CN115068408B - PH response 3D printing drug controlled release hydrogel and preparation method and application thereof - Google Patents
PH response 3D printing drug controlled release hydrogel and preparation method and application thereof Download PDFInfo
- Publication number
- CN115068408B CN115068408B CN202210661111.1A CN202210661111A CN115068408B CN 115068408 B CN115068408 B CN 115068408B CN 202210661111 A CN202210661111 A CN 202210661111A CN 115068408 B CN115068408 B CN 115068408B
- Authority
- CN
- China
- Prior art keywords
- printing
- hydrogel
- solution
- model
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000000017 hydrogel Substances 0.000 title claims abstract description 100
- 239000003814 drug Substances 0.000 title claims abstract description 94
- 238000010146 3D printing Methods 0.000 title claims abstract description 88
- 229940079593 drug Drugs 0.000 title claims abstract description 72
- 230000004044 response Effects 0.000 title claims abstract description 37
- 238000013270 controlled release Methods 0.000 title claims abstract description 32
- 238000002360 preparation method Methods 0.000 title claims abstract description 15
- 229920000642 polymer Polymers 0.000 claims abstract description 47
- 229920002125 Sokalan® Polymers 0.000 claims abstract description 44
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims abstract description 43
- 229960001631 carbomer Drugs 0.000 claims abstract description 43
- 238000011049 filling Methods 0.000 claims abstract description 18
- 230000008014 freezing Effects 0.000 claims abstract description 12
- 238000007710 freezing Methods 0.000 claims abstract description 12
- 238000002156 mixing Methods 0.000 claims abstract description 9
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 34
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 34
- 238000001125 extrusion Methods 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 12
- 229920001661 Chitosan Polymers 0.000 claims description 10
- 239000002202 Polyethylene glycol Substances 0.000 claims description 10
- 229920001223 polyethylene glycol Polymers 0.000 claims description 10
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 claims description 5
- 108091003079 Bovine Serum Albumin Proteins 0.000 claims description 5
- VOVIALXJUBGFJZ-KWVAZRHASA-N Budesonide Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@@H]2[C@@H]1[C@@H]1C[C@H]3OC(CCC)O[C@@]3(C(=O)CO)[C@@]1(C)C[C@@H]2O VOVIALXJUBGFJZ-KWVAZRHASA-N 0.000 claims description 5
- 229940098773 bovine serum albumin Drugs 0.000 claims description 5
- 229960004436 budesonide Drugs 0.000 claims description 5
- 229960000381 omeprazole Drugs 0.000 claims description 5
- WWYNJERNGUHSAO-XUDSTZEESA-N (+)-Norgestrel Chemical compound O=C1CC[C@@H]2[C@H]3CC[C@](CC)([C@](CC4)(O)C#C)[C@@H]4[C@@H]3CCC2=C1 WWYNJERNGUHSAO-XUDSTZEESA-N 0.000 claims description 3
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 3
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 3
- 229960004400 levonorgestrel Drugs 0.000 claims description 3
- 229960004157 rabeprazole Drugs 0.000 claims description 3
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 3
- 238000013268 sustained release Methods 0.000 claims 1
- 239000012730 sustained-release form Substances 0.000 claims 1
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 8
- 210000002784 stomach Anatomy 0.000 abstract description 8
- 230000008961 swelling Effects 0.000 abstract description 7
- 239000000243 solution Substances 0.000 description 85
- 239000000976 ink Substances 0.000 description 34
- 239000000843 powder Substances 0.000 description 20
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 239000007787 solid Substances 0.000 description 18
- 239000000523 sample Substances 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 12
- 239000008367 deionised water Substances 0.000 description 12
- 229910021641 deionized water Inorganic materials 0.000 description 12
- 239000000463 material Substances 0.000 description 11
- 238000007639 printing Methods 0.000 description 9
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 7
- 238000010257 thawing Methods 0.000 description 7
- 230000002378 acidificating effect Effects 0.000 description 4
- 238000004132 cross linking Methods 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- JVTIXNMXDLQEJE-UHFFFAOYSA-N 2-decanoyloxypropyl decanoate 2-octanoyloxypropyl octanoate Chemical compound C(CCCCCCC)(=O)OCC(C)OC(CCCCCCC)=O.C(=O)(CCCCCCCCC)OCC(C)OC(=O)CCCCCCCCC JVTIXNMXDLQEJE-UHFFFAOYSA-N 0.000 description 3
- WLAMNBDJUVNPJU-UHFFFAOYSA-N 2-methylbutyric acid Chemical compound CCC(C)C(O)=O WLAMNBDJUVNPJU-UHFFFAOYSA-N 0.000 description 3
- 229940049638 carbomer homopolymer type c Drugs 0.000 description 3
- 229940082484 carbomer-934 Drugs 0.000 description 3
- 229940043234 carbomer-940 Drugs 0.000 description 3
- 239000012520 frozen sample Substances 0.000 description 3
- 238000003760 magnetic stirring Methods 0.000 description 3
- 230000007935 neutral effect Effects 0.000 description 3
- 108090000765 processed proteins & peptides Proteins 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000013267 controlled drug release Methods 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 210000000214 mouth Anatomy 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 230000005588 protonation Effects 0.000 description 2
- 239000006254 rheological additive Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000002522 swelling effect Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000984642 Cura Species 0.000 description 1
- 125000000174 L-prolyl group Chemical group [H]N1C([H])([H])C([H])([H])C([H])([H])[C@@]1([H])C(*)=O 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000005595 deprotonation Effects 0.000 description 1
- 238000010537 deprotonation reaction Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000003238 esophagus Anatomy 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000011056 performance test Methods 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 229940126586 small molecule drug Drugs 0.000 description 1
