CN107033369B - A kind of preparation method of the enteric solubility hybridized hydrogel based on tyrosine - Google Patents
A kind of preparation method of the enteric solubility hybridized hydrogel based on tyrosine Download PDFInfo
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- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 title claims abstract description 71
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 239000000017 hydrogel Substances 0.000 title claims abstract description 60
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 239000008273 gelatin Substances 0.000 claims abstract description 43
- 229920000159 gelatin Polymers 0.000 claims abstract description 43
- 108010010803 Gelatin Proteins 0.000 claims abstract description 41
- 235000019322 gelatine Nutrition 0.000 claims abstract description 41
- 235000011852 gelatine desserts Nutrition 0.000 claims abstract description 41
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims abstract description 39
- 235000011121 sodium hydroxide Nutrition 0.000 claims abstract description 13
- 239000007787 solid Substances 0.000 claims abstract description 7
- 238000003756 stirring Methods 0.000 claims abstract description 7
- 238000002156 mixing Methods 0.000 claims abstract description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- 239000004033 plastic Substances 0.000 claims description 9
- 239000003292 glue Substances 0.000 claims description 6
- DHRJHCZIYIQEBH-QFIPXVFZSA-N (2S)-2-(9H-fluoren-1-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical group C1(=CC=CC=2C3=CC=CC=C3CC1=2)COC(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O DHRJHCZIYIQEBH-QFIPXVFZSA-N 0.000 claims description 3
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 210000004051 gastric juice Anatomy 0.000 abstract description 14
- 230000000968 intestinal effect Effects 0.000 abstract description 6
- 230000007935 neutral effect Effects 0.000 abstract description 5
- 239000000499 gel Substances 0.000 abstract description 4
- 230000004043 responsiveness Effects 0.000 abstract description 3
- 230000002378 acidificating effect Effects 0.000 abstract description 2
- 239000002520 smart material Substances 0.000 abstract 1
- 108010059881 Lactase Proteins 0.000 description 21
- 108010005774 beta-Galactosidase Proteins 0.000 description 21
- 102100026189 Beta-galactosidase Human genes 0.000 description 20
- 229940116108 lactase Drugs 0.000 description 20
- 239000000243 solution Substances 0.000 description 20
- 108090000790 Enzymes Proteins 0.000 description 18
- 102000004190 Enzymes Human genes 0.000 description 18
- 229940088598 enzyme Drugs 0.000 description 18
- 230000000694 effects Effects 0.000 description 13
- 239000003814 drug Substances 0.000 description 11
- 239000000463 material Substances 0.000 description 11
- 108090000765 processed proteins & peptides Proteins 0.000 description 11
- 238000004090 dissolution Methods 0.000 description 10
- 102000004196 processed proteins & peptides Human genes 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 229920001184 polypeptide Polymers 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 9
- SWZCTMTWRHEBIN-QFIPXVFZSA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-(4-hydroxyphenyl)propanoic acid Chemical compound C([C@@H](C(=O)O)NC(=O)OCC1C2=CC=CC=C2C2=CC=CC=C21)C1=CC=C(O)C=C1 SWZCTMTWRHEBIN-QFIPXVFZSA-N 0.000 description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 8
- 150000001413 amino acids Chemical class 0.000 description 8
- 239000000084 colloidal system Substances 0.000 description 8
- 239000000975 dye Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 6
- YIQKLZYTHXTDDT-UHFFFAOYSA-H Sirius red F3B Chemical compound C1=CC(=CC=C1N=NC2=CC(=C(C=C2)N=NC3=C(C=C4C=C(C=CC4=C3[O-])NC(=O)NC5=CC6=CC(=C(C(=C6C=C5)[O-])N=NC7=C(C=C(C=C7)N=NC8=CC=C(C=C8)S(=O)(=O)[O-])S(=O)(=O)[O-])S(=O)(=O)O)S(=O)(=O)O)S(=O)(=O)[O-])S(=O)(=O)[O-].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+] YIQKLZYTHXTDDT-UHFFFAOYSA-H 0.000 description 5
- 229920000297 Rayon Polymers 0.000 description 4
- 238000009825 accumulation Methods 0.000 description 4
- 239000007853 buffer solution Substances 0.000 description 4
- 239000008367 deionised water Substances 0.000 description 4
- 229910021641 deionized water Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 4
- 238000003760 magnetic stirring Methods 0.000 description 4
- 230000010355 oscillation Effects 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000001338 self-assembly Methods 0.000 description 4
- 238000002604 ultrasonography Methods 0.000 description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 3
- 235000013305 food Nutrition 0.000 description 3
- 210000004211 gastric acid Anatomy 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- -1 Fmoc amino acid Chemical class 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920001577 copolymer Polymers 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000003205 fragrance Substances 0.000 description 2
