CN110812687A - Preparation method of porous polymer microneedle - Google Patents
Preparation method of porous polymer microneedle Download PDFInfo
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- CN110812687A CN110812687A CN201911125347.8A CN201911125347A CN110812687A CN 110812687 A CN110812687 A CN 110812687A CN 201911125347 A CN201911125347 A CN 201911125347A CN 110812687 A CN110812687 A CN 110812687A
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- Prior art keywords
- porous polymer
- microneedle
- polyvinyl alcohol
- microneedles
- cellulose
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- 229920000642 polymer Polymers 0.000 title claims abstract description 35
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 239000004372 Polyvinyl alcohol Substances 0.000 claims abstract description 33
- 229920002451 polyvinyl alcohol Polymers 0.000 claims abstract description 33
- 239000001913 cellulose Substances 0.000 claims abstract description 22
- 229920002678 cellulose Polymers 0.000 claims abstract description 22
- 238000010438 heat treatment Methods 0.000 claims abstract description 19
- 238000000034 method Methods 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 238000011282 treatment Methods 0.000 claims abstract description 14
- 238000005213 imbibition Methods 0.000 claims abstract description 10
- 238000004519 manufacturing process Methods 0.000 claims abstract description 10
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 8
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 12
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 8
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 8
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 238000005266 casting Methods 0.000 claims description 7
- 229910052751 metal Inorganic materials 0.000 claims description 7
- 239000002184 metal Substances 0.000 claims description 7
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 claims description 6
- 150000001299 aldehydes Chemical group 0.000 claims description 5
- 229910000881 Cu alloy Inorganic materials 0.000 claims description 4
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000990 Ni alloy Inorganic materials 0.000 claims description 4
- 230000018044 dehydration Effects 0.000 claims description 4
- 238000006297 dehydration reaction Methods 0.000 claims description 4
- 238000004512 die casting Methods 0.000 claims description 4
- LEQAOMBKQFMDFZ-UHFFFAOYSA-N glyoxal Chemical compound O=CC=O LEQAOMBKQFMDFZ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052710 silicon Inorganic materials 0.000 claims description 4
- 239000010703 silicon Substances 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- UMHJEEQLYBKSAN-UHFFFAOYSA-N Adipaldehyde Chemical compound O=CCCCCC=O UMHJEEQLYBKSAN-UHFFFAOYSA-N 0.000 claims description 3
- VYZAMTAEIAYCRO-UHFFFAOYSA-N Chromium Chemical compound [Cr] VYZAMTAEIAYCRO-UHFFFAOYSA-N 0.000 claims description 3
- HZEWFHLRYVTOIW-UHFFFAOYSA-N [Ti].[Ni] Chemical compound [Ti].[Ni] HZEWFHLRYVTOIW-UHFFFAOYSA-N 0.000 claims description 3
- 239000004205 dimethyl polysiloxane Substances 0.000 claims description 3
- 238000000465 moulding Methods 0.000 claims description 3
- 229910052759 nickel Inorganic materials 0.000 claims description 3
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims description 3
- 229920003229 poly(methyl methacrylate) Polymers 0.000 claims description 3
- -1 polydimethylsiloxane Polymers 0.000 claims description 3
- 239000004926 polymethyl methacrylate Substances 0.000 claims description 3
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 claims description 2
- 229910000914 Mn alloy Inorganic materials 0.000 claims description 2
- 229910001069 Ti alloy Inorganic materials 0.000 claims description 2
- RTAQQCXQSZGOHL-UHFFFAOYSA-N Titanium Chemical compound [Ti] RTAQQCXQSZGOHL-UHFFFAOYSA-N 0.000 claims description 2
- 239000007864 aqueous solution Substances 0.000 claims description 2
- 238000006243 chemical reaction Methods 0.000 claims description 2
- 229910052804 chromium Inorganic materials 0.000 claims description 2
- 239000011651 chromium Substances 0.000 claims description 2
- 229910052802 copper Inorganic materials 0.000 claims description 2
- 239000010949 copper Substances 0.000 claims description 2
- HPDFFVBPXCTEDN-UHFFFAOYSA-N copper manganese Chemical compound [Mn].[Cu] HPDFFVBPXCTEDN-UHFFFAOYSA-N 0.000 claims description 2
- YOCUPQPZWBBYIX-UHFFFAOYSA-N copper nickel Chemical compound [Ni].[Cu] YOCUPQPZWBBYIX-UHFFFAOYSA-N 0.000 claims description 2