- 238000007910 systemic administration Methods 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
- A61K38/385—Serum albumin
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- 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
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- 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
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y10/00—Processes of additive manufacturing
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y70/00—Materials specially adapted for additive manufacturing
- B33Y70/10—Composites of different types of material, e.g. mixtures of ceramics and polymers or mixtures of metals and biomaterials
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B33—ADDITIVE MANUFACTURING TECHNOLOGY
- B33Y—ADDITIVE MANUFACTURING, i.e. MANUFACTURING OF THREE-DIMENSIONAL [3-D] OBJECTS BY ADDITIVE DEPOSITION, ADDITIVE AGGLOMERATION OR ADDITIVE LAYERING, e.g. BY 3-D PRINTING, STEREOLITHOGRAPHY OR SELECTIVE LASER SINTERING
- B33Y80/00—Products made by additive manufacturing
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Materials Engineering (AREA)
- Manufacturing & Machinery (AREA)
- Inorganic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Zoology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Ceramic Engineering (AREA)
- Civil Engineering (AREA)
- Composite Materials (AREA)
- Structural Engineering (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention provides a pH response 3D printing drug controlled release hydrogel and a preparation method and application thereof, and belongs to the field of intelligent hydrogels. Providing a polymer solution; providing a carbomer solution; providing a model drug solution; mixing a polymer solution, a carbomer solution and a model drug solution to obtain 3D printing ink; constructing a 3D printing hydrogel model, wherein the internal filling shape of the 3D printing hydrogel model is honeycomb; converting the 3D printed hydrogel model into G codes; and 3D printing is carried out on the 3D printing ink according to the G code, and then freezing and standing at normal temperature are sequentially carried out after a sample is obtained, so that the pH response 3D printing medicine controlled release hydrogel is obtained. The pH response 3D printing medicine controlled release hydrogel disclosed by the invention is not swelled or even deswelled in the stomach, so that the release rate of the medicine is also smaller, and when the hydrogel passes through the intestinal tract, the release rate of the medicine is increased along with the increase of the swelling degree due to the increase of the pH value, and the intestinal tract controllable release of the medicine can be realized.
Description
Technical Field
The invention relates to the technical field of intelligent hydrogels, in particular to a pH response 3D printing drug controlled release hydrogel and a preparation method and application thereof.
Background
Hydrogels are polymeric materials that are insoluble in water at physiological temperatures and pH values, but swell in aqueous media. Hydrogels are of particular interest in controlled drug release applications because of their good biocompatibility, the cross-linked polymer chains form a three-dimensional network that provides a matrix for drug entrapment, where the drug is readily dispersed, and the controlled drug release can be achieved by adjusting the physical and chemical properties of the polymer network.
The oral medicament is a medicament administration mode which has simple operation, high compliance and no invasive injury to the body of a patient. The medicine is absorbed or discharged out of the body after passing through the oral cavity, esophagus and gastrointestinal tract sequentially. During the whole administration process, the medicine needs to be subjected to pH value change, and the medicine finally reaches intestinal tracts with pH value of about 7.4 from oral cavity environment with pH value of 6.7-7.5 to stomach strong acid environment with pH value of about 1.2.
The mass production and use of pharmaceutically active peptides and proteins has become a trend. However, peptide and protein drugs are easily degraded by the low pH gastric juice in the stomach. Traditional drugs cannot be administered at the appropriate time (time-modulated) and/or at the appropriate site (specific site targeting) in a manner that exactly matches the physiological needs.
The 3D printing method can rapidly form the intelligent response hydrogel drug carrier with a unique structure, and can provide novel, effective and price-effective personalized custom drugs for patients.
Disclosure of Invention
In view of the above, the invention aims to provide a pH response 3D printing drug controlled release hydrogel, and a preparation method and application thereof. The pH response 3D printing drug controlled release hydrogel prepared by the invention can realize the controllable release of the drug in intestinal tracts.
In order to achieve the above object, the present invention provides the following technical solutions:
the invention provides a preparation method of pH response 3D printing drug controlled release hydrogel, which comprises the following steps:
providing a polymer solution, wherein the polymer in the polymer solution comprises one or more of polyethylene glycol, polyvinyl alcohol and chitosan;
providing a carbomer solution;
providing a model drug solution;
mixing the polymer solution, the carbomer solution and the model drug solution to obtain 3D printing ink;
constructing a 3D printing hydrogel model by utilizing three-dimensional modeling software, wherein the internal filling shape of the 3D printing hydrogel model is honeycomb;
converting the 3D printed hydrogel model into a G code;
3D printing is carried out on the 3D printing ink according to the G code, so that a sample is obtained;
and sequentially freezing and standing the sample to obtain the pH response 3D printing drug controlled release hydrogel.