- 238000001879 gelation Methods 0.000 description 2
- 239000004310 lactic acid Substances 0.000 description 2
- 235000014655 lactic acid Nutrition 0.000 description 2
- 230000014759 maintenance of location Effects 0.000 description 2
- 125000005395 methacrylic acid group Chemical group 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- 238000004088 simulation Methods 0.000 description 2
- KUWPCJHYPSUOFW-SCWFEDMQSA-N (2r,3r,4s,5r)-2-(hydroxymethyl)-6-(2-nitrophenoxy)oxane-3,4,5-triol Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)OC1OC1=CC=CC=C1[N+]([O-])=O KUWPCJHYPSUOFW-SCWFEDMQSA-N 0.000 description 1
- QCVGEOXPDFCNHA-UHFFFAOYSA-N 5,5-dimethyl-2,4-dioxo-1,3-oxazolidine-3-carboxamide Chemical compound CC1(C)OC(=O)N(C(N)=O)C1=O QCVGEOXPDFCNHA-UHFFFAOYSA-N 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 102000002322 Egg Proteins Human genes 0.000 description 1
- 108010000912 Egg Proteins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical group COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 1
- 238000005903 acid hydrolysis reaction Methods 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229920006243 acrylic copolymer Polymers 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 235000014103 egg white Nutrition 0.000 description 1
- 210000000969 egg white Anatomy 0.000 description 1
- 230000007071 enzymatic hydrolysis Effects 0.000 description 1
- 238000006047 enzymatic hydrolysis reaction Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 230000015784 hyperosmotic salinity response Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 description 1
- 239000008055 phosphate buffer solution Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- FGIUAXJPYTZDNR-UHFFFAOYSA-N potassium nitrate Chemical group [K+].[O-][N+]([O-])=O FGIUAXJPYTZDNR-UHFFFAOYSA-N 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 238000003746 solid phase reaction Methods 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 238000010671 solid-state reaction Methods 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J3/00—Processes of treating or compounding macromolecular substances
- C08J3/02—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques
- C08J3/03—Making solutions, dispersions, lattices or gels by other methods than by solution, emulsion or suspension polymerisation techniques in aqueous media
- C08J3/075—Macromolecular gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/16—Nitrogen-containing compounds
- C08K5/20—Carboxylic acid amides
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- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08J—WORKING-UP; GENERAL PROCESSES OF COMPOUNDING; AFTER-TREATMENT NOT COVERED BY SUBCLASSES C08B, C08C, C08F, C08G or C08H
- C08J2389/00—Characterised by the use of proteins; Derivatives thereof
- C08J2389/04—Products derived from waste materials, e.g. horn, hoof or hair
- C08J2389/06—Products derived from waste materials, e.g. horn, hoof or hair derived from leather or skin
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- Chemical & Material Sciences (AREA)
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- Life Sciences & Earth Sciences (AREA)
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- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Inorganic Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- General Chemical & Material Sciences (AREA)
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Abstract
一种基于酪氨酸的肠溶性杂化水凝胶的制备方法，包括以下步骤：将酪氨酸的烧碱溶液与明胶混合，在50‑57℃下用40‑80转/分钟的速度均匀搅拌至明胶固体完全溶解后，超声10‑50s，再调节pH至6.5以下，在1000~1200转/分钟的速度下振荡10‑30s,在0~50℃下静置10分钟以上，待其成胶，即成。本发明制备的杂化水凝胶具有pH响应性，在33℃以上，可以在酸性下成胶，在中性或者碱性环境中溶胶，符合肠溶性智能材料的要求。本发明制备方法步骤简单、成本低，只需混合搅拌即可成胶，不易变质，环境友好，且可在模拟胃液环境中保持胶体状态，模拟肠道环境中溶解。
A preparation method of a tyrosine-based enteric hybrid hydrogel, comprising the following steps: mixing a caustic soda solution of tyrosine with gelatin, and uniformly stirring at a speed of 40-80 rpm at 50-57° C. After the gelatin solid is completely dissolved, ultrasonicate for 10-50s, then adjust the pH to below 6.5, shake for 10-30s at a speed of 1000~1200 rpm, and let stand at 0~50°C for more than 10 minutes, until it becomes gelatinized , and you're done. The hybrid hydrogel prepared by the present invention has pH responsiveness, and can form a gel in an acidic condition above 33° C., and can be sol in a neutral or alkaline environment, which meets the requirements of enteric-soluble smart materials. The preparation method of the invention has simple steps and low cost, only needs to be mixed and stirred to form a gel, is not easy to deteriorate, and is environmentally friendly, and can maintain a colloidal state in a simulated gastric juice environment and dissolve in a simulated intestinal environment.