- IUYOGGFTLHZHEG-UHFFFAOYSA-N copper titanium Chemical compound [Ti].[Cu] IUYOGGFTLHZHEG-UHFFFAOYSA-N 0.000 claims description 2
- 229940015043 glyoxal Drugs 0.000 claims description 2
- MECMQNITHCOSAF-UHFFFAOYSA-N manganese titanium Chemical compound [Ti].[Mn] MECMQNITHCOSAF-UHFFFAOYSA-N 0.000 claims description 2
- WPBNNNQJVZRUHP-UHFFFAOYSA-L manganese(2+);methyl n-[[2-(methoxycarbonylcarbamothioylamino)phenyl]carbamothioyl]carbamate;n-[2-(sulfidocarbothioylamino)ethyl]carbamodithioate Chemical compound [Mn+2].[S-]C(=S)NCCNC([S-])=S.COC(=O)NC(=S)NC1=CC=CC=C1NC(=S)NC(=O)OC WPBNNNQJVZRUHP-UHFFFAOYSA-L 0.000 claims description 2
- 238000002844 melting Methods 0.000 claims description 2
- 230000008018 melting Effects 0.000 claims description 2
- WSFSSNUMVMOOMR-NJFSPNSNSA-N methanone Chemical compound O=[14CH2] WSFSSNUMVMOOMR-NJFSPNSNSA-N 0.000 claims description 2
- 229920002120 photoresistant polymer Polymers 0.000 claims description 2
- 239000010936 titanium Substances 0.000 claims description 2
- 229910052719 titanium Inorganic materials 0.000 claims description 2
- WFKWXMTUELFFGS-UHFFFAOYSA-N tungsten Chemical compound [W] WFKWXMTUELFFGS-UHFFFAOYSA-N 0.000 claims description 2
- 229910052721 tungsten Inorganic materials 0.000 claims description 2
- 239000010937 tungsten Substances 0.000 claims description 2
- 229910001179 chromel Inorganic materials 0.000 claims 1
- 229910001026 inconel Inorganic materials 0.000 claims 1
- OEIJHBUUFURJLI-UHFFFAOYSA-N octane-1,8-diol Chemical compound OCCCCCCCCO OEIJHBUUFURJLI-UHFFFAOYSA-N 0.000 claims 1
- 230000000149 penetrating effect Effects 0.000 claims 1
- 238000002156 mixing Methods 0.000 abstract description 14
- 239000004088 foaming agent Substances 0.000 abstract description 6
- 238000001816 cooling Methods 0.000 abstract description 3
- 238000004140 cleaning Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000003756 stirring Methods 0.000 description 12
- 239000000126 substance Substances 0.000 description 12
- 239000003814 drug Substances 0.000 description 11
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000012153 distilled water Substances 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 238000005303 weighing Methods 0.000 description 6
- 239000000463 material Substances 0.000 description 5
- 210000003491 skin Anatomy 0.000 description 5
- 238000004108 freeze drying Methods 0.000 description 4
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 3
- 229910052755 nonmetal Inorganic materials 0.000 description 3
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 239000008098 formaldehyde solution Substances 0.000 description 2
- 235000015097 nutrients Nutrition 0.000 description 2
- OADYBSJSJUFUBR-UHFFFAOYSA-N octanedial Chemical compound O=CCCCCCCC=O OADYBSJSJUFUBR-UHFFFAOYSA-N 0.000 description 2
- 230000037368 penetrate the skin Effects 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000002344 surface layer Substances 0.000 description 2
- 241001391944 Commicarpus scandens Species 0.000 description 1
- 101001018064 Homo sapiens Lysosomal-trafficking regulator Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229910001030 Iron–nickel alloy Inorganic materials 0.000 description 1
- 102100033472 Lysosomal-trafficking regulator Human genes 0.000 description 1
- 235000010703 Modiola caroliniana Nutrition 0.000 description 1
- 244000038561 Modiola caroliniana Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003796 beauty Effects 0.000 description 1
- BIJOYKCOMBZXAE-UHFFFAOYSA-N chromium iron nickel Chemical compound [Cr].[Fe].[Ni] BIJOYKCOMBZXAE-UHFFFAOYSA-N 0.000 description 1
- VNNRSPGTAMTISX-UHFFFAOYSA-N chromium nickel Chemical compound [Cr].[Ni] VNNRSPGTAMTISX-UHFFFAOYSA-N 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000007598 dipping method Methods 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 238000000554 physical therapy Methods 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 238000004064 recycling Methods 0.000 description 1
- 238000002791 soaking Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 230000037317 transdermal delivery Effects 0.000 description 1
- 238000013271 transdermal drug delivery Methods 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
-
- 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
- A61K47/38—Cellulose; Derivatives thereof
-
- 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
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