Preferably, the mass ratio of the polymer to the carbomer in the carbomer solution to the model drug in the model drug solution is 5-20:1-5:0.05-1.
Preferably, the polymer is a mixture of polyethylene glycol and polyvinyl alcohol or a mixture of polyvinyl alcohol and chitosan.
Preferably, the model drug in the model drug solution comprises one or more of aspirin, bovine serum albumin, budesonide, omeprazole, rabeprazole, and levonorgestrel.
Preferably, the internal filling rate of the 3D printing hydrogel model is 40% -100%.
Preferably, the conditions of 3D printing include: the diameter of the extrusion head of the 3D printer is 200-500 nm, the moving speed of the extrusion head is 5-20 mm/s, the extrusion pressure is 50-100 Pa, and the rotating speed of the screw is 30-100 rad/min.
Preferably, the freezing temperature is-20 ℃ and the time is 12-24 hours.
Preferably, the temperature of the standing is 20-25 ℃ and the time is 12-24 h.
The invention also provides the pH response 3D printing medicine controlled release hydrogel prepared by the preparation method.
The invention also provides application of the pH response 3D printing medicine controlled release hydrogel in preparing a controlled release medicine.
The invention provides a preparation method of pH response 3D printing drug controlled release hydrogel, which comprises the following steps: providing a polymer solution, wherein the polymer in the polymer solution comprises one or more of polyethylene glycol, polyvinyl alcohol and chitosan; providing a carbomer solution; providing a model drug solution; mixing the polymer solution, the carbomer solution and the model drug solution to obtain 3D printing ink; constructing a 3D printing hydrogel model by utilizing three-dimensional modeling software, wherein the internal filling shape of the 3D printing hydrogel model is honeycomb; converting the 3D printed hydrogel model into a G code; 3D printing is carried out on the 3D printing ink according to the G code, so that a sample is obtained; and sequentially freezing and standing the sample to obtain the pH response 3D printing drug controlled release hydrogel.
The pH response 3D printing medicine controlled release hydrogel prepared by the invention is not swelled or even deswelled by carbomer protonation under the acidic condition in the stomach, so that the release rate of the medicine is smaller, when the hydrogel passes through the intestinal tract, the carbomer is deprotonated due to the increase of the pH value, the release rate of the medicine is increased along with the increase of the swelling degree, the controllable release of the medicine in the intestinal tract can be realized, active peptides and protein medicines can be protected from being degraded by gastric acid, the adverse reaction of systemic administration is greatly reduced, and the treatment effect is improved to the maximum extent. The carrier of the pH response 3D printing drug controlled release hydrogel is formed by taking a physical crosslinking hydrogel polymer as a mechanical supporting part, taking carbomer as a rheological modifier with shear thinning performance as a pH response component, and realizing the controlled release of a micromolecular drug by protonation and deprotonation of carboxyl on a molecular chain of the pH response component. Carbomer molecules, as carboxyl donors, can thicken by bonding with one or more hydroxyl groups to form hydrogen bonds, and thus can act as rheology modifiers, imparting 3D printing properties to the ink. Under stomach acidic condition, pH response carbomer molecular chain is protonated, pH response hydrogel is contracted, carboxyl on the carbomer molecular chain is deprotonated under intestinal neutral pH value condition, pH response hydrogel is swelled, and 3D printing pH response hydrogel model medicine is released; the interior of the 3D printing hydrogel model is filled with honeycomb grids with larger specific surface areas, pH response hydrogel carrier structures with different specific surface areas are constructed in a 3D printing mode, the hydrogel response speed can be accelerated due to low filling density and large specific surface area, and the drug controlled release is realized by adjusting the specific surface area of the pH response hydrogel.
Furthermore, in the invention, the drug release rate can be controlled by the hydrogel network crosslinking density and the network size, and increasing the times of freezing and standing (freeze thawing) of the pH responsive hydrogel can enable polymer molecular chains to form more crystal hydrogen bonds, so that the pH responsive hydrogel crosslinking density is increased, pores among the polymer molecular chains are reduced, and the model drug release rate is changed.
Drawings
FIG. 1 is a graph of the shear thinning performance test of a 3D printed carbomer-polyvinyl alcohol pH responsive hydrogel ink of example 1;
FIG. 2 is a photograph showing the preparation process and optics of the 3D printed carbomer-polyvinyl alcohol pH responsive hydrogel material prepared in example 1;
FIG. 3 is a graph showing the swelling curve of a 3D printed carbomer-polyvinyl alcohol pH responsive hydrogel of example 1;
FIG. 4 is a graph showing the pH-responsive hydrogel drug release profile of 3D printed carbomer-polyvinyl alcohol of example 1.