Description
Technical field
The preparation method of the present invention relates to a kind of enteric solubility hybridized hydrogel based on tyrosine.
Background technique
Currently, certain play active substance (such as drug, enzyme preparation, lactic acid bacteria) in enteron aisle, and when by oral, meeting
It is destroyed by gastric juice, enteron aisle can not be reached and play a role that (pH value of human stomach is about 2.0, and the pH value of small intestine is about
7.4-7.6).It in response to this problem, is the hot and difficult issue studied both at home and abroad currently, design oral intestinal canal discharges embedded material.Mesh
Preceding enteron aisle release embedded material is mostly cellulose family, poly- ethylene methacrylic ether-maleic acid, formaldehyde-gelatin, acrylic acid-methyl
Acrylic copolymers, shellac etc..But these materials all have certain problems: cellulose material, poly- ethylene methacrylic ether-horse
Carry out the needs such as acid copolymer, formaldehyde-gelatin to be modified in foundation structure, complicated for operation, process is more；Acrylic acid-methyl-prop
Olefin(e) acid copolymer analog material fragility is big, needs to be added plasticizer plastic；Shellac is unstable in enteron aisle disintegration.
Hydrogel (hydrogel) is the semisolid colloid substance prepared by gelator and water.In recent years, with polypeptide or
Amino acid is that the supramolecular hydrogel of gelator receives a large amount of concern.Since the preparation process of polypeptide hydrogel is usually
In aqueous environments, hydrogelator passes through intermolecular non-chemical bonding force (hydrogen bond, ionic bond, hydrophobic effect, pi-pi accumulation, model
De Huali etc.), it is self-assembly of tridimensional network, forms semisolid g., jelly-like gelatinous mass with this Bound Water Molecules.Cause
This polypeptide hydrogel has better biocompatibility and biodegradability than other supramolecular hydrogels and high-molecular gel,
And it can be self-assembly of colloid, and cost of manufacture is cheap, easy to operate.
Commercial amino acid includes the commercial amino acid with protection, generally there is tertbutyloxycarbonyl (Boc) protected amino acid and N-
Fluorenylmethyloxycarbonyl (Fmoc) protected amino acid, these band protected amino acids have industrialized, and are mainly used for polypeptide or protein
Synthesis.After Nobel chemistry Prize winner R. Bruce Merrifield since 1984 develops polypeptide solid-state reaction method,
The artificial synthesized of polypeptide soon realizes industrialization.Until now, most of commercialization customization polypeptide chains are protected using Fmoc
The amino acid of shield is obtained by Solid-phase synthesis peptides technology.The commercialization of Fmoc amino acid is greatly promoted polypeptide and egg
White Quality Research and application.
As a member in the polypeptide hydrogel factor, the amino acid or small peptide hydrogel of N- fluorenylmethyloxycarbonyl (Fmoc) have
Bio-compatible is good, biology is degradable, it is chemical modify and many advantageous properties of cheap easily preparation etc., be widely used in cell
The fields such as culture, organizational project, medicament slow release, biological medicine.Fmoc-Y(Fmoc-Tyrosine, N- fluorenylmethyloxycarbonyl-junket ammonia
Acid) as a member in N- fluorenylmethyloxycarbonyl amino acid, there is armaticity, can occur under the action of pi-pi accumulation and hydrogen bond
Self assembly effect.The gel that commercial tyrosine is self-assembly of has special correspondence to pH: can in acid condition plastic, in
Colloidal sol (Aufderhorst-Roberts, et.al, Soft matter, 2012,8,5940- under property slight alkali environment
5946).However, commercial tyrosine hydrogel mechanicalness is lower, aperture is larger, so that commercial tyrosine hydrogel can not be resisted
Destruction of the acid molecule to embedded object (such as enzyme material) in gastric acid.Therefore, the single hydrogel formed by commercial tyrosine is simultaneously
It cannot achieve the effect that protection embedded object in gastric juice, enteron aisle release embedded object very well.
