. The method according to claim 11, wherein the annealing temperature is 20 to 100 K lower than that of the first annealing step, and the annealing time is 5 min to 3 h.

13. Use of the amino acid based biomolecular glass according to claims 1 to 9 in additive manufacturing, compost, tissue engineering, tooth or bone repair, controlled drug release, cell or protein isolation and storage, optical fiber communication, coating layers or precision instruments.

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