Detailed Description
The invention provides a preparation method of a pH response 3D printing drug controlled release hydrogel, which comprises the following steps of;
providing a polymer solution, wherein the polymer in the polymer solution comprises one or more of polyethylene glycol, polyvinyl alcohol and chitosan;
providing a carbomer solution;
providing a model drug solution;
mixing the polymer solution, the carbomer solution and the model drug solution to obtain 3D printing ink;
constructing a 3D printing hydrogel model by utilizing three-dimensional modeling software, wherein the internal filling shape of the 3D printing hydrogel model is honeycomb;
converting the 3D printed hydrogel model into a G code;
3D printing is carried out on the 3D printing ink according to the G code, so that a sample is obtained;
and sequentially freezing and standing the sample to obtain the pH response 3D printing drug controlled release hydrogel.
The present invention provides a polymer solution, wherein the polymer in the polymer solution comprises one or more of polyethylene glycol, polyvinyl alcohol and chitosan.
In the present invention, the polymer is preferably a mixture of polyethylene glycol and polyvinyl alcohol or a mixture of polyvinyl alcohol and chitosan. When the polymer is preferably a mixture, the mass ratio of each substance in the mixture is not particularly limited, and any mixture may be used in any ratio.
In the present invention, the solvent of the polymer solution is preferably deionized water or acetic acid solution. In the present invention, the preferred concentration of the acetic acid solution is 0.01mol/L, and the method for preparing the acetic acid solution is not particularly limited, and a method for preparing a solution known to those skilled in the art may be used.
The method for preparing the polymer solution is not particularly limited, and methods for preparing solutions known to those skilled in the art may be employed.
In the present invention, the concentration of the polymer solution is preferably 33 to 1000mg/mL.
The present invention provides carbomer solutions.
In the present invention, carbomers in the carbomer solution preferably include one or more of carbomer 934, carbomer 940 and carbomer 941.
In the present invention, the solvent of the carbomer solution is preferably deionized water or sodium hydroxide solution. In the present invention, the concentration of the sodium hydroxide solution is preferably 0.01 to 0.05mol/L, and the method for preparing the sodium hydroxide solution is not particularly limited, and a method for preparing a solution known to those skilled in the art may be used.
The method for preparing the carbomer solution is not particularly limited, and a method for preparing a solution well known to those skilled in the art may be employed.
In the present invention, the concentration of the carbomer solution is preferably 10 to 50mg/mL.
The model drug solution of the invention.
In the present invention, the model drug in the model drug solution preferably includes one or more of aspirin, bovine serum albumin, budesonide, omeprazole, rabeprazole and levonorgestrel.
In the present invention, the solvent of the model drug solution is preferably deionized water. The method for preparing the model drug solution is not particularly limited, and the method for preparing the solution is well known to those skilled in the art.
In the present invention, the concentration of the model drug solution is preferably 5 to 1000mg/mL.
After the polymer solution, the carbomer solution and the model drug solution are obtained, the polymer solution, the carbomer solution and the model drug solution are mixed to obtain the 3D printing ink.
In the invention, the mass ratio of the polymer, the carbomer in the carbomer solution and the model drug in the model drug solution is preferably 5-20:1-5:0.05-1.
In the present invention, the volume ratio of the polymer solution, the carbomer solution and the model drug solution is preferably 10:10:1 to 10:50:1.
After mixing, the obtained mixed solution is preferably transferred into a needle tube matched with an ink direct-writing type 3D printer, mixed for 1-10 min by adopting a planetary stirrer, and defoamed for 0.5-5 min, so that the 3D printing ink is obtained.
The method utilizes three-dimensional modeling software to construct the 3D printing hydrogel model, and the internal filling shape of the 3D printing hydrogel model is honeycomb.
In the present invention, the internal filling rate of the 3D printing hydrogel model is preferably 40% to 100%, more preferably 60%.
In the invention, the 3D printing hydrogel model is preferably a cylinder, the diameter of the cylinder is preferably 0.5-1 cm, the height of the cylinder is preferably 0.5-1 cm, the thickness of the shell layer is preferably 0.2-0.5 cm, and the thickness of the printing layer is preferably 0.2-0.5 cm.
In the present invention, the three-dimensional modeling software preferably includes 3D MAX, auto CAD, solid Works, CATIA, or Pro/E.
After the 3D printed hydrogel model is obtained, the present invention preferably uses slicing software to convert the 3D printed hydrogel model into G-codes.
In the invention, the slicing software is preferably slice 3r and Cura, the constructed 3D printing hydrogel model is sliced, detailed printing parameters are set, and the slice software is further converted into a G code file which can be identified by a printer.
According to the G code, 3D printing is carried out on the 3D printing ink, and a sample is obtained.
The invention preferably installs the needle tube filled with the 3D printing ink on an ink direct-writing type 3D printer, and performs the 3D printing after the preset G code runs without errors.
In the present invention, the detailed parameters of the 3D printing include: the extrusion head diameter of the 3D printer is preferably 200 to 500nm, more preferably 300 to 400nm, the extrusion head moving speed is preferably 5 to 20mm/s, more preferably 10 to 15mm/s, the extrusion pressure is preferably 50 to 100Pa, more preferably 60 to 80Pa, the screw rotation speed is preferably 30 to 100rad/min, more preferably 60 to 80rad/min, and the extrusion head temperature is preferably room temperature.
According to the invention, the G code is read by the ink direct-writing type 3D printer, 3D printing ink is extruded according to a preset three-dimensional shape, and physical crosslinking points are formed among polymer molecular chains through repeated freeze thawing, so that the three-dimensional structure of the 3D printing hydrogel is further fixed.