Gelatin is collagen by part Acid hydrolysis (type A gelatin), alkali process hydrolysis (type B gelatin) and enzymatic hydrolysis, purification
And a kind of high molecular weight protein obtained.Gelatin molecule structure is highly stable, can water swelling formed hydrogel, and have it is good
Good biocompatibility and mouthfeel, widely uses as food function substance and nutritional ingredient.Meanwhile unique big point of gelatin
Sub- protein structure characteristic is but also it has the ability for resisting gastric acid.But its thermal stability is poor, at 37 DEG C of normal body temperature
Under melted, and it does not have environment-responsive, therefore limits its answering separately as oral intestinal canal release embedded material
With.
Summary of the invention
The technical problem to be solved by the present invention is to overcome drawbacks described above existing for existing embedded material, provide a kind of base
In the preparation method of the enteric solubility hybridized hydrogel of tyrosine, gained enteric solubility hybridized hydrogel is at 33 DEG C or more, in acid item
Plastic under part, in neutral or basic conditions colloidal sol.
The further technical problems to be solved of the present invention are to overcome drawbacks described above existing for existing embedded material, provide one
Kind good biocompatibility, preparation method is easy, the preparation method of the enteric solubility hybridized hydrogel at low cost based on tyrosine.
The technical solution adopted by the present invention to solve the technical problems is as follows:
A kind of preparation method of the enteric solubility hybridized hydrogel based on tyrosine stirs tyrosine solution and gelatin mixed
It closes,.
The mass ratio of tyrosine and gelatin in the tyrosine solution is preferred 1:12 ~ 16 1:1 ~ 18().
Further, the tyrosine is preferably that (i.e. fmoc- tyrosine, is abbreviated as Fmoc- to N- fluorenylmethyloxycarbonyl-tyrosine
Tyr-OH).
The gelatin can be obtained by commercially available approach.
It further, is the soda bath of tyrosine containing edible caustic soda in the tyrosine solution.
Further, the present invention is used at 50-57 DEG C the following steps are included: mixing the soda bath of tyrosine with gelatin
After 40-80 revs/min of speed uniform stirring is completely dissolved to gelatin solid, ultrasonic 10-50s, then pH is adjusted to 6.5 or less
(preferably 1.5-6.4) vibrates 10-30s under 1000 ~ 1200 revs/min of speed, stands 10 minutes or more at 0 ~ 50 DEG C,
To its plastic,.
Further, in the soda bath of the tyrosine, the concentration of tyrosine is 1.05-147.5mg/mL.Tyrosine
If concentration is lower than 1.05 mg/mL, it is unfavorable for hybridized hydrogel plastic below, and influence its pH responsiveness, and the concentration of tyrosine
If being higher than 147.5 mg/mL, since the solubility of tyrosine is not high, the concentration inaccuracy of tyrosine in the solution will cause, and
It is mixed with gelatin unevenly, eventually leads to that hybridized hydrogel is uneven, and property is unstable.
Further, edible caustic soda is added in the tyrosine solution, it is therefore an objective to adjust pH, and the additive amount of edible caustic soda is
The 8-12% of contained tyrosine in tyrosine solution.The concentration of edible caustic soda is less than the 8% of tyrosine, then can reduce the molten of tyrosine
Xie Du, the concentration for eating caustic soda are greater than the 12% of tyrosine, then will affect the pH of solution, the final formation for influencing hybridized hydrogel.
Further, the mass ratio of the tyrosine in the tyrosine solution and gelatin is 1:1 ~ 18, and gelatin proportion is low
When the ratio, the acid resistance of hybridized hydrogel is not high；When gelatin proportion is higher than the ratio, the temperature of hybridized hydrogel is resistance to
It is reduced by property, i.e., it can colloidal sol at 37 DEG C of human body temperature.
Further, gelling temperature is between 0 ~ 50 DEG C；Lower than 0 DEG C, or it is higher than 50 DEG C, hybridized glue is difficult to form.