- A61K9/0021—Intradermal administration, e.g. through microneedle arrays, needleless injectors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M37/00—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin
- A61M37/0015—Other apparatus for introducing media into the body; Percutany, i.e. introducing medicines into the body by diffusion through the skin by using microneedles
- A61M2037/0053—Methods for producing microneedles
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Inorganic Chemistry (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hematology (AREA)
- Materials For Medical Uses (AREA)
Abstract
The invention provides a preparation method of a porous polymer microneedle, which comprises the steps of heating and dissolving polyvinyl alcohol (PVA) in water, uniformly mixing the PVA with cellulose subjected to full imbibition treatment, and cooling to 30-45 ℃; then adding a cross-linking agent, and dropwise adding acid to adjust the pH value; and (4) forming on a female die, and dehydrating to obtain the porous polymer microneedle. The invention has simple and easy operation process, easily obtained raw materials and convenient production control. The method does not need to carry out subsequent cleaning and removal on the pore-foaming agent, simplifies the process flow and lightens the pressure of post-treatment.
Description
Technical Field
The invention relates to a preparation method of a porous polymer microneedle, which is used for the transdermal drug delivery or the beauty skin care industry and belongs to the field of biomedical high polymer materials.
Background
The micro-needle can be used for transdermal delivery of medicines or nutrients as a physical permeation promoting mode, and can also be used for treating diseases by using a physical therapy electrode. The microneedle has the characteristics of small size and no contact with the nerves of the dermis, so that the microneedle does not cause pain in the use process and can be suitable for most people; in addition, in the aspect of transdermal absorption, the gel patch can replace a common gel patch to realize continuous painless administration, the micro-needle penetrates into the skin to generate a micro-channel, and the medicine can directly enter the human body by bypassing the epidermis through the channel, so that the effective utilization rate is improved. The demand for microneedles is also increasing dramatically with the increasing demand for quality of life.
Microneedles are currently roughly classified into solid microneedles and hollow microneedles, wherein the hollow microneedles further include porous microneedles, the hollow microneedles can maintain large-dose continuous delivery of drugs or nutrients for a long time, and the porous microneedles are mostly used for small-dose drug delivery and can be used together with different drugs according to circumstances, so that the microneedles are favored. From the viewpoint of manufacturing materials, microneedles can be classified into three categories, namely, metal, polymer, and inorganic nonmetal. Since the microneedles need to penetrate the skin, the materials used for them need to be considered for biocompatibility and for expulsion in or on the body. The biocompatibility of metal and inorganic nonmetal, especially glass, silicon and other materials in the inorganic nonmetal is relatively poor, so that slight inflammation is easily caused to a punctured part, and the surface of the microneedle needs to be treated. The polymer has good biocompatibility, but the hollow microneedle has poor strength and is not easy to pierce into the skin, so that the base material is organically combined with the medicament when the microneedle is manufactured and exists in a solid microneedle form, the fit between the material and the medicament needs to be considered in the manufacturing process, and meanwhile, higher requirements are provided for the storage of microneedle finished products. Compared with hollow microneedles, the porous polymer microneedles are higher in strength, can be matched with different medicines according to conditions, can be used at any time, are prepared by mixing polymers and foaming agents or pore-forming agents and then removing the pore-forming agents to obtain the porous microneedles. However, the removal of the pore-forming agent generally requires acid-base soaking (volatile pore-forming agent can be directly removed, but the cost is high, and the pore-forming agent needs to be subjected to post-treatment and recycling), the steps are complicated, and the post-treatment is troublesome.