After the sample is obtained, the sample is frozen and kept stand in sequence, so that the pH response 3D printing drug controlled release hydrogel is obtained.
In the present invention, the temperature of the freezing is preferably-20℃and the time is preferably 12 to 24 hours.
In the present invention, the temperature of the standing is preferably 20 to 25 ℃, more preferably room temperature, and the time is preferably 12 to 24 hours.
The above-mentioned one-time freezing and standing are freezing and thawing processes, and the cycle steps of the freezing and thawing are preferably 2 to 5 times, more preferably 3 to 4 times.
The invention also provides the pH response 3D printing medicine controlled release hydrogel prepared by the preparation method.
The invention also provides application of the pH response 3D printing medicine controlled release hydrogel in preparing a controlled release medicine.
For further explanation of the present invention, the pH-responsive 3D-printed controlled release hydrogel provided by the present invention, and the preparation method and application thereof, are described in detail below with reference to examples, but they should not be construed as limiting the scope of the present invention.
Example 1
1. Weighing 10g of polyvinyl alcohol solid powder, adding the powder into 100mL of deionized water, and magnetically stirring the powder at 90 ℃ for 10 hours (the rotating speed is 1000 r/min) to dissolve the solid powder; a polymer solution was obtained at a concentration of 100mg/mL.
2. 1g, 2g and 3g carbomer 940 solid powder are respectively weighed and added into 100mL deionized water, the solid powder is dissolved by magnetic stirring at room temperature (the rotating speed is 500 r/min) for 3h, 1mL and 1mol/L sodium hydroxide solution are added and uniformly mixed to obtain carbomer solutions, and the concentrations are respectively 10mg/mL, 20mg/mL and 30mg/mL.
3. 1000mg of bovine serum albumin is weighed and added into 100mL of deionized water, and the mixture is magnetically stirred at 4 ℃ for 1h (the rotating speed is 500 r/min) to dissolve solid powder, so that a model drug solution with the concentration of 10mg/mL is obtained.
4. And transferring the prepared polymer solution, carbomer solution and model drug solution into a needle tube adapted to an ink direct-writing type 3D printer according to the volume ratio of 10:10:1, mixing for 1min by adopting a planetary stirrer, and defoaming for 1min to obtain the 3D printing ink.
5. The three-dimensional modeling software builds a 3D printing hydrogel model which is a cylinder with the diameter of 1cm and the height of 1 cm. The three-dimensional model is converted into G codes by adopting slicing software, the thickness of a cylindrical shell layer is set to be 0.2cm, the internal filling shape is honeycomb-shaped, the filling rate is 100%, and the thickness of a printing layer is set to be 0.3cm.
6. And (3) mounting a needle tube filled with 3D printing ink on an ink direct-writing type 3D printer, and selecting an extrusion head with the diameter of 300nm after a preset G code runs correctly, wherein the movement speed of the extrusion head of the printer is 10mm/s, the extrusion pressure is 80Pa, and the rotating speed of a screw is 60rad/min for printing.
7. Transferring the printed sample into a refrigerator with the temperature of minus 20 ℃ to freeze for 12 hours, transferring the frozen sample to room temperature to stand for 12 hours, and circulating the steps for 3 times to prepare the 3D printing pH response hydrogel.
The physical cross-linked network material used in this example is polyvinyl alcohol, the pH responsive polymer is carbomer 940, the model drug is bovine serum albumin, a cylinder with a diameter of 1cm and a height of 1cm and a filling rate of 100% is printed, the number of freeze thawing cycles is 3, and the samples are named as PC10, PC20 and PC30 according to different concentrations of carbomer.
Example 2
1. Weighing 10g of chitosan solid powder and 5g of polyvinyl alcohol solid powder, adding the powder into 100mL of deionized water, adding 1mL of acetic acid solution with the concentration of 1mol/L, and magnetically stirring at 90 ℃ for 12 hours (the rotating speed is 1000 r/min) to dissolve the solid powder; a polymer solution was obtained, wherein the chitosan concentration was 100mg/mL and the polyvinyl alcohol concentration was 50mg/mL.
2. 5g of carbomer 934 solid powder is weighed and added into 100mL of deionized water, the solid powder is dissolved by magnetic stirring (the rotating speed is 500 r/min) for 3h at room temperature, 1.5mL of 1mol/L sodium hydroxide solution is added and uniformly mixed, and carbomer solution is obtained, and the concentration is 50mg/mL.
3. 500mg of budesonide is weighed and added into 100mL of deionized water, and the solution is magnetically stirred at 4 ℃ for 1h (the rotating speed is 500 r/min) to dissolve the solid powder, so that a model drug solution with the concentration of 5mg/mL is obtained.
4. And transferring the prepared polymer solution, carbomer solution and model drug solution into a needle tube adapted to an ink direct-writing type 3D printer according to the volume ratio of 10:20:1, mixing for 3min by adopting a planetary stirrer, and defoaming for 1min to obtain the 3D printing ink.