The principle of the present invention is: in acid condition, tyrosine and gelatin are acted synergistically by fragrance accumulation and hydrogen bond, from
Assembling forms three-dimensional net structure, with this Bound Water Molecules, enzyme or drug molecule.And in neutral or basic conditions,
The charge that commercial tyrosine carries changes, and intermolecular repulsive force increases, and repulsion is greater than fragrance accumulation and hydrogen bond synergistic effect
Power, so as to cause cross-linked structure relevant to tyrosine collapsing, so as to cause colloid dissolution.
The obtained enteric solubility hybridized hydrogel based on tyrosine of the present invention, the colloid property are: at 33 DEG C or more, glue
Body will form colloid in acidic environment, and not by the influence of acid solution or simulate the gastric juice；By the hybridized hydrogel of formation
It is put into neutral or alkalinity solution, or in simulation enteron aisle solution, colloid can automatic colloidal sol.Therefore it is made in the present invention
Hybridized hydrogel can wrap up directly red 80 and wait dyestuffs, enzyme, drug molecule, at colloidality not by these dyestuffs, enzyme or drug
The influence of molecule.Therefore the present invention is expected to be applied to drug, or is easily destroyed, needed to enteron aisle to reach control release by gastric acid
The enteron aisle of the enzyme isoreactivity substance of effect controls release.
Beneficial effects of the present invention are as follows:
(1) hybridized hydrogel prepared by the present invention has pH responsiveness, and at 33 DEG C or more, (gelatin is unable to the temperature of plastic
In), the requirement of enteric solubility intellectual material can be met in plastic under acidity, the colloidal sol in neutral or alkaline environment.The present invention
Preparation method step is simple, at low cost, need to only be mixed can plastic, be unlikely to deteriorate, it is environmental-friendly, and can be in simulate the gastric juice
Colloidal state is kept in environment, is simulated and is dissolved in intestinal environment.
(2) hybridized hydrogel prepared by the present invention can wrap up directly red 80 and wait dyestuffs, enzyme material or drug molecule,
Gelation is not influenced by these dyestuffs, enzyme or drug molecule, in addition, having good biofacies in view of tyrosine, gelatin
Capacitive, hybridized hydrogel prepared by the present invention are expected to being applied to drug isoreactivity substance (such as enzyme, sour intolerance lactic acid bacteria)
Enteron aisle controls release field.
(3) hybridized hydrogel prepared by the present invention still may exist in high concentration salt solutions, that is, ionic strength is to it
Its Effect of Gelation is little.Therefore, which is salt tolerance hydrogel.
(4) preparation method step of the present invention is simple, low in cost, is unlikely to deteriorate, environmental-friendly.
Detailed description of the invention
Fig. 1 is different proportion tyrosine/gelatin digital photograph.A ~ E be respectively tyrosine concentration be 10 mg/
ML, gelatin mass concentration be respectively 10,50,100,140,180 mg/mL, the hybridized hydrogel that pH is formed at 5.5.
F is the picture of colloid 1h after the buffer solution that pH is 7.5 is added of corresponding A, and so on, G ~ J is to respectively correspond B ~ E's
The digital photograph of hybridized hydrogel 1h after the buffer solution that pH is 7.5 is added.
Fig. 2 is 1(of embodiment of the present invention tyrosine and gelatin mass ratio is 1:8) made of hybridized hydrogel scanning electron microscope
Figure.(as can be seen from Figure, there is 10-50 μm of hole in tyrosine/gelatin hybridized hydrogel microstructure, can be used to wrap
Bury dyestuff, enzyme or drug).
Fig. 3 is that the hybridized hydrogel of embodiment 3 embeds directly red 80 dyestuff, the release profiles at different pH.(by up to
Lower pH is followed successively by 9.0,7.5,7.0,6.0,1.7).
Fig. 4 is the activity of the lactase of different disposal method processing measured in the embodiment of the present invention 4；
The lactase of lactase, gelatin embedding without embedding is that the enzyme activity in the simulate the gastric juice after simulate the gastric juice is added is protected
Stay rate；The lactase of tyrosine hydrogel embedding, the lactase of hybridized hydrogel embedding are by simulate the gastric juice, simulation intestines are added
After liquid, the enzyme activity retention rate of lactase in simulated intestinal fluid.
Specific embodiment
Below with reference to embodiment and attached drawing, the invention will be further described.