Disclosure of Invention
Aiming at the problems in the preparation of the porous microneedle, the invention provides a preparation method of the porous polymer microneedle, which takes water-insoluble cellulose as a pore-foaming agent, utilizes the characteristic of water swelling of the pore-foaming agent, mixes the pore-foaming agent with cross-linked PVA, and then performs injection molding and dehydration to obtain the porous polymer microneedle. The method does not need to remove pore-forming agent, the microneedle has good compatibility with skin, high toughness and strength and is not easy to break, and the microneedle can be used for loading a certain dose of medicine and treating diseases.
The technical scheme adopted by the invention is as follows:
heating and dissolving polyvinyl alcohol (PVA) in water, uniformly mixing the PVA with cellulose subjected to full imbibition treatment, and cooling to 30-45 ℃; then adding a cross-linking agent, and dropwise adding acid to adjust the pH value; and (4) forming on a female die, and dehydrating to obtain the porous polymer microneedle.
The preparation method comprises the following steps:
the concentration of the aqueous solution of the polyvinyl alcohol is 8-40%;
the mass ratio of the polyvinyl alcohol to the cellulose is 1: 0.1-20;
the cellulose is water-insoluble cellulose, and the size of the cellulose is 5-100 mu m;
the acid is any one of hydrochloric acid, sulfuric acid and acetic acid;
the cross-linking agent is an aldehyde cross-linking agent, and can be selected from formaldehyde, glutaraldehyde, glyoxal, adipaldehyde, suberaldehyde and the like, preferably formaldehyde;
the two ends of the female die are communicated, the female die is made of metal, polymer, silicon or photoresist, the female die does not react with or is dissolved in acid, water, aldehyde and polyvinyl alcohol in a reaction system, and the melting point or softening temperature is higher than the microneedle manufacturing temperature; the metal is any one of copper, chromium, nickel, tungsten, manganese, titanium, chromium-nickel alloy, titanium-nickel alloy, copper-titanium alloy, titanium-manganese alloy, nickel-copper alloy, manganese-copper alloy and chromium-nickel-iron alloy; the polymer is polymethyl methacrylate or polydimethylsiloxane.
The method for forming on the female die is casting or die-casting; wherein, vacuum is needed on the other side during casting so that the solution fills the female die; in the forming process, the female die needs to be heated, the temperature is 50-100 ℃, and the heating time is 5-180 s;
the dehydration is vacuum drying or freeze vacuum drying under a heating state.
The invention has simple and easy operation process, easily obtained raw materials and convenient production control. Wherein the cellulose is a water-insoluble pore-forming agent, absorbs water to expand, the PVA shrinks to a certain extent in the cross-linking process, the water absorbed by the cellulose and the water in the PVA solution are removed in the dehydration process, a channel with a certain aperture is formed around the cellulose, and the medicine can rapidly enter and exit and diffuse through the channel; in addition, the cellulose can also provide certain support for the cross-linked PVA, so that the cross-linked PVA is enhanced, and the microneedle can smoothly penetrate into the skin to operate. Meanwhile, the method does not need to carry out subsequent cleaning and removal on the pore-foaming agent, simplifies the process flow and reduces the pressure of post-treatment.