5. The three-dimensional modeling software builds a 3D printing hydrogel model which is a cylinder with the diameter of 1cm and the height of 0.5cm. The three-dimensional model is converted into G codes by adopting slicing software, the thickness of a cylindrical shell layer is set to be 0.2cm, the internal filling shape is honeycomb-shaped, the filling rate is 60%, and the thickness of a printing layer is set to be 0.2cm.
6. And (3) mounting a needle tube filled with 3D printing ink on an ink direct-writing type 3D printer, and selecting an extrusion head with the diameter of 200nm after a preset G code runs correctly, wherein the movement speed of the extrusion head of the printer is 20mm/s, the extrusion pressure is 60Pa, and the rotating speed of a screw is 100rad/min for printing.
7. Transferring the printed sample into a refrigerator with the temperature of minus 20 ℃ to freeze for 24 hours, transferring the frozen sample to room temperature to stand for 12 hours, and circulating the steps for 5 times to prepare the 3D printing pH response hydrogel.
The physical crosslinked hydrogel material used in this example was chitosan, polyvinyl alcohol, the pH-responsive polymer was carbomer 934, the model drug was budesonide, and a cylinder with a diameter of 1cm, a height of 0.5cm, and a filling rate of 60% was printed, with freeze-thawing cycles 5 times.
Example 3
1. 30g of polyethylene glycol solid powder and 4g of polyvinyl alcohol solid powder are weighed and added into 100mL of deionized water, and the mixture is magnetically stirred at 95 ℃ for 8 hours (the rotating speed is 1000 r/min) to dissolve the solid powder; a polymer solution was obtained, in which the polyethylene glycol concentration was 300mg/mL and the polyvinyl alcohol concentration was 40mg/mL.
2. 4g of carbomer 941 solid powder is weighed and added into 80mL of deionized water, and the solid powder is dissolved by magnetic stirring (the rotating speed is 500 r/min) for 3 hours at room temperature, and 1mL of 1mol/L sodium hydroxide solution is added and uniformly mixed to obtain carbomer solution, wherein the concentration is 50mg/mL.
3. 100mg of omeprazole is weighed and added into 1mL of deionized water, and the mixture is magnetically stirred at room temperature (the rotating speed is 500 r/min) for 1h to dissolve solid powder, so that a model drug solution with the concentration of 100mg/mL is obtained.
4. And transferring the prepared polymer solution, carbomer solution and model drug solution into a needle tube adapted to an ink direct-writing type 3D printer according to the volume ratio of 10:30:1, mixing for 3min by adopting a planetary stirrer, and defoaming for 2min to obtain the 3D printing ink.
5. The three-dimensional modeling software builds a 3D printing hydrogel model which is a cylinder with the diameter of 1cm and the height of 1 cm. The three-dimensional model is converted into G codes by adopting slicing software, the thickness of a cylindrical shell layer is set to be 0.3cm, the internal filling shape is honeycomb-shaped, the filling rate is 40%, and the thickness of a printing layer is set to be 0.3cm.
6. And (3) mounting a needle tube filled with 3D printing ink on an ink direct-writing type 3D printer, and selecting an extrusion head with the diameter of 300nm after a preset G code runs correctly, wherein the movement speed of the extrusion head of the printer is 20mm/s, the extrusion pressure is 50Pa, and the rotating speed of a screw is 80rad/min for printing.
7. Transferring the printed sample into a refrigerator with the temperature of minus 20 ℃ to freeze for 24 hours, transferring the frozen sample to room temperature to stand for 24 hours, and circulating the steps for 3 times to prepare the 3D printing pH response hydrogel.
The physical crosslinked hydrogel material used in this example was polyethylene glycol, polyvinyl alcohol, the pH-responsive polymer was carbomer 941, the model drug was omeprazole, and cylinders with a diameter of 1cm, a height of 1cm, and a fill factor of 40% were printed, with 3 freeze-thaw cycles.
The shear thinning performance of the 3D printing carbomer-polyvinyl alcohol pH-responsive hydrogel ink in example 1 is shown in fig. 1, and the viscosity of the carbomer-polyvinyl alcohol pH-responsive hydrogel ink decreases with increasing shear rate, so that the carbomer-polyvinyl alcohol pH-responsive hydrogel ink has good shear thinning performance and is suitable for ink direct writing 3D printing. The shear thinning properties of the 3D printing hydrogel inks prepared in the remaining examples are similar.
The preparation process and the optical photograph of the 3D printing carbomer-polyvinyl alcohol pH-responsive hydrogel material prepared in example 1 are shown in fig. 2, wherein a is that the carbomer-polyvinyl alcohol pH-responsive hydrogel ink is extruded and deposited into a pre-designed cylinder structure layer by layer along with the movement of the extrusion head of the 3D printer, b is that the photo of the carbomer-polyvinyl alcohol pH-responsive hydrogel sample is printed, and the sample after repeated freeze thawing can maintain the pre-designed cylinder; and has certain mechanical strength and elasticity, is convenient to swallow and can bear the contraction force of stomach. The 3D printed hydrogel material printing process prepared in the remaining examples was similar to that of the printed samples.