Tyrosine used in the embodiment of the present invention is that (i.e. fmoc- tyrosine, is abbreviated as N- fluorenylmethyloxycarbonyl-tyrosine
Fmoc-Tyr-OH), it is purchased from gill biochemistry (Shanghai) Co., Ltd.；Chemical reagent used in other, unless otherwise specified,
It is obtained by routine business approach.
Embodiment 1
The preparation method of the enteric solubility hybridized hydrogel based on tyrosine of the present embodiment, comprising the following steps: weigh food
With caustic soda 4mg, 1mL deionized water is added and obtains soda bath after completely dissolution；40 mg of fmoc- tyrosine powder is taken, is added and burns
In aqueous slkali, after ultrasonic dissolution, 320 mg gelatin is added, is put into 50 DEG C of magnetic stirring apparatus and is uniformly stirred with the speed of 60 turns/min
It mixes to gelatin solid after being completely dissolved, 10 s of ultrasound, adjusts pH to 5.5 with hydrochloric acid solution, shaken with the vortex oscillation instrument of 1000rpm
10s is swung, is rested in 37 DEG C of water-baths 0.5 hour,.
Embodiment 2
The preparation method of the enteric solubility hybridized hydrogel based on tyrosine of the present embodiment, comprising the following steps: weigh food
With 1 mg of caustic soda, 1mL deionized water is added, after completely dissolution, takes fmoc- tyrosine powder 10mg, is added in soda bath, surpass
After sound dissolution, 140 mg gelatin are added, are put into the speed uniform stirring of 60 turns/min in 50 DEG C of magnetic stirring apparatus to gelatin solid
After being completely dissolved, 20 s of ultrasound adjust pH to 5.5 with hydrochloric acid solution, 10 s are vibrated with the vortex oscillation instrument of 1000rpm, in room
Temperature is lower to stand 70 minutes to get the enteric solubility hybridized hydrogel based on tyrosine (referring to Fig. 1, D).PH is added to hybridized hydrogel
For 7.5 phosphate buffer solution, colloid solution after 1h (referring to Fig. 1, L).
Embodiment 3
The preparation method of the enteric solubility hybridized hydrogel based on tyrosine of the present embodiment, include the following steps (tyrosine/
Gelatin hybridized hydrogel embeds directly red 80 dyestuff, and studies hybridized glue and make at different pH to the release of direct red 80 dyestuff
With): edible caustic soda 2mg is weighed, 1mL deionized water is added, after completely dissolution, fmoc- tyrosine powder 20mg is taken, caustic soda is added
In solution, after ultrasonic dissolution, 100 mg gelatin is added, are put into the speed uniform stirring in 50 DEG C of magnetic stirring apparatus with 60 turns/min
After being completely dissolved to gelatin solid, 20 s of ultrasound adjust pH to 5.5 with hydrochloric acid solution, are rapidly added the direct of 0.7 mmol/L
Red 80 dyestuff vibrates 10 s with the vortex oscillation instrument of 1000rpm, stands at room temperature, direct red 80 have been embedded after 100 minutes
Enteric solubility hybridized hydrogel generates.By the enteric solubility hybridized hydrogel for having embedded direct red 80 dyestuff be respectively placed in pH be 1.7,6,
7, in 7.5,9 buffer solution, every 30 minutes, the absorbance of solution is detected at 525nm using ultraviolet specrophotometer.And
It compares, is detected in different pH value with the absorbance of direct red 80 dyestuff of the same concentration not embedded at 525nm
Release action of the hybridized glue to direct red 80 dyestuff of embedding in buffer solution (referring to Fig. 3).
Embodiment 4
The preparation method of the enteric solubility hybridized hydrogel based on tyrosine of the present embodiment, includes the following steps (for hydridization
Hydrogel embeds lactase, and studies hybridized glue at different pH to the release action of lactase): edible 6 mg of caustic soda is weighed,
1mL deionized water is added, after completely dissolution, takes fmoc- tyrosine powder 60mg, is added in soda bath, after ultrasonic dissolution, adds
Enter 300 mg gelatin, is put into 50 DEG C of magnetic stirring apparatus and is completely dissolved with the speed uniform stirring of 60 turns/min to gelatin solid
Afterwards, 20 s of ultrasound adjust pH to 6 with hydrochloric acid solution, are rapidly added 0.5 mL of lactose enzyme aqueous solution of 10 mg/mL, use
The vortex oscillation instrument of 1000rpm vibrates 10s, to get the hybridized hydrogel of embedding lactase after standing 120 minutes at 37 DEG C.
Take the tyrosine hydrogel of the hybridized hydrogel that lactase is embedded in the present embodiment, the lactase for embedding same amount
Each 0.5g of gelatin block (only with gelatin embedding) and embedding amount of the lactase of (being embedded only with tyrosine), embedding same amount
Identical individual lactase (amount for the lactase being added in each test tube is all identical), is put into equipped with 5mL simulate the gastric juice
(1,2,3, No. 4 test tube is respectively corresponded) in test tube, the 2h in 37 DEG C, 100rpm/min water bath chader.
The results show that the gelatin block of the lactase of embedding same amount has dissolved at 37 DEG C.Utilize ortho-nitrophenyl-β-D-
Galactoside method, which directly measures, to be added the simulate the gastric juice (No. 4 test tubes) for the individual lactase not embedded, embedding same amount is added
Lactase gelatin block simulate the gastric juice (No. 3 test tubes) lactase enzyme activity.
It is handled by same simulate the gastric juice, lactase blob of viscose (No. 2 test tubes) and utilization using the embedding of tyrosine hydrogel
There is no dissolutions for the lactase blob of viscose (No. 1 test tube) of hybridized hydrogel embedding, therefore the blob of viscose taken out in simulate the gastric juice is put in dress
Have in the simulated intestinal fluid that 5mL pH is 7.5 and (respectively correspond 5, No. 6 test tubes), is completely dissolved at 37 DEG C to blob of viscose, utilizes adjacent nitre
Base benzene-β-D- galactoside method measures the enzyme activity in 5, No. 6 test tube solutions.
With the enzyme activity of the same amount of lactase handled without simulate the gastric juice for 100% enzyme activity, in triplicate, calculate opposite
Enzyme activity, as enzyme activity retention rate (result is referring to fig. 4).
Claims (4)
1. a kind of preparation method of the enteric solubility hybridized hydrogel based on tyrosine, it is characterised in that: by tyrosine solution and bright
Glue is stirred,；
The mass ratio of tyrosine and gelatin in the tyrosine solution is 1:1 ~ 18；
It is the soda bath of tyrosine containing edible caustic soda in the tyrosine solution；
Preparation method uses 40-80 at 50-57 DEG C specifically includes the following steps: mixing the soda bath of tyrosine with gelatin
Rev/min speed uniform stirring be completely dissolved to gelatin solid after, ultrasonic 10-50s, then adjust pH to 6.5 hereinafter, 1000
10-30s is vibrated under ~ 1200 revs/min of speed, stands 10 minutes or more at 0 ~ 50 DEG C, to its plastic,；
In the soda bath of the tyrosine, the concentration of tyrosine is 1.05-147.5mg/mL；
The additive amount that caustic soda is eaten in the tyrosine solution is the 8-12% of contained tyrosine in tyrosine solution.
2. the preparation method of the enteric solubility hybridized hydrogel according to claim 1 based on tyrosine, it is characterised in that: institute
The mass ratio for stating the tyrosine and gelatin in tyrosine solution is 1:12 ~ 16.
3. the preparation method of the enteric solubility hybridized hydrogel according to claim 1 or 2 based on tyrosine, feature exist
In: the tyrosine is N- fluorenylmethyloxycarbonyl-tyrosine.
4. the preparation method of the enteric solubility hybridized hydrogel according to claim 1 or 2 based on tyrosine, feature exist
In: adjust pH to 1.5-6.4.
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| CN103819610A (en) * | 2012-11-16 | 2014-05-28 | 江南大学 | Preparation method for pH-sensitive inorganic polymer hybrid hydrogel |
| CN106309379A (en) * | 2015-07-01 | 2017-01-11 | 华中药业股份有限公司 | Tyrosine particles and preparation method thereof |
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| CN103819610A (en) * | 2012-11-16 | 2014-05-28 | 江南大学 | Preparation method for pH-sensitive inorganic polymer hybrid hydrogel |
| CN103356692A (en) * | 2013-07-24 | 2013-10-23 | 广东泰宝医疗科技股份有限公司 | Composite antibacterial gel and preparation method thereof |
| CN106309379A (en) * | 2015-07-01 | 2017-01-11 | 华中药业股份有限公司 | Tyrosine particles and preparation method thereof |
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