Detailed Description
The invention provides a preparation method of a porous polymer microneedle, which comprises the following steps: heating polyvinyl alcohol (PVA) in water to dissolve, uniformly mixing with cellulose subjected to full imbibition treatment, cooling to 30-45 ℃, adding acid and a crosslinking agent, and forming on a female die, wherein in the forming process, the female die is heated at 50-100 ℃ for 5-180 s; and then dehydrated to obtain the porous polymer microneedle.
Example one
Weighing 2.5g of polyvinyl alcohol, adding 15g of distilled water, stirring and heating at 85 ℃ for dissolving, adding 0.3g of 100 mu m cellulose subjected to complete imbibition treatment after the polyvinyl alcohol is completely dissolved, uniformly mixing, reducing the temperature to 40 ℃, adding 3.8mL of formaldehyde solution into a liquid-transfering gun, slowly dropwise adding hydrochloric acid until the pH value is 2, continuously stirring and mixing for 10min, casting a mixed substance on a polydimethylsiloxane female die, applying vacuum on the other side of the die, heating the die for 180s at 50 ℃ after the mixed substance is filled in a die cavity, dehydrating in a vacuum box at 40 ℃, and slightly separating a forming film with microneedles from the die to obtain the porous polymer microneedles.
Example two
Weighing 3g of polyvinyl alcohol, adding 10g of distilled water, stirring and heating at 80 ℃ for dissolving, adding 10g of 50 mu m cellulose subjected to complete imbibition treatment after the polyvinyl alcohol is completely dissolved, uniformly mixing, reducing the temperature to 30 ℃, adding 4mL of suberaldehyde solution into a liquid transfer gun, slowly dropwise adding sulfuric acid until the pH value is 3, continuously stirring and mixing for 10min, casting a mixed substance on a silicon female mold, applying vacuum on the other side of the mold, heating the mold at 65 ℃ for 120s after the mixed substance is filled in the mold cavity, dehydrating in a 50 ℃ vacuum box, and slightly separating a molding film with microneedles from the mold to obtain the porous polymer microneedles.
EXAMPLE III
Weighing 3.5g of polyvinyl alcohol, adding 7g of distilled water, stirring and heating at 90 ℃ for dissolving, adding 30g of 30 mu m cellulose subjected to complete imbibition treatment after the polyvinyl alcohol is completely dissolved, uniformly mixing, reducing the temperature to 45 ℃, adding 3.8mL of hexanedial solution into a liquid-transfering gun, slowly dropwise adding sulfuric acid until the pH value is 2, continuously stirring and mixing for 10min, casting a mixed substance on a polymethyl methacrylate female mould, applying vacuum on the other side of the mould, heating the mould at 80 ℃ for 60s after the mould cavity is filled with the mixed substance, freeze-drying and dehydrating at-20 ℃, and slightly separating a forming film with the microneedle from the mould to obtain the porous polymer microneedle.
Example four
Weighing 4g of polyvinyl alcohol, adding 10g of distilled water, stirring and heating at 95 ℃ for dissolving, adding 50g of 20 mu m cellulose subjected to complete imbibition treatment after the polyvinyl alcohol is completely dissolved, uniformly mixing, reducing the temperature to 35 ℃, adding 5mL of glutaraldehyde solution into a pipette gun, slowly dropwise adding hydrochloric acid until the pH value is 3, continuously stirring and mixing for 10min, casting a mixed substance on a titanium-nickel alloy female die, applying vacuum on the other side of the die, heating the die at 95 ℃ for 15s after the mixed substance is filled in a die cavity, freeze-drying and dehydrating at-20 ℃, and slightly separating a forming film with microneedles from the die to obtain the porous polymer microneedles.
EXAMPLE five
Weighing 5g of polyvinyl alcohol, adding 55g of distilled water, adding 75g of cellulose with 10 mu m of complete imbibition treatment, stirring and heating at 85 ℃, dissolving, reducing the temperature to 40 ℃ after the polyvinyl alcohol is completely dissolved, adding 3mL of formaldehyde solution into a pipette, slowly dropwise adding acetic acid until the pH value is 4, continuously stirring and mixing for 10min, die-casting a miscible substance on a chromium metal female die, constantly heating the die at 70 ℃ for 100s after the miscible substance is filled in a die cavity, freeze-drying and dehydrating at-20 ℃, and slightly separating a molding film with microneedles from the die to obtain the porous polymer microneedles.
EXAMPLE six
Weighing 5g of polyvinyl alcohol, adding 7.5g of distilled water, adding 95g of cellulose with 5 microns and complete imbibition treatment, stirring at 95 ℃, heating for dissolving, reducing the temperature to 45 ℃ after the polyvinyl alcohol is completely dissolved, adding 7mL of glutaraldehyde solution into a pipette gun, slowly dropwise adding acetic acid until the pH value is 3, continuously stirring and mixing for 10min, die-casting a mixed substance on a nickel metal female die, constantly heating the die at 100 ℃ for 5s after the mixed substance is filled in a die cavity, freeze-drying and dehydrating at-20 ℃, and slightly separating a formed film with microneedles from the die to obtain the porous polymer microneedles.
Test experiments
Dipping the prepared microneedle with a mauve model drug-sulfonylrhodamine B agent, filling the porous microneedle with the model drug, pricking the unhaired fresh pigskin surface layer with a needle point, pressing the microneedle forcefully for 1 minute, removing the microneedle after 5 minutes, and observing the effect by a microscope. The microneedle was observed to penetrate with clear red pinholes and the rest intact, indicating that the microneedle can effectively penetrate the skin surface layer to deliver the drug.
Claims (10)
1. A preparation method of a porous polymer microneedle is characterized in that polyvinyl alcohol (PVA) is heated and dissolved in water, and is uniformly mixed with cellulose which is fully subjected to imbibition treatment, and then the temperature is reduced to 30-45 ℃; then adding a cross-linking agent, and dropwise adding acid to adjust the pH value; forming on the female die; dehydrating to obtain the porous polymer microneedle.
2. The method of preparing a porous polymer microneedle according to claim 1, wherein the concentration of the aqueous solution of polyvinyl alcohol is 8 to 40%; the mass ratio of the polyvinyl alcohol to the cellulose is 1: 0.1-20.
3. The method of manufacturing a porous polymer microneedle according to claim 1, wherein the cellulose is water-insoluble cellulose having a size of 5 to 100 μm.
4. The method of manufacturing porous polymer microneedles in claim 1, wherein the acid is any one of hydrochloric acid, sulfuric acid, or acetic acid.
5. The method of manufacturing porous polymer microneedles in claim 1, wherein the cross-linking agent is an aldehyde cross-linking agent.
6. The method of preparing a porous polymer microneedle according to claim 5, wherein the aldehyde-based cross-linking agent is any one of formaldehyde, glutaraldehyde, glyoxal, adipaldehyde, or octanediol, preferably formaldehyde.
7. The method for preparing a porous polymer microneedle according to claim 1, wherein the female mold is made of metal, polymer, silicon or photoresist, has two ends penetrating, does not react with or be dissolved in acid, water, aldehyde, polyvinyl alcohol in the reaction system, and has a melting point or softening temperature higher than the microneedle preparation temperature.
8. The method of manufacturing a porous polymer microneedle according to claim 7, wherein the metal is any one of copper, chromium, nickel, tungsten, manganese, titanium, chromel, titanium-nickel alloy, copper-titanium alloy, titanium-manganese alloy, nickel-copper alloy, manganese-copper alloy, and inconel; the polymer is polymethyl methacrylate or polydimethylsiloxane.
9. The method of preparing porous polymer microneedles in claim 1, wherein the method of molding on a female mold is casting or die casting; in the forming process, the female die needs to be heated, the temperature is 50-100 ℃, and the heating time is 5-180 s.
10. A method of fabricating porous polymer microneedles in any one of claims 1-9, wherein the dehydration is vacuum drying or freeze vacuum drying under heating.
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