Swelling properties of the 3D printed carbomer-polyvinyl alcohol pH responsive hydrogel material prepared in example 1 at different pH values are shown in fig. 3, when the external swelling medium mimics the acidic stomach environment, the pH value is 1.2, the pKa of Yu Kabo m is less, the carboxyl groups on the carbomer molecular chain are protonated, and the 3D printed carbomer-polyvinyl alcohol pH responsive hydrogel undergoes deswelling; when the external swelling medium simulates the neutral environment of intestinal canal, the pH value is 7.4, and when the pH value exceeds the pKa of carbomer, the carboxyl on the carbomer molecular chain is deprotonated, and the hydrogel network is expanded. The swelling properties of the 3D printed pH-responsive hydrogel materials prepared in the remaining examples were similar.
The drug controlled release performance of the 3D printed carbomer-polyvinyl alcohol pH-responsive hydrogel material prepared in example 1 at different pH values is shown in fig. 4, when the external swelling medium simulates the stomach acidic environment, the pH value is 1.2, the carboxyl groups on the carbomer molecular chains are protonated, the 3D printed carbomer-polyvinyl alcohol pH-responsive hydrogel molecular network shrinks, and the small molecule drug is difficult to diffuse outside the hydrogel; when the external swelling medium simulates the neutral environment of intestinal tracts, and when the pH is larger than the pKa of Yu Kabo mu, the carboxyl on the carbomer molecular chain is deprotonated, the hydrogel network is swelled, and the small molecular medicine can be rapidly released from the hydrogel three-dimensional network to the outside. The 3D printing carbomer-polyvinyl alcohol pH response hydrogel can realize release of small molecular medicines at different rates by adjusting the carbomer concentration in the system. The drug controlled release properties of the 3D printed pH responsive hydrogel materials prepared in the remaining examples are similar.
The foregoing is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. It should be noted that modifications and adaptations to the present invention may occur to one skilled in the art without departing from the principles of the present invention and are intended to be comprehended within the scope of the present invention.
Claims (6)
1. The preparation method of the pH response 3D printing drug controlled release hydrogel is characterized by comprising the following steps of:
providing a polymer solution, wherein the polymer in the polymer solution is polyvinyl alcohol, a mixture of polyethylene glycol and polyvinyl alcohol or a mixture of polyvinyl alcohol and chitosan;
providing a carbomer solution;
providing a model drug solution;
mixing the polymer solution, the carbomer solution and the model drug solution to obtain 3D printing ink;
constructing a 3D printing hydrogel model by utilizing three-dimensional modeling software, wherein the internal filling shape of the 3D printing hydrogel model is honeycomb;
converting the 3D printed hydrogel model into a G code;
3D printing is carried out on the 3D printing ink according to the G code, so that a sample is obtained;
freezing and standing the sample in sequence to obtain the pH response 3D printing drug controlled release hydrogel;
the mass ratio of the polymer to the carbomer in the carbomer solution to the model drug in the model drug solution is 5-20:1-5:0.05-1;
the model drug in the model drug solution comprises one or more of aspirin, bovine serum albumin, budesonide, omeprazole, rabeprazole and levonorgestrel;
the conditions of 3D printing include: the diameter of an extrusion head of the 3D printer is 200-500 nm, the moving speed of the extrusion head is 5-20 mm/s, the extrusion pressure is 50-100 Pa, and the rotating speed of a screw is 30-100 rad/min.
2. The method of claim 1, wherein the 3D printed hydrogel model has an internal filling rate of 40% -100%.
3. The method according to claim 1, wherein the freezing temperature is-20 ℃ and the time is 12-24 hours.
4. The method according to claim 1 or 3, wherein the standing temperature is 20 to 25 ℃ and the time is 12 to 24 hours.
5. The pH-responsive 3D-printed drug controlled release hydrogel prepared by the method of any one of claims 1-4.
6. The use of the pH-responsive 3D printing drug controlled release hydrogel of claim 5 in the preparation of a sustained release drug.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210661111.1A CN115068408B (en) | 2022-06-13 | 2022-06-13 | PH response 3D printing drug controlled release hydrogel and preparation method and application thereof |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202210661111.1A CN115068408B (en) | 2022-06-13 | 2022-06-13 | PH response 3D printing drug controlled release hydrogel and preparation method and application thereof |
Publications (2)
Publication Number | Publication Date |
---|---|
CN115068408A CN115068408A (en) | 2022-09-20 |
CN115068408B true CN115068408B (en) | 2024-01-26 |
Family
ID=83250384
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202210661111.1A Active CN115068408B (en) | 2022-06-13 | 2022-06-13 | PH response 3D printing drug controlled release hydrogel and preparation method and application thereof |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN115068408B (en) |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107365158A (en) * | 2017-08-28 | 2017-11-21 | 武汉理工大学 | A kind of structural ceramics lotion for extruded type 3D printing and preparation method thereof |
CN107412853A (en) * | 2017-05-19 | 2017-12-01 | 暨南大学 | Shape memory gel and the application in controlled release preparation made of 3D printing |
CN108582765A (en) * | 2018-01-09 | 2018-09-28 | 南京三迭纪医药科技有限公司 | A kind of drug 3 D-printing device of precision |
CN111655240A (en) * | 2018-01-09 | 2020-09-11 | 南京三迭纪医药科技有限公司 | Dosage forms capable of achieving targeted release profiles and methods of designing and preparing same |
CN111973568A (en) * | 2020-08-28 | 2020-11-24 | 广东药科大学 | 3D printing-based preparation floatable drug sustained-release carrier with micro air bags and preparation method and application thereof |
WO2021081540A1 (en) * | 2019-10-24 | 2021-04-29 | Briopryme Biologics, Inc. | Preparation and use of therapeutic hydrogels |
CN113398085A (en) * | 2021-05-17 | 2021-09-17 | 吉林大学 | Programmable controlled-release temperature response type hydrogel capsule shell and preparation method thereof |
CN114316685A (en) * | 2021-12-21 | 2022-04-12 | 江南大学 | Ink direct-writing 3D printing PEDOT/PSS composite hydrogel and preparation method thereof |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20210138066A1 (en) * | 2019-11-08 | 2021-05-13 | California Institute Of Technology | Remote-controlled image-guided drug delivery via ultrasound-modulated molecular diffusion |
KR102474673B1 (en) * | 2020-10-15 | 2022-12-08 | 한국재료연구원 | Method of manufacturing free-standing ceramic 3D printing structure |
-
2022
- 2022-06-13 CN CN202210661111.1A patent/CN115068408B/en active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN107412853A (en) * | 2017-05-19 | 2017-12-01 | 暨南大学 | Shape memory gel and the application in controlled release preparation made of 3D printing |
CN107365158A (en) * | 2017-08-28 | 2017-11-21 | 武汉理工大学 | A kind of structural ceramics lotion for extruded type 3D printing and preparation method thereof |
CN108582765A (en) * | 2018-01-09 | 2018-09-28 | 南京三迭纪医药科技有限公司 | A kind of drug 3 D-printing device of precision |
CN111655240A (en) * | 2018-01-09 | 2020-09-11 | 南京三迭纪医药科技有限公司 | Dosage forms capable of achieving targeted release profiles and methods of designing and preparing same |
WO2021081540A1 (en) * | 2019-10-24 | 2021-04-29 | Briopryme Biologics, Inc. | Preparation and use of therapeutic hydrogels |
CN111973568A (en) * | 2020-08-28 | 2020-11-24 | 广东药科大学 | 3D printing-based preparation floatable drug sustained-release carrier with micro air bags and preparation method and application thereof |
CN113398085A (en) * | 2021-05-17 | 2021-09-17 | 吉林大学 | Programmable controlled-release temperature response type hydrogel capsule shell and preparation method thereof |
CN114316685A (en) * | 2021-12-21 | 2022-04-12 | 江南大学 | Ink direct-writing 3D printing PEDOT/PSS composite hydrogel and preparation method thereof |
Also Published As
Publication number | Publication date |
---|---|
CN115068408A (en) | 2022-09-20 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Kashyap et al. | Hydrogels for pharmaceutical and biomedical applications | |
KR0146960B1 (en) | Solid porous unitary form comprising micro-particles and/or nano-particles, and its preparation | |
US6200600B1 (en) | Controlled delay release device | |
EP1697481A2 (en) | Bioadhesive polymers with catechol functionality | |
JPH11507343A (en) | Apparatus and method for delivering a bioactive substance to a biological environment | |
EP0384642A1 (en) | Dispensing device | |
JPH03167116A (en) | Sustained release element and its preparation | |
CN102604065B (en) | Cross-linked biologically degradable carrier polymer, micelle and vesicle, and preparation method and application of the cross-linked biologically degradable carrier polymer, micelle and vesicle | |
Anal | Stimuli-induced pulsatile or triggered release delivery systems for bioactive compounds | |
CN107982239B (en) | Protein-based non-spherical microcapsule with hydrophobic drug crystal as template and preparation method thereof | |
CN115192542B (en) | Oral nanometer drug delivery system mediated by small molecule nutrient substances | |
CN112641931A (en) | Preparation method of exenatide microneedle | |
CN115068408B (en) | PH response 3D printing drug controlled release hydrogel and preparation method and application thereof | |
TWI619517B (en) | Gel composition and method for manufacturing gel composition | |
CN105534878A (en) | Preparation of dual-responsive injectable supramolecular intelligent hydrogel | |
MohanKumar et al. | Hydrogels: potential aid in tissue engineering—a review | |
JP2007516220A (en) | Method for producing thermoforming composition containing acrylic polymer adhesive, pharmaceutical preparation and method for producing the preparation | |
CN102657871B (en) | Oral slow release preparation, entrapment material and preparation method | |
WO2021047628A1 (en) | Sustained-release microneedle patch and preparation method therefor | |
Saharan et al. | Hydrogel-based Drug Delivery System in Diabetes Management | |
Li et al. | Advances and applications of metal-organic framework nanomaterials as oral delivery carriers: A review | |
Lee et al. | Biphasic release characteristics of dual drug-loaded alginate beads | |
Tiwari et al. | A Review-Nanogel Drug Delivery System | |
CN1101185C (en) | Release-controlling medicinal capsule able to form on-wall porous structure in body | |
CN114984244A (en) | Hyperbranched polylysine-containing hydrogel carrier material and preparation method thereof |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |