CN117462836A - Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof - Google Patents
Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof Download PDFInfo
- Publication number
- CN117462836A CN117462836A CN202311799034.7A CN202311799034A CN117462836A CN 117462836 A CN117462836 A CN 117462836A CN 202311799034 A CN202311799034 A CN 202311799034A CN 117462836 A CN117462836 A CN 117462836A
- Authority
- CN
- China
- Prior art keywords
- drug
- ultrasonic
- release
- solution
- puncture
- 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.)
- Pending
Links
- 238000013270 controlled release Methods 0.000 title claims abstract description 55
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 199
- 229940079593 drug Drugs 0.000 claims abstract description 152
- 208000002193 Pain Diseases 0.000 claims abstract description 65
- 230000036407 pain Effects 0.000 claims abstract description 62
- 230000001580 bacterial effect Effects 0.000 claims abstract description 53
- 238000011109 contamination Methods 0.000 claims abstract description 52
- 238000003860 storage Methods 0.000 claims abstract description 33
- 230000000007 visual effect Effects 0.000 claims abstract description 23
- 238000005253 cladding Methods 0.000 claims abstract description 18
- 238000003825 pressing Methods 0.000 claims abstract description 4
- 239000000243 solution Substances 0.000 claims description 90
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 65
- 239000011248 coating agent Substances 0.000 claims description 61
- 238000000576 coating method Methods 0.000 claims description 61
- 239000000017 hydrogel Substances 0.000 claims description 61
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 60
- 239000002502 liposome Substances 0.000 claims description 56
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 48
- 238000002156 mixing Methods 0.000 claims description 43
- 238000003756 stirring Methods 0.000 claims description 38
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 36
- 239000002122 magnetic nanoparticle Substances 0.000 claims description 26
- 239000000463 material Substances 0.000 claims description 26
- JQWAHKMIYCERGA-UHFFFAOYSA-N (2-nonanoyloxy-3-octadeca-9,12-dienoyloxypropoxy)-[2-(trimethylazaniumyl)ethyl]phosphinate Chemical compound CCCCCCCCC(=O)OC(COP([O-])(=O)CC[N+](C)(C)C)COC(=O)CCCCCCCC=CCC=CCCCCC JQWAHKMIYCERGA-UHFFFAOYSA-N 0.000 claims description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 24
- 235000012000 cholesterol Nutrition 0.000 claims description 24
- 239000003995 emulsifying agent Substances 0.000 claims description 24
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 23
- 239000000725 suspension Substances 0.000 claims description 23
- 238000009210 therapy by ultrasound Methods 0.000 claims description 23
- 239000000203 mixture Substances 0.000 claims description 21
- 239000006185 dispersion Substances 0.000 claims description 20
- 239000003094 microcapsule Substances 0.000 claims description 20
- 239000007788 liquid Substances 0.000 claims description 19
- 239000012528 membrane Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 19
- 238000001914 filtration Methods 0.000 claims description 18
- 238000005303 weighing Methods 0.000 claims description 18
- 235000019441 ethanol Nutrition 0.000 claims description 16
- 239000003071 vasodilator agent Substances 0.000 claims description 15
- 239000003960 organic solvent Substances 0.000 claims description 14
- RBTBFTRPCNLSDE-UHFFFAOYSA-N 3,7-bis(dimethylamino)phenothiazin-5-ium Chemical compound C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 RBTBFTRPCNLSDE-UHFFFAOYSA-N 0.000 claims description 13
- IFBHRQDFSNCLOZ-IIRVCBMXSA-N 4-nitrophenyl-α-d-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1OC1=CC=C([N+]([O-])=O)C=C1 IFBHRQDFSNCLOZ-IIRVCBMXSA-N 0.000 claims description 13
- 102000008186 Collagen Human genes 0.000 claims description 13
- 108010035532 Collagen Proteins 0.000 claims description 13
- 229920001436 collagen Polymers 0.000 claims description 13
- 229960000907 methylthioninium chloride Drugs 0.000 claims description 13
- 239000011259 mixed solution Substances 0.000 claims description 13
- 229940124549 vasodilator Drugs 0.000 claims description 13
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 claims description 12
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 claims description 12
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 claims description 12
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 11
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 11
- 229920000084 Gum arabic Polymers 0.000 claims description 11
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 11
- 239000005913 Maltodextrin Substances 0.000 claims description 11
- 229920002774 Maltodextrin Polymers 0.000 claims description 11
- 241000978776 Senegalia senegal Species 0.000 claims description 11
- 229920002472 Starch Polymers 0.000 claims description 11
- 239000000205 acacia gum Substances 0.000 claims description 11
- 235000010489 acacia gum Nutrition 0.000 claims description 11
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 11
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 11
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 11
- 150000001875 compounds Chemical class 0.000 claims description 11
- 239000011521 glass Substances 0.000 claims description 11
- 229940035034 maltodextrin Drugs 0.000 claims description 11
- ZIUHHBKFKCYYJD-UHFFFAOYSA-N n,n'-methylenebisacrylamide Chemical compound C=CC(=O)NCNC(=O)C=C ZIUHHBKFKCYYJD-UHFFFAOYSA-N 0.000 claims description 11
- QNILTEGFHQSKFF-UHFFFAOYSA-N n-propan-2-ylprop-2-enamide Chemical compound CC(C)NC(=O)C=C QNILTEGFHQSKFF-UHFFFAOYSA-N 0.000 claims description 11
- 238000006116 polymerization reaction Methods 0.000 claims description 11
- 229910052708 sodium Inorganic materials 0.000 claims description 11
- 239000011734 sodium Substances 0.000 claims description 11
- 238000001694 spray drying Methods 0.000 claims description 11
- 239000008107 starch Substances 0.000 claims description 11
- 235000019698 starch Nutrition 0.000 claims description 11
- 229910021642 ultra pure water Inorganic materials 0.000 claims description 11
- 239000012498 ultrapure water Substances 0.000 claims description 11
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 10
- -1 sucrose fatty acid ester Chemical class 0.000 claims description 10
- 229930006000 Sucrose Natural products 0.000 claims description 9
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 9
- 238000001704 evaporation Methods 0.000 claims description 9
- 239000000194 fatty acid Substances 0.000 claims description 9
- 229930195729 fatty acid Natural products 0.000 claims description 9
- 239000005457 ice water Substances 0.000 claims description 9
- 150000002632 lipids Chemical class 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 9
- 239000008213 purified water Substances 0.000 claims description 9
- 239000005720 sucrose Substances 0.000 claims description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- 230000005540 biological transmission Effects 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 239000004033 plastic Substances 0.000 claims description 5
- 229920003023 plastic Polymers 0.000 claims description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 4
- 238000007723 die pressing method Methods 0.000 claims description 4
- LWNPNOFGINFGGV-UHFFFAOYSA-N 2-(diethylamino)-n-(2,6-dimethylphenyl)acetamide;2-(dimethylamino)ethyl 4-(butylamino)benzoate Chemical compound CCN(CC)CC(=O)NC1=C(C)C=CC=C1C.CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 LWNPNOFGINFGGV-UHFFFAOYSA-N 0.000 claims description 3
- 229960002494 tetracaine hydrochloride Drugs 0.000 claims description 3
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 claims description 2
- 239000000006 Nitroglycerin Substances 0.000 claims description 2
- 239000004793 Polystyrene Substances 0.000 claims description 2
- 229910052782 aluminium Inorganic materials 0.000 claims description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 claims description 2
- 239000000919 ceramic Substances 0.000 claims description 2
- 238000013329 compounding Methods 0.000 claims description 2
- VFHVQBAGLAREND-UHFFFAOYSA-N diphenylphosphoryl-(2,4,6-trimethylphenyl)methanone Chemical compound CC1=CC(C)=CC(C)=C1C(=O)P(=O)(C=1C=CC=CC=1)C1=CC=CC=C1 VFHVQBAGLAREND-UHFFFAOYSA-N 0.000 claims description 2
- NJDNXYGOVLYJHP-UHFFFAOYSA-L disodium;2-(3-oxido-6-oxoxanthen-9-yl)benzoate Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=CC(=O)C=C2OC2=CC([O-])=CC=C21 NJDNXYGOVLYJHP-UHFFFAOYSA-L 0.000 claims description 2
- 230000001804 emulsifying effect Effects 0.000 claims description 2
- 239000011888 foil Substances 0.000 claims description 2
- 229960003711 glyceryl trinitrate Drugs 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 239000002184 metal Substances 0.000 claims description 2
- 238000000465 moulding Methods 0.000 claims description 2
- MRBDMNSDAVCSSF-UHFFFAOYSA-N phentolamine Chemical compound C1=CC(C)=CC=C1N(C=1C=C(O)C=CC=1)CC1=NCCN1 MRBDMNSDAVCSSF-UHFFFAOYSA-N 0.000 claims description 2
- 229960001999 phentolamine Drugs 0.000 claims description 2
- 229920006289 polycarbonate film Polymers 0.000 claims description 2
- 229920002223 polystyrene Polymers 0.000 claims description 2
- 239000004800 polyvinyl chloride Substances 0.000 claims description 2
- 229920000915 polyvinyl chloride Polymers 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 238000002390 rotary evaporation Methods 0.000 claims description 2
- 238000002791 soaking Methods 0.000 claims description 2
- 230000000304 vasodilatating effect Effects 0.000 claims description 2
- 239000011162 core material Substances 0.000 claims 1
- 238000005516 engineering process Methods 0.000 abstract description 5
- 230000024883 vasodilation Effects 0.000 abstract description 4
- 238000012377 drug delivery Methods 0.000 abstract description 3
- 238000012544 monitoring process Methods 0.000 abstract description 3
- 230000008685 targeting Effects 0.000 abstract description 3
- 238000012800 visualization Methods 0.000 abstract description 2
- 230000009977 dual effect Effects 0.000 abstract 1
- 239000011505 plaster Substances 0.000 abstract 1
- 238000011002 quantification Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 32
- 239000010410 layer Substances 0.000 description 29
- 230000000694 effects Effects 0.000 description 21
- 229910001873 dinitrogen Inorganic materials 0.000 description 13
- 210000003491 skin Anatomy 0.000 description 12
- 238000012360 testing method Methods 0.000 description 12
- 210000004204 blood vessel Anatomy 0.000 description 10
- 230000000202 analgesic effect Effects 0.000 description 8
- 238000001746 injection moulding Methods 0.000 description 7
- 238000010025 steaming Methods 0.000 description 7
- 238000004090 dissolution Methods 0.000 description 6
- 238000005538 encapsulation Methods 0.000 description 6
- 238000000338 in vitro Methods 0.000 description 6
- 238000011084 recovery Methods 0.000 description 6
- 206010061218 Inflammation Diseases 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 230000003467 diminishing effect Effects 0.000 description 5
- 230000004054 inflammatory process Effects 0.000 description 5
- 230000000916 dilatatory effect Effects 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 229940113478 lecithin 200 mg Drugs 0.000 description 4
- 238000011068 loading method Methods 0.000 description 4
- 238000005259 measurement Methods 0.000 description 4
- 238000002604 ultrasonography Methods 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 3
- 206010040880 Skin irritation Diseases 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 229940035676 analgesics Drugs 0.000 description 3
- 239000000730 antalgic agent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000009792 diffusion process Methods 0.000 description 3
- 229960001483 eosin Drugs 0.000 description 3
- SEACYXSIPDVVMV-UHFFFAOYSA-L eosin Y Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(Br)C(=O)C(Br)=C2OC2=C(Br)C([O-])=C(Br)C=C21 SEACYXSIPDVVMV-UHFFFAOYSA-L 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 230000036556 skin irritation Effects 0.000 description 3
- 231100000475 skin irritation Toxicity 0.000 description 3
- 238000013112 stability test Methods 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000012790 adhesive layer Substances 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- 230000000181 anti-adherent effect Effects 0.000 description 2
- 238000005336 cracking Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000005286 illumination Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 230000001737 promoting effect Effects 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 208000004550 Postoperative Pain Diseases 0.000 description 1
- 206010040830 Skin discomfort Diseases 0.000 description 1
- 206010072170 Skin wound Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 230000036592 analgesia Effects 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000001574 biopsy Methods 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 210000004207 dermis Anatomy 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 210000002615 epidermis Anatomy 0.000 description 1
- YMCOIFVFCYKISC-UHFFFAOYSA-N ethoxy-[2-(2,4,6-trimethylbenzoyl)phenyl]phosphinic acid Chemical compound CCOP(O)(=O)c1ccccc1C(=O)c1c(C)cc(C)cc1C YMCOIFVFCYKISC-UHFFFAOYSA-N 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 210000003128 head Anatomy 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 229940088500 lecithin 400 mg Drugs 0.000 description 1
- 229940087400 lecithin 50 mg Drugs 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002539 nanocarrier Substances 0.000 description 1
- 239000004745 nonwoven fabric Substances 0.000 description 1
- 230000037368 penetrate the skin Effects 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000004088 simulation Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 210000003857 wrist joint Anatomy 0.000 description 1
Abstract
The invention discloses a functional ultrasonic controlled-release puncture dressing patch and a preparation method thereof. The dressing plaster main body consists of a double-layer parallel structure and an annular cladding structure. The double-layer parallel structure is an energy conducting sheet and a visual drug storage and delivery system, and the structure combines an ultrasonic technology, can promote transdermal targeting high-permeability drug delivery, and realizes quantification and controllability of the drug; the energy conducting sheet is used for gathering, guiding and transmitting ultrasonic waves, so that the directional acting force of the energy conducting sheet on the medicine can be improved; the visual drug storage and delivery system can improve drug storage property and skin affinity, realize dual functions of drug quick release and slow release, reduce pain before and after puncture, promote vasodilation and improve puncture success rate; the annular cladding structure contains two kinds of indication windows, adopts the mould pressing technology preparation, can connect, fix and protect whole frame, realizes bacterial contamination monitoring and medicine release degree visualization, and helps medicine to stabilize and effectively play a role.
Description
Technical Field
The invention relates to the technical field of medical appliances, in particular to a functional ultrasonic controlled-release puncture dressing patch and a preparation method thereof.
Background
In the medical field, due to anesthesia and surgery, puncture operations, such as biopsy and catheterization, are often performed on patients.
However, since the puncture needle is long and thick, the patient feels pain during the puncture, and the patient is further frightened, stressed and anxious, so that the circulation function is changed, and the normal operation is affected, especially for patients who frequently need the puncture, such as patients with long-term transfusion, diabetes, renal dialysis and the like. Currently, clinicians will alleviate the pain of pre-operative punctures by injecting local anesthetic drugs. Although percutaneous injection provides analgesia, percutaneous injection itself can produce pain, and can also produce other side effects such as deformation of the operative site, stress atmosphere, etc., and continuous pain after puncture can also lead to patient's conflict.
Moreover, the failure rate of the first puncture operation is higher, especially for patients with smaller own vessel diameter and high puncture operation difficulty or easy tension, the repeated puncture failure can bring psychological burden to the patients and family members thereof, the risk of infection is increased, the recovery and treatment of the bodies of the patients are not facilitated, and the treatment scheme of medical workers is also not facilitated. In addition, the drugs in conventional patches cannot be effectively utilized, and the extent of drug release cannot be clearly known, affecting the course of treatment.
Therefore, to solve the above clinical problems, the following technical bottlenecks must be overcome:
(1) The puncture pretreatment must be a noninvasive design to avoid secondary skin wounds;
(2) The auxiliary device is aimed at medicaments for promoting vasodilation and is used before operation to improve the success rate of puncture;
(3) The auxiliary device is used before operation by aiming at the medicine for relieving the puncture pain, so that the pain in the puncture process is relieved by ensuring the rapid effect before the puncture, and the continuous pain relieving after the puncture is finished is ensured;
(4) The drug release should have certain targeting property, and can be effectively utilized by target vascular tissues to achieve the effective concentration of the drug, thereby avoiding excessive loss of the drug;
(5) The application of the medicine should be controllable, quantifiable and visual, and different dosages of the medicine can be selected according to different puncture positions or puncture depths or puncture types so as to meet various clinical requirements, and the degree of medicine release should be known.
The prior patent CN 106074849B provides a blood vessel dilating pain relieving and inflammation diminishing patch for arteriovenous puncture, which consists of an outer layer, a heating layer, a middle layer, a traditional Chinese medicine pain relieving and inflammation diminishing layer and an inner layer, wherein isolation layers are arranged between the layers. The heating layer has the effects of increasing the temperature of the back of the hand, dilating blood vessels, relieving pain and diminishing inflammation, and the Chinese medicine pain relieving and diminishing inflammation layer has the effects of relieving pain and diminishing inflammation, and the painless anesthetic layer has the effects of local surface anesthesia and has a certain effect when being used in the process of arteriovenous injection and puncture. However, the ferrule type structural design can lead to the appearance of a response area corresponding to the patch functional area in the area to be punctured, so that the same skin cannot be subjected to anesthesia, pain relieving and heating effects at the same time, the quick effect of the medicine is not facilitated, the effect is unstable, the application range is small, and the inclusion is poor. Secondly, the medicine in the patch only passively and randomly enters the part to be punctured according to the molecular diffusion and similar compatibility principles, no targeting is achieved, the effective treatment concentration of the medicine cannot be ensured, the medicine release and absorption efficiency is slow, the utilization rate is low, and the medicine waste and the treatment effect are poor; finally, the patch cannot be controlled, quantified and visualized by changing the drug release rate, depth and extent, and in addition, the problem of postoperative pain at the puncture site cannot be solved.
In addition, CN 104367416A discloses a method for rapidly stopping pain by vascular puncture in children and an analgesic patch, which is a medical adhesive patch prepared in advance, namely, an analgesic patch, wherein one or more analgesic drugs are placed in the analgesic patch. Before puncturing blood vessel, the analgesic patch is covered on skin of puncture part to make analgesic absorbed by skin, so that no pain or pain is reduced during puncturing. However, the analgesic patch has only analgesic drugs, cannot dilate blood vessels, cannot evaluate whether the patch is infected by bacteria, cannot ensure rapid release and effective utilization of the drugs, cannot solve the problem of pain at a puncture site after operation, and cannot quantify and control drug release and visualize drug loading.
Disclosure of Invention
One of the purposes of the present invention is to provide a functionalized ultrasonic controlled release dressing patch for solving the above technical problems.
The second object of the invention is to provide a preparation method of the functionalized ultrasonic controlled release puncture dressing, which comprises the following operation steps:
(1) Preparation of drug-loaded ethosome: weighing egg yolk lecithin, cholesterol, a vasodilator and a pain relieving medicine according to a formula, stirring and dissolving the egg yolk lecithin, the cholesterol, the vasodilator and the pain relieving medicine in absolute ethyl alcohol at 30 ℃; injecting ultrapure water into the absolute ethyl alcohol at the flow rate of 200 mu L/min, stirring for 30 min, performing ice water bath ultrasonic treatment, and filtering with a 0.22 mu m filter membrane to obtain a drug-carrying ethosome;
To better practice the invention, further, the formulation: 100-300 mg of egg yolk lecithin, 30-100 mg of cholesterol, 30-70 mg of vasodilator, 30-70 mg of pain relieving medicine and 1-5 mL of ultrapure water;
in order to better realize the invention, the vasodilator is one of nitroglycerin and phentolamine;
in order to better realize the invention, the pain relieving medicine is one of lidocaine and tetracaine hydrochloride;
in order to better realize the invention, further, the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min;
(2) Preparation of drug-loaded liposome: weighing egg yolk lecithin, cholesterol and a pain relieving medicine according to a formula, fixing the volume to 10 mL by using a composite organic solvent, stirring, mixing and dissolving, decompressing and evaporating under a water bath at 30 ℃ until a lipid film layer is formed, injecting nitrogen, then adding sodium cholate solution, removing the organic solvent by rotary evaporation until liposome suspension is formed, injecting nitrogen again, carrying out ultrasonic treatment, and filtering by using a 0.22 mu m filter membrane to obtain the drug-loaded liposome;
to better practice the invention, further, the formulation: 100-300 mg of egg yolk lecithin, 30-100 mg of cholesterol and 30-70 mg of pain relieving drugs;
In order to better realize the invention, the compound organic solvent is further prepared by mixing chloroform and methanol according to the volume ratio of 1:1;
in order to better realize the invention, the pain relieving medicine is one of lidocaine and tetracaine hydrochloride;
in order to better realize the invention, the concentration of the sodium cholate solution is 1-5%, and the addition amount is 7-13 mL;
in order to better realize the invention, further, the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min;
(3) Preparing an annular cladding structure: injecting ABS into a mold cavity, and performing a mold pressing process to obtain an annular coating structure containing a bacterial contamination indication window and a drug release indication window;
to better implement the invention, further, the molding process parameters are as follows: the temperature of the die is 60-65 ℃, the die pressing time is 180-700 s, and the die pressing pressure is 1-9 bar;
(4) Preparation of magnetic hydrogel prepolymerization solution: the acetone solution containing ferrocene is mixed with 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, and after being cooled, the mixture is washed and redispersed to obtain magnetic nanoparticle dispersion liquid; uniformly mixing N-isopropyl acrylamide, acrylic acid and N, N' -methylene bisacrylamide into an ethanol and ethylene glycol mixed solution, and then adding a photoinitiator for light-shielding and uniformly mixing to obtain a hydrogel prepolymerization solution; uniformly mixing the hydrogel prepolymerization solution, the magnetic nanoparticle dispersion liquid and the collagen according to a proportion in a dark place to obtain a magnetic hydrogel prepolymerization solution;
In order to better realize the invention, the concentration of the acetone solution containing ferrocene is 0.9-1.1%, 30% H 2 O 2 The addition amount is 2.0-3.0%; the redispersion refers to redispersing magnetic nano particles with certain mass into glycol solution, so that the concentration of the magnetic nano particles in the solution is 30 mg/mL;
in order to better realize the invention, the concentrations of the N-isopropyl acrylamide, the acrylic acid and the N, N' -methylene bisacrylamide in the ethanol and ethylene glycol mixed solution are respectively 0.55-0.75 g/mL, 5.5-7.5% and 18-22 mg/mL;
in order to better realize the invention, the weight ratio of the ethanol to the glycol in the ethanol and glycol mixed solution is (0.9-1.1): 1;
in order to better realize the invention, the photoinitiator is one of 2,4, 6-trimethylbenzoyl diphenyl phosphine oxide and 2,4, 6-trimethylbenzoyl phenyl phosphonic acid ethyl ester, and the addition amount of the photoinitiator is 1.25-1.45%;
in order to better realize the invention, the ratio of the hydrogel prepolymerization solution, the magnetic nanoparticle dispersion liquid and the collagen is (25-35) 10:1;
(5) Visual drug storage delivery system preparation: placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet light environment of 356 nm for polymerization reaction to obtain magnetic hydrogel; placing the magnetic hydrogel in a suspension of drug-carrying liposome and drug-carrying ethosome, and soaking at 25 ℃ for 72 h to obtain a visual drug storage and delivery system;
In order to better realize the invention, the size of the glass mold is consistent with that of the annular cladding structure, and the polymerization reaction time is 2-4 min;
in order to better realize the invention, further, the solute of the suspension is a mixture of the drug-loaded liposome and the drug-loaded ethosome according to the mass ratio of 1:1, and the concentration of the mixture in the suspension is 70-90%;
(6) The preparation of the coating for the bacterial contamination indicator window comprises the following steps: stirring sucrose fatty acid ester and dissolving in water to obtain an emulsifier; uniformly mixing maltodextrin and gum arabic according to a proportion, and dissolving the mixture in water to obtain a wall material solution; adding an emulsifying agent and PNPG into the wall material solution, emulsifying, adding methylene blue and tetrabromo sodium fluorescein, and uniformly mixing again; mixing, ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; homogenizing, and then spray drying to obtain microcapsules; adding the microcapsule, the carboxymethyl cellulose and the starch into the purified water according to the formula, and stirring and uniformly mixing to prepare the coating for the bacterial contamination indicator window;
in order to better realize the invention, the concentration of the emulsifier is 0.1-1.0%;
in order to better realize the invention, the even mixing proportion of the maltodextrin and the gum arabic is (1-5): 1;
In order to better realize the invention, the wall material concentration is 33-47%;
in order to better realize the invention, further, the emulsifier, PNPG, methylene blue and tetrabromo sodium are added into the wall material solution, wherein the concentrations of the emulsifier, PNPG, methylene blue and tetrabromo sodium are respectively 1-3%, 15-25% and 15-25%;
to better practice the invention, further, the spray drying parameters are: the air inlet temperature is 140-160 ℃, and the feeding flow is 15-20 mL/min -1 The air outlet temperature is 70-80 ℃;
in order to better realize the invention, the formula of the coating for the bacterial contamination indicator window comprises 25-65% of microcapsules, 2-10% of carboxymethyl cellulose and 2-10% of starch;
(7) Preparation of a functional ultrasonic controlled-release puncture dressing patch: inverting the annular coating structure, firstly placing an energy conducting sheet, then coating a bacterial contamination indication window coating on the bacterial contamination indication window of the annular coating structure, then attaching a visual drug storage and delivery system on the energy conducting sheet and completely covering the bacterial contamination indication window coating, and then compounding a tearable anti-sticking layer to obtain a functional ultrasonic controlled release puncture dressing;
in order to better realize the invention, further, the ultrasonic transmission material used by the energy conducting sheet is one of metal, ceramic and plastic;
In order to better realize the invention, the tearable anti-adhesive layer is one of a polystyrene film, an aluminum foil, a siliconized polyvinyl chloride film and a polycarbonate film.
The components used in the present invention are all commercially available products, the structure and composition of which are known to those skilled in the art.
The invention has the beneficial effects that:
1. the functional ultrasonic controlled-release puncture dressing patch provided by the invention can avoid secondary injury to skin. The medicine can directly reach the puncture part through skin and biomembrane to form high-concentration medicine aggregation, achieves the effect of needleless injection transdermal administration, and belongs to a green, safe and effective administration mode.
2. According to the functional ultrasonic controlled-release puncture dressing patch provided by the invention, the annular coating structure is provided with the medicine real-time monitoring window, and the medicine release degree can be directly judged through the color change of the window, so that a prompt is given to medical workers, and the visualization of the medicine release degree is realized. The change in color of the window is from a visual change in color of the drug storage delivery system, i.e., the system appears red when it is full of drug, and the system color changes gradually from red to blue as the drug is released.
3. The annular coating structure of the functional ultrasonic controlled-release puncture dressing patch provided by the invention is provided with the bacterial infection prompt window for daily monitoring whether the functional ultrasonic controlled-release puncture dressing patch is polluted by bacteria, so that the aim of helping medical workers judge whether the functional ultrasonic controlled-release puncture dressing patch can be applied to clinic as a qualified product or not is achieved, and skin infection of patients is avoided. In addition, the annular cladding structure is also used for connecting, fixing and protecting the integral frame, and assisting the sustained release of the medicine.
4. The functional ultrasonic controlled-release puncture dressing patch provided by the invention can be combined with an ultrasonic technology to realize targeted drug delivery, biological pore making and pressure driving. The method can adjust the release, absorption and utilization efficiency of the drug by changing the frequency, intensity, continuous or pulse mode and the like of ultrasonic waves, and can target the drug to the target tissue at the same time, thereby realizing the quantifiable drug delivery and controllable release. In addition, the ultrasound conducting layer can be used for both ultrasound collection and conduction and for the gel backing layer, in one instance.
5. The functional ultrasonic controlled-release puncture dressing patch provided by the invention contains a visual drug storage and delivery system, and the system has the following advantages:
first, the system contains pain-relieving medications that can improve patient comfort and acceptance; meanwhile, the puncture needle contains the medicine for dilating blood vessels, so that the blood circulation is promoted, the diameter of the blood vessels is increased, the puncture operation is easier to carry out, and the puncture accuracy and efficiency are improved;
secondly, the medicine is wrapped by the ethosome and the liposome, so that the storage resistance of the medicine can be improved, and the denaturation and failure of the medicine are avoided; most importantly, the ethosome has small particle size, strong transdermal performance and good skin tolerance performance, effectively enhances the transdermal permeability of the medicine, can rapidly take effect, and the liposome can form a medicine reservoir in epidermis dermis, so that the medicine is slowly released, and the local pain relieving effect can be permanently exerted. The system combines the advantages of the ethosome and the liposome to realize the slow release and quick release dual-functionalization of the medicine, thereby relieving pain before and after puncture, simultaneously promoting vasodilation, improving the success rate of puncture and relieving pain of patients;
Finally, the system is embedded with various components such as collagen, and the like, so that the transdermal property, skin-friendly property, softness and comfortableness of the patch can be enhanced, skin discomfort is avoided, the patch can be better attached to the skin, and the transdermal release of nano drug carrier particles is cooperated.
Drawings
Fig. 1 is a three-dimensional structure diagram of a functionalized ultrasonic controlled release puncture dressing patch
FIG. 2 is a view showing the structure of the longitudinal section of the functionalized ultrasonic controlled release puncture dressing patch
FIG. 3 is a top plan view of a functionalized ultrasonic controlled release puncture dressing patch
FIG. 4 is a diagram of the internal microstructure of a visualized drug storage delivery system
FIG. 5 is a schematic view of a longitudinal section of a functionalized ultrasound controlled release puncture dressing patch in ultrasound guided clinical application
FIG. 6 is a graph showing the results of in vitro drug release tests in the functionalized ultrasonic controlled release puncture dressing drug-loaded ethosome
FIG. 7 is a graph showing the results of in vitro drug release test in functionalized ultrasonic controlled release puncture dressing drug-loaded liposome
Reference numerals: 1. the medical ultrasonic puncture device comprises an annular coating structure, 2, an energy conducting sheet, 3, a visual drug storage and delivery system, 4, a tearable anti-adhesive layer, 5, a bacterial contamination indication window, 6, a drug release indication window, 7, a three-dimensional cross-linked network, 8, magnetic nano particles, 9, a drug carrying ethosome, 10, a drug carrying liposome, 11, a chain photon crystal structure, 12, a handheld medical ultrasonic instrument, 13, a functional ultrasonic controlled release puncture dressing patch, 14, skin to be punctured, 15, a percutaneous puncture site, 16, a blood vessel to be punctured subcutaneously, 17 and an ultrasonic propagation simulation track.
Detailed Description
The technical scheme of the present invention will be described in further detail with reference to examples and comparative examples, but the present invention is not limited by these specific examples.
The following are examples and comparative examples.
Example 1
Weighing egg yolk lecithin 200 mg, cholesterol 65 mg, vasodilator 50 mg and pain relieving 50 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 3 mL of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment for 5 min (in an ice water bath) at a concentration of 105 w, and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 200 mg, cholesterol 65 mg and pain relieving medicine 50 mg, fixing the volume to 10 mL with a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30deg.C in water bath to form a lipid film layer, injecting nitrogen gas, adding 3% sodium cholate solution 10 mL, steaming to form liposome suspension, injecting nitrogen gas, performing ultrasonic treatment 105 w for 5 min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding 440, s ABS into a mold cavity at 62.5 ℃ and 5 bar. 30 mL A solution of 1.0% ferrocene in acetone was mixed with 0.75 mL of 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, is cooled, washed and redispersed in glycol (30 mg/mL) to obtain a dispersion liquid of the magnetic nano particles 8; 1.0 g of N-isopropyl acrylamide, 0.1. 0.1 mL acrylic acid and 30 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1:1), and then 20 mu L of photoinitiator is added and uniformly mixed in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 30:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet environment of 356 nm for polymerization reaction for 3 min to obtain magnetic hydrogel; the magnetic hydrogel was placed in a suspension of 80% drug-loaded liposomes 10 and drug-loaded liposomes 9 and soaked 72 h at 25 ℃ to give a visualized drug storage delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 05% of an emulsifying agent; dissolving maltodextrin and gum arabic in water according to a ratio of 3:1 to obtain a 40% wall material solution; adding 2% of emulsifying agent, 20% of PNPG, 20% of methylene blue and 20% of tetrabromofluorescein sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 150 ℃ C., feed flow rate 17 mL/min) -1 The temperature of the air outlet is 75 ℃), and the microcapsule is obtained; adding 45% microcapsule, 6% carboxymethyl cellulose and 6% starch into purified water, stirring and mixing uniformly to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 2
Weighing egg yolk lecithin 100 mg, cholesterol 30 mg, vasodilator 30 mg and pain relieving 30 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 1. 1 mL of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment for 1 min (in an ice-water bath) at 100 w, and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 100 mg, cholesterol 30 mg and pain relieving medicine 30 mg, fixing the volume to 10 mL with a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30deg.C in water bath to form a lipid film layer, injecting nitrogen gas, adding 1% sodium cholate solution 7 mL, steaming to form liposome suspension, injecting nitrogen gas, performing ultrasonic treatment for 1 min at 100 w, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding of ABS into a mold cavity at 60 ℃ and 1 bar at 180 s. 30 mL A solution of 0.9% ferrocene in acetone was mixed with 0.6 mL of 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, is cooled, washed and redispersed in glycol (30 mg/mL) to obtain a dispersion liquid of the magnetic nano particles 8; 0.83 g of N-isopropyl acrylamide, 0.083 mL acrylic acid and 27 mg of N, N' -methylenebisacrylamide are evenly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 0.9:1),then adding 18 mu L of photoinitiator, and mixing uniformly in a dark place to obtain a hydrogel prepolymerization solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and collagen in a proportion of 25:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet environment of 356 nm for polymerization reaction for 4 min to obtain magnetic hydrogel; the magnetic hydrogel was placed in a suspension of 70% drug-loaded liposomes 10 and drug-loaded liposomes 9 and soaked 72 h at 25 ℃ to give a visualized drug storage delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 0.1% emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 1:1 to obtain 33% wall material solution; adding 1% of emulsifying agent, 15% of PNPG, 15% of methylene blue and 15% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 140 ℃ C., feed flow 15 mL/min) -1 The temperature of the air outlet is 70 ℃), and the microcapsule is obtained; and adding 25% of microcapsules, 2% of carboxymethyl cellulose and 2% of starch into the purified water, and stirring and uniformly mixing to prepare the bacterial contamination indicating window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 3
Weighing egg yolk lecithin 300 mg, cholesterol 100 mg, vasodilator 70 mg and pain relieving 70 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 5. 5 mL of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing 110 w ultrasonic treatment for 9 min (in an ice water bath), and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 300 mg, cholesterol 100 mg and pain relieving medicine 70 mg, fixing volume to 10 mL with compound organic solvent, stirring for dissolving, evaporating under reduced pressure at 30deg.C water bath to form a lipid film layer, injecting nitrogen gas, adding 5% sodium cholate solution 13 mL, steaming to form liposome suspension, and injecting Introducing nitrogen, performing ultrasonic treatment for 9 min at 110 and w, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding 700 s of ABS into a mold cavity at 65 ℃ and 9 bar. 30 mL A solution of 1.1% ferrocene in acetone was mixed with 0.9 mL of 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, is cooled, washed and redispersed in glycol (30 mg/mL) to obtain a dispersion liquid of the magnetic nano particles 8; 1.13 g of N-isopropyl acrylamide, 0.113 mL acrylic acid and 33 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1.1:1), and then 22 mu L of photoinitiator is added and uniformly mixed in a dark place, so as to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 35:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet environment of 356 nm for polymerization reaction for 2 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 90% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so that the visualized drug storage and delivery system 3 is obtained. Dissolving sucrose fatty acid ester in water to obtain 1.0% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 5:1 to obtain a 47% wall material solution; adding 3% of emulsifying agent, 25% of PNPG, 25% of methylene blue and 25% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 160 ℃ C., feed flow 20 mL/min) -1 The temperature of the air outlet is 80 ℃), and the microcapsule is obtained; adding 65% of microcapsule, 10% of carboxymethyl cellulose and 10% of starch into purified water, and stirring and uniformly mixing to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 4
Weighing egg yolk lecithin 200 mg, cholesterol 65 mg and dilated bloodTube drug 50 mg mg and pain relieving drug 50 mg, dissolved in absolute ethanol by stirring at 30deg.C; measuring 1. 1 mL of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment for 1 min (in an ice-water bath) at 100 w, and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 300 mg, cholesterol 100 mg and pain relieving medicine 70 mg, fixing the volume to 10 mL with a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30deg.C in water bath to form a lipid film layer, injecting nitrogen gas, adding 5% sodium cholate solution 13 mL, steaming to form liposome suspension, injecting nitrogen gas, performing ultrasonic treatment for 9 min at 110 w, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding 700 s of ABS into a mold cavity at 65 ℃ and 9 bar. 30 mL A solution of 1.0% ferrocene in acetone was mixed with 0.75 mL of 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, is cooled, washed and redispersed in glycol (30 mg/mL) to obtain a dispersion liquid of the magnetic nano particles 8; 1.0 g of N-isopropyl acrylamide, 0.1. 0.1 mL acrylic acid and 30 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1:1), and then 20 mu L of photoinitiator is added and uniformly mixed in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 30:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet environment of 356 nm for polymerization reaction for 3 min to obtain magnetic hydrogel; the magnetic hydrogel was placed in a suspension of 80% drug-loaded liposomes 10 and drug-loaded liposomes 9 and soaked 72 h at 25 ℃ to give a visualized drug storage delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 0.5% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 5:1 to obtain 33% wall material solution; adding 2% of emulsifying agent, 20% of PNPG, 20% of methylene blue and 20% of tetrabromofluorescein sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 160 ℃ C., feed flow 20 mL/min) -1 The temperature of the air outlet is 80 ℃), and the microcapsule is obtained; adding 25% microcapsule, 2% carboxymethyl cellulose and 2% starch into purified water,stirring and mixing uniformly to obtain the coating for the bacterial contamination indicating window. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 5
Weighing egg yolk lecithin 100 mg, cholesterol 30 mg, vasodilator 30 mg and pain relieving 30 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 5. 5 mL of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing 110 w ultrasonic treatment for 9 min (in an ice water bath), and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 200 mg, cholesterol 65 mg and pain relieving medicine 50 mg, fixing the volume to 10 mL with a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30deg.C in water bath to form a lipid film layer, injecting nitrogen gas, adding 3% sodium cholate solution 10 mL, steaming to form liposome suspension, injecting nitrogen gas, performing ultrasonic treatment 105 w for 5 min, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding 700 s of ABS into a mold cavity at 65 ℃ and 9 bar. 30 mL A solution of 0.9% ferrocene in acetone was mixed with 0.6 mL of 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, is cooled, washed and redispersed in glycol (30 mg/mL) to obtain a dispersion liquid of the magnetic nano particles 8; 0.83 g of N-isopropyl acrylamide, 0.083 mL acrylic acid and 27 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 0.9:1), and then 18 mu L of photoinitiator is added and uniformly mixed in a dark place, so as to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and collagen in a proportion of 25:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet environment of 356 nm for polymerization reaction for 4 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in 70% of suspension of drug-loaded liposome 10 and drug-loaded ethosome 9In the above, 72 h was soaked at 25 ℃ to obtain a visualized drug storage and delivery system 3. Dissolving sucrose fatty acid ester in water to obtain 1.0% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 3:1 to obtain 33% wall material solution; adding 3% of emulsifying agent, 25% of PNPG, 25% of methylene blue and 25% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 150 ℃ C., feed flow rate 17 mL/min) -1 The temperature of the air outlet is 75 ℃), and the microcapsule is obtained; and adding 25% of microcapsules, 2% of carboxymethyl cellulose and 2% of starch into the purified water, and stirring and uniformly mixing to prepare the bacterial contamination indicating window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Example 6
Weighing egg yolk lecithin 300 mg, cholesterol 100 mg, vasodilator 70 mg and pain relieving 70 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring 3 mL of ultrapure water, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment for 5 min (in an ice water bath) at a concentration of 105 w, and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 100 mg, cholesterol 30 mg and pain relieving medicine 30 mg, fixing the volume to 10 mL with a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30deg.C in water bath to form a lipid film layer, injecting nitrogen gas, adding 1% sodium cholate solution 7 mL, steaming to form liposome suspension, injecting nitrogen gas, performing ultrasonic treatment for 1 min at 100 w, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding 440, s ABS into a mold cavity at 62.5 ℃ and 5 bar. 30 mL A solution of 1.1% ferrocene in acetone was mixed with 0.9 mL of 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, is cooled, washed and redispersed in glycol (30 mg/mL) to obtain a dispersion liquid of the magnetic nano particles 8; 1.13 g of N-isopropylacrylamide and 0.113. 0.113 mL g of acrylic acidAnd 33 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5-mL ethanol and ethylene glycol (weight ratio is 1.1:1), and then 22 mu L of photoinitiator is added and uniformly mixed in a dark place, so as to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 35:10:1 in a dark place to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet environment of 356 nm for polymerization reaction for 2 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in a suspension of 90% drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so that the visualized drug storage and delivery system 3 is obtained. Dissolving sucrose fatty acid ester in water to obtain 0.1% emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 5:1 to obtain a 40% wall material solution; adding 1% of emulsifying agent, 15% of PNPG, 15% of methylene blue and 15% of tetrabromo sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 160 ℃ C., feed flow 20 mL/min) -1 The temperature of the air outlet is 80 ℃), and the microcapsule is obtained; adding 45% microcapsule, 6% carboxymethyl cellulose and 6% starch into purified water, stirring and mixing uniformly to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
Comparative example 1
Comparative example 1 is substantially the same as example 1 except that: in example 1, an annular coating structure 1 having a bacterial contamination indicating window 5 and a drug release indicating window 6 was used, whereas comparative example 1 had no annular coating structure 1, and simultaneously had no bacterial contamination indicating window 5 and no drug release indicating window 6.
Comparative example 2
Comparative example 2 is substantially the same as example 1 except that: in example 1, an energy conducting sheet 2 was used, and in comparative example 2, a layer of nonwoven fabric was used.
Comparative example 3
Comparative example 3 is substantially the same as example 1 except that: example 1 a magnetic hydrogel was placed in 80% drug-loaded liposomes and drug-loaded ethosome suspension and soaked 72 h at 25 ℃ to give a visualized drug storage delivery system 3; while comparative example 3 did not prepare an ethosome or liposome for loading and protecting the drug, the magnetic hydrogel was placed in a mixed solution of 80% vasodilator drug and pain-relieving drug (mass ratio of vasodilator drug to pain-relieving drug 1:1), and immersed in 72 h at 25 ℃.
Comparative example 4
Comparative example 4 is substantially the same as example 1 except that: example 1 contains both drug-loaded ethosome 9 and drug-loaded liposome 10, whereas comparative example 4 has only drug-loaded ethosome 9 and no drug-loaded liposome 10.
Comparative example 5
Comparative example 5 is substantially the same as example 1 except that: example 1 contains both drug-loaded liposomes 9 and drug-loaded liposomes 10, whereas comparative example 5 has only drug-loaded liposomes 10, without drug-loaded liposomes 9.
Comparative example 6
Weighing egg yolk lecithin 50 mg, cholesterol 150 mg, vasodilator 50 mg and pain relieving 50 mg, stirring at 30deg.C to dissolve in absolute ethanol; measuring ultrapure water 7 mL, injecting into the absolute ethyl alcohol at a flow rate of 200 mu L/min, stirring for 30 min, performing ultrasonic treatment at 150 w for 12 min (in an ice water bath), and filtering with a 0.22 mu m filter membrane to obtain a drug-loaded ethosome 9. Weighing egg yolk lecithin 400 mg, cholesterol 20 mg and pain relieving medicine 50 mg, fixing the volume to 10 mL with a compound organic solvent, stirring for dissolution, evaporating under reduced pressure at 30deg.C in water bath to form a lipid film layer, injecting nitrogen gas, adding 3% sodium cholate solution 10 mL, steaming to form liposome suspension, injecting nitrogen gas, performing ultrasonic treatment for 15 min at 150 w, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome 10. The annular cladding structure 1 was produced by injection molding 440, s ABS into a mold cavity at 62.5 ℃ and 5 bar. 30 mL A solution of 0.2% ferrocene in acetone was mixed with 1.5 mL of 30% H 2 O 2 Mixing, reacting at 180deg.C for 70 h, cooling, washing, and dispersing into ethylene glycol (30 mg/m)L) obtaining a dispersion of magnetic nanoparticles 8; 1.8 g of N-isopropyl acrylamide, 0.18 mL acrylic acid and 3 mg of N, N' -methylene bisacrylamide are uniformly mixed and dissolved in a mixed solution of 1.5 mL ethanol and ethylene glycol (weight ratio of 1:1), and then 2 mu L of photoinitiator is added and uniformly mixed in a dark place to obtain a hydrogel prepolymer solution; and then uniformly mixing the hydrogel prepolymerization solution, the dispersion liquid of the magnetic nano particles 8 and the collagen in a ratio of 10:10:1 in a dark way to obtain the magnetic hydrogel prepolymerization solution. Placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet light environment of 356 nm for polymerization reaction for 1 min to obtain magnetic hydrogel; the magnetic hydrogel is placed in 50% of a suspension of drug-loaded liposome 10 and drug-loaded ethosome 9, and soaked at 25 ℃ for 72 h, so that the visualized drug storage and delivery system 3 is obtained. Dissolving sucrose fatty acid ester in water to obtain 0.5% of emulsifier; dissolving maltodextrin and gum arabic in water according to a ratio of 3:1 to obtain a 40% wall material solution; adding 2% of emulsifying agent, 20% of PNPG, 20% of methylene blue and 20% of tetrabromofluorescein sodium into the wall material solution, and uniformly mixing; ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; spray drying (inlet air temperature 150 ℃ C., feed flow rate 17 mL/min) -1 The temperature of the air outlet is 75 ℃), and the microcapsule is obtained; adding 45% microcapsule, 6% carboxymethyl cellulose and 6% starch into purified water, stirring and mixing uniformly to obtain the bacterial contamination indicator window coating. The annular coating structure 1 is inverted, the energy conducting sheet 2 is firstly placed, then the bacterial contamination indicating window coating is coated on the bacterial contamination indicating window 5 of the annular coating structure 1, the visual drug storage and delivery system 3 is attached to the energy conducting sheet 2 and completely covers the bacterial contamination indicating window coating, and then the tearable anti-sticking layer 4 is compounded, so that the functional ultrasonic controlled release puncture dressing 13 is obtained.
The detection method of the functionalized ultrasonic controlled-release puncture dressing 13 in the invention comprises the following steps:
1. drug encapsulation efficiency determination of liposomes and ethosomes
High performance liquid chromatography is used for measurement.
2. Determination of drug recovery rate in functionalized ultrasonic controlled-release puncture dressing patch 13
High performance liquid chromatography is used for measurement.
3. Stability test of functional ultrasonic controlled-release puncture dressing patch 13
Considering the influence of illumination, humidity and temperature on the properties and the drug content of the functionalized ultrasonic controlled-release puncture dressing 13 (the drug-loaded ethosome 9 in the functionalized ultrasonic controlled-release puncture dressing 13 is selected as a measurement object). Setting conditions: light (colorless transparent sealed plastic bag, 4500, lx, relative humidity 50%, constant temperature 25 ℃, standing for 30 days), humidity (black sealed plastic bag, relative humidity 75%, constant temperature 25 ℃, standing for 30 days), temperature (black sealed plastic bag, relative humidity 75%, constant temperature 60 ℃, standing for 30 days).
4. In-vitro percutaneous release test of medicine in functionalized ultrasonic controlled-release puncture dressing patch 13
The in vitro diffusion method is adopted for testing, and the diffusion membrane is the in vitro abdomen skin of the mouse.
5. Skin irritation test of functionalized ultrasonic controlled release puncture dressing patch 13
The measurement was performed using symmetrical hairless skin on both sides of the back of the rabbits.
6. Bacterial contamination indicator window 5 and drug release indicator window 6 display efficacy test
(1) (1) bacterial contamination indicator window 5 display: 0.5 mL of 3X 10 solution was added dropwise to the vicinity of the bacterial contamination indicator window 5 in examples 1 to 6 of the present invention 8 CFU/mL strain 1 (escherichia coli) and 0.5. 0.5 mL strain 2 (staphylococcus aureus), standing for 5 min, and observing the color of the bacterial contamination indicator window 5 with normal naked eyes indoors;
(2) Drug release indicator window 6 displays: the clinical use process was simulated, and the color change of the drug release indicator window 6 was observed with a normal naked eye indoors.
7. Clinical trial effects
Clinical protocol: 240 cases of operation patients needing to be punctured by the venous indwelling needle are selected, 60 cases are observation groups, and example 1 is adopted as a test sample; 60 cases are placebo groups, and gauze stained with physiological saline is used as a test sample; 60 cases are comparative group 1, and comparative example 4 is used as a test article; 60 cases are comparative group 2, and comparative example 5 is used as a test article; all groups of puncture parts are 1-2 cm away from the proximal end of the wrist joint by the left-hand head vein, and ultrasonic treatment is carried out by combining an ultrasonic technology;
(1) After the puncture is finished, inquiring the pain feeling of the patient in the puncture operation process in a way of oral question and answer, dividing the pain level of the patient according to the VAS score, and judging the pain level of the patient so as to evaluate the rapid pain relieving effect of the functional ultrasonic controlled-release puncture dressing 13;
(2) After the puncture is finished, inquiring a doctor in a way of oral question and answer, recording the puncture operation difficulty and confirming whether the first puncture is successful or not, thereby evaluating the vasodilation effect of the functionalized ultrasonic controlled-release puncture dressing 13;
(3) After the puncture is finished, the pain feeling of the patient at rest in the ward is inquired in a way of oral question answering, the pain level of the patient is divided according to the VAS score, and the pain degree of the patient is judged, so that the continuous pain relieving effect of the functional ultrasonic controlled-release puncture dressing 13 is evaluated.
The drug encapsulation efficiency, recovery rate, stability, in vitro percutaneous permeability, skin irritation and other properties of the functionalized ultrasonic controlled-release puncture dressing 13 were detected and the clinical trial therapeutic effects were observed according to the detection methods, and the results are shown in tables 1, 2, 3, 4, 5, 6 and 7.
TABLE 1 detection results tables of examples 1 to 6 of the present invention
TABLE 2 comparative examples 1-6 test results Table of the present invention
TABLE 3 results of stability test (drug content,%) of inventive examples 1-6
TABLE 4 results of stability test (drug content,%) of comparative examples 1-6 of the present invention
TABLE 5 evaluation results of pain class during and after puncture
TABLE 6 evaluation results of dilated blood vessel
As can be seen from table 1 to table 6, fig. 6 and fig. 7, the functionalized ultrasonic controlled-release puncture dressing patch 13 designed by the invention has higher ethosome encapsulation rate, liposome encapsulation rate and drug recovery rate, and the protection of the annular coating structure 1 ensures that the dressing patch has more stable properties, including external properties, drug release and drug content, and is hardly influenced by illumination, high temperature and high humidity; has no irritation to skin and good skin affinity; by combining the ultrasonic technology, the drug-loaded ethosome 9 can be basically released completely within about 10 minutes before puncture, and then the sustained release effect of the drug-loaded liposome 10 can also continuously and stably release the analgesic drug; meanwhile, the two indication windows can monitor bacterial pollution and drug release degree; finally, according to clinical research results, the invention can effectively relieve pain before and after puncture, and simultaneously can dilate blood vessels to be punctured, reduce puncture difficulty, improve puncture success rate and further relieve pain of patients.
As can be seen from examples 1-6 of table 1 and comparative example 1 of table 2, the edge of the dressing patch is severely deformed without the protection of the annular coating structure 1, and the phenomena of dry cracking, breakage and delamination occur, so that the product is disqualified, and the bacteria pollution indication window 5 and the drug release indication window 6 are not provided, which is inconvenient to use; meanwhile, as is clear from comparative example 1 of examples 1 to 6 and 4 of table 3, without the protection of the annular cladding structure 1, the visual drug storage and delivery system 3 is damaged, in which the drug storability is deteriorated, and is susceptible to environmental factors, particularly temperature; furthermore, as can be seen from fig. 6 and 7, the total drug release, release rate and release stability are also reduced without the protection of the annular cladding structure 1.
As is clear from comparative examples 2 of tables 1 to 6 and 2, tables 3 and 4, and fig. 6 and 7, the visual drug storage and delivery system 3 was exposed to air without the energy transmission sheet 2, and it was also found that the problems such as cracking, breakage, inactivation of the drug, unstable drug release, and low drug release were caused, and the desired therapeutic effect was not achieved.
As can be seen from examples 1-6 of table 1, comparative example 3 of table 2, table 3, table 4, and fig. 6 and 7, there is no nanocarrier (ethosome, liposome) for loading and protecting the drug, the drug recovery rate is very low, and the drug loading is also low as can be seen from the color change of the indication window; in addition, the drug cannot effectively penetrate the skin into the target tissue, and the release amount is low and slow, and the slow release effect is not achieved.
As can be seen from table 5, example 1 (observation group) contains both drug-loaded liposome 10 and drug-loaded ethosome 9, which can reduce the pain during and after the operation; in contrast, comparative example 4 (control group 1) has no drug-loaded liposome 10 and only drug-loaded ethosome 9, so that the drug-loaded ethosome has better effects of stopping pain and dilating blood vessels before operation, but has no continuous effect of stopping pain after operation; in contrast, comparative example 5 (control group 2) has no drug-loaded ethosome 9 and only drug-loaded liposome 10, so that the drug-loaded ethosome has a better postoperative continuous analgesic effect, but has no preoperative analgesic and vasodilatory effects.
As can be seen from table 6, the degree of reduction of the surgical difficulty after the use of the functionalized ultrasonic controlled release puncture dressing 13 improves the success rate of the first puncture.
As can be seen from comparative examples 6 of examples 1-6 and tables 2, 3 and 4, and FIGS. 6 and 7, comparative example 6 has unsuitable preparation process parameters, so that the ethosome encapsulation efficiency, the liposome encapsulation efficiency, and the adjuvant patch drug recovery rate, and the dressing stability, the adjuvant patch skin irritation, and the indicator window color development effect test indexes of the functionalized ultrasonic controlled-release puncture dressing 13 are all not ideal.
The result shows that the functional ultrasonic controlled-release puncture dressing 13 designed by the invention has good properties and clinical application value.
While the present invention has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the invention. Many modifications and substitutions of the present invention will become apparent to those of ordinary skill in the art upon reading the foregoing description, and any variations that would occur to those skilled in the art are intended to be within the scope of the invention.
Claims (9)
1. The functional ultrasonic controlled release puncture dressing patch is characterized by comprising a double-layer parallel structure, an annular cladding structure and a tearable anti-sticking layer; the double-layer parallel structure is used as a core material and consists of an energy conducting sheet and a visual drug storage and delivery system, and is arranged concentrically and vertically; the energy conducting sheet is made of an ultrasonic wave transmission material; the visual drug storage and delivery system consists of hydrogel embedded with drug-carrying alcohol bodies, drug-carrying liposomes, magnetic nanoparticles and collagen; the annular cladding structure is used as a cladding material and comprises a bacterial contamination indicating window and a drug release indicating window, and is used for connecting, fixing and protecting the integral frame and indicating the bacterial contamination and drug release degree, and is manufactured through a mould pressing process.
2. A method for preparing the functionalized ultrasonic controlled-release puncture dressing according to claim 1, which is characterized by comprising the following steps:
(1) Preparation of drug-loaded ethosome: weighing egg yolk lecithin, cholesterol, a vasodilator and a pain relieving medicine according to a formula, stirring and dissolving the egg yolk lecithin, the cholesterol, the vasodilator and the pain relieving medicine in absolute ethyl alcohol at 30 ℃; injecting ultrapure water into the absolute ethyl alcohol at the flow rate of 200 mu L/min, stirring for 30 min, performing ice water bath ultrasonic treatment, and filtering with a 0.22 mu m filter membrane to obtain a drug-carrying ethosome;
(2) Preparation of drug-loaded liposome: weighing egg yolk lecithin, cholesterol, pain relieving medicine and compound organic solvent according to a formula, stirring, mixing and dissolving; evaporating under reduced pressure in 30deg.C water bath to form a lipid film layer, injecting nitrogen, adding sodium cholate solution, removing organic solvent by rotary evaporation to form liposome suspension, injecting nitrogen again, performing ultrasonic treatment, and filtering with 0.22 μm filter membrane to obtain drug-loaded liposome;
(3) Preparing an annular cladding structure: injecting ABS into a mold cavity, and performing a mold pressing process to obtain an annular coating structure containing a bacterial contamination indication window and a drug release indication window;
(4) Preparation of magnetic hydrogel prepolymerization solution: the acetone solution containing ferrocene is mixed with 30% H 2 O 2 After being evenly mixed, the mixture reacts at 180 ℃ for 70 h, and after being cooled, the mixture is washed and redispersed to obtain magnetic nanoparticle dispersion liquid; uniformly mixing N-isopropyl acrylamide, acrylic acid and N, N' -methylene bisacrylamide, dissolving the mixture in an ethanol and ethylene glycol mixed organic solution, and then adding a photoinitiator, and uniformly mixing the mixture in a dark place to obtain a hydrogel prepolymerization solution; uniformly mixing the hydrogel prepolymerization solution, the magnetic nanoparticle dispersion liquid and the collagen according to a proportion in a dark place to obtain a magnetic hydrogel prepolymerization solution;
(5) Visual drug storage delivery system preparation: placing a glass mold containing the magnetic hydrogel prepolymerization solution in a magnetic field of 0.2T and an ultraviolet light environment of 356 nm for polymerization reaction to obtain magnetic hydrogel; placing the magnetic hydrogel in a suspension of drug-carrying liposome and drug-carrying ethosome, and soaking at 25 ℃ for 72 h to obtain a visual drug storage and delivery system;
(6) The preparation of the coating for the bacterial contamination indicator window comprises the following steps: stirring sucrose fatty acid ester and dissolving in water to obtain an emulsifier; uniformly mixing maltodextrin and gum arabic according to a proportion, and dissolving the mixture in water to obtain a wall material solution; adding an emulsifying agent and PNPG into the wall material solution, emulsifying, adding methylene blue and tetrabromo sodium fluorescein, and uniformly mixing again; mixing, ultrasonic embedding for 30 min, homogenizing under 30 MPa for 5 times, and 1 min each time; homogenizing, and then spray drying to obtain microcapsules; adding the microcapsule, the carboxymethyl cellulose and the starch into the purified water according to the formula, and stirring and uniformly mixing to prepare the coating for the bacterial contamination indicator window;
(7) Preparation of a functional ultrasonic controlled-release puncture dressing patch: inverting the annular coating structure, firstly placing an energy conducting sheet, then coating the bacterial contamination indication window coating on the bacterial contamination indication window of the annular coating structure, then attaching a visual drug storage and delivery system on the energy conducting sheet and completely covering the bacterial contamination indication window coating, and then compounding a tearable anti-sticking layer to obtain the functional ultrasonic controlled release puncture dressing.
3. The method for preparing a functionalized ultrasonic controlled release dressing patch according to claim 2, wherein the formula in step (1) is as follows: 3-7% of egg yolk lecithin, 0.1-1.1% of cholesterol, 4-6% of vasodilating drugs, 4-6% of pain relieving drugs, 30-40% of absolute ethyl alcohol and 58.9-39.9% of ultrapure water; the vasodilator is one of nitroglycerin and phentolamine; the pain relieving medicine is one of lidocaine and tetracaine hydrochloride; and the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min.
4. The method for preparing a functionalized ultrasonic controlled release dressing patch according to claim 2, wherein the formula in step (2) is as follows: 1-5% of egg yolk lecithin, 0.5-1.5% of cholesterol, 4-6% of pain relieving drugs, 42-52% of compound organic solvent and 52.5-42.5% of sodium cholate solution; the compound organic solvent is prepared by mixing chloroform and methanol according to a volume ratio of 1:1; the concentration of the sodium cholate solution is 1-5%; and the ultrasonic treatment is carried out with parameters of ultrasonic power of 100-110 w and ultrasonic time of 1-9 min.
5. The method for preparing a functionalized ultrasonic controlled-release puncture dressing according to claim 2, wherein the molding process parameters in step (3) are as follows: the temperature of the die is 60-65 ℃, the die pressing time is 180-700 s, and the die pressing pressure is 1-9 bar.
6. The method for preparing the functionalized ultrasonic controlled-release puncture dressing patch according to claim 2, wherein the concentration of the acetone solution containing ferrocene in the step (4) is 0.9-1.1%, and the concentration of the acetone solution containing ferrocene is 30% H 2 O 2 The addition amount is 2.0-3.0%;the redispersion refers to redispersing magnetic nano particles with certain mass into glycol solution, so that the concentration of the magnetic nano particles in the solution is 30 mg/mL; the concentration of the N-isopropyl acrylamide, the acrylic acid and the N, N' -methylene bisacrylamide in the ethanol and ethylene glycol mixed solution is 0.55-0.75 g/mL, 5.5-7.5% and 18-22 mg/mL respectively; the weight ratio of the ethanol to the glycol in the ethanol and glycol mixed solution is (0.9-1.1): 1; the photoinitiator is one of 2,4, 6-trimethylbenzoyl diphenyl phosphine oxide and 2,4, 6-trimethylbenzoyl phenyl ethyl phosphonate, and the addition amount of the photoinitiator is 1.25-1.45%; the ratio of the hydrogel prepolymerization solution to the magnetic nanoparticle dispersion liquid to the collagen is (25-35) 10:1.
7. The method for preparing the functionalized ultrasonic controlled-release puncture dressing patch according to claim 2, wherein the size of the glass mold in the step (5) is consistent with that of the annular coating structure, and the polymerization reaction time is 2-4 min; the solute of the suspension is a mixture of the drug-carrying liposome and the drug-carrying ethosome according to the mass ratio of 1:1, and the concentration of the mixture in the suspension is 70-90%.
8. The method for preparing the functionalized ultrasonic controlled-release puncture dressing patch according to claim 2, wherein the concentration of the emulsifier in the step (6) is 0.1-1.0%; the mixing proportion of maltodextrin and gum arabic is (1-5) 1; the wall material concentration is 33-47%; adding an emulsifier, PNPG, methylene blue and tetrabromo sodium into the wall material solution, wherein the concentrations of the emulsifier, PNPG, methylene blue and tetrabromo sodium are respectively 1-3%, 15-25% and 15-25%; the spray drying parameters were: the air inlet temperature is 140-160 ℃, and the feeding flow is 15-20 mL/min -1 The air outlet temperature is 70-80 ℃; the formula of the coating for the bacterial contamination indicator window comprises 25-65% of microcapsules, 2-10% of carboxymethyl cellulose and 2-10% of starch.
9. The method for preparing a functionalized ultrasonic controlled-release puncture dressing according to claim 2, wherein the ultrasonic transmission material used in the energy transmission sheet in the step (7) is one of metal, ceramic and plastic; the tearable anti-sticking layer is one of a polystyrene film, an aluminum foil, a siliconized polyvinyl chloride film and a polycarbonate film.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311799034.7A CN117462836A (en) | 2023-12-26 | 2023-12-26 | Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311799034.7A CN117462836A (en) | 2023-12-26 | 2023-12-26 | Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN117462836A true CN117462836A (en) | 2024-01-30 |
Family
ID=89633253
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311799034.7A Pending CN117462836A (en) | 2023-12-26 | 2023-12-26 | Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN117462836A (en) |
Citations (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3814095A (en) * | 1972-03-24 | 1974-06-04 | H Lubens | Occlusively applied anesthetic patch |
| JPH06145051A (en) * | 1992-02-25 | 1994-05-24 | Nitto Denko Corp | Patch for application before treatment of centesis and method for alleviating pain during centesis |
| US5466465A (en) * | 1993-12-30 | 1995-11-14 | Harrogate Holdings, Limited | Transdermal drug delivery system |
| US6477410B1 (en) * | 2000-05-31 | 2002-11-05 | Biophoretic Therapeutic Systems, Llc | Electrokinetic delivery of medicaments |
| CN1479615A (en) * | 2000-11-16 | 2004-03-03 | 克里斯・利佩尔 | Medicuted tattoos |
| CN1543342A (en) * | 2001-06-11 | 2004-11-03 | 沙斯公司 | Controlled heat induced rapid delivery of pharmaceuticals from skin depot |
| US20090123527A1 (en) * | 2006-07-24 | 2009-05-14 | Akorn, Inc. | Method of inducing topical anesthesia and transdermal patch |
| CN101500640A (en) * | 2006-06-15 | 2009-08-05 | 海鸥Ip有限公司 | A delivery system and process |
| CN101744842A (en) * | 2008-12-01 | 2010-06-23 | 马德林 | Lipidosome Chinese traditional medicine membranous plaster |
| CN103505806A (en) * | 2012-12-27 | 2014-01-15 | 中国人民解放军第二军医大学 | Electret nanoparticle cutaneous penetration system |
| CN103505322A (en) * | 2012-06-26 | 2014-01-15 | 陕西远光高科技有限公司 | Functional dressing (film) |
| CN104367416A (en) * | 2014-11-07 | 2015-02-25 | 薛景 | Fast pain relieving method for children blood vessel puncture and pain relieving paste |
| CN106074849A (en) * | 2016-06-30 | 2016-11-09 | 柳州市妇幼保健院 | A kind of artery and vein puncture expansion blood vessel analgesic antiphlogistic patch |
| CN107049994A (en) * | 2017-03-27 | 2017-08-18 | 华南农业大学 | A kind of multi-functional controlled release anti-inflammatory and antalgic patch and its preparation method and application |
| CN209137791U (en) * | 2018-01-18 | 2019-07-23 | 珠海全德科技有限公司 | A kind of ultrasound electro photoluminescence combination therapy instrument |
| US20190224363A1 (en) * | 2016-09-08 | 2019-07-25 | Sefar Ag | Indicator dressing and method for indicating a contamination, in particular of a wound |
| CN209751381U (en) * | 2019-02-22 | 2019-12-10 | 临汾市中心医院 | Foam dressing for preventing phlebitis |
| CN210750879U (en) * | 2019-08-14 | 2020-06-16 | 中国人民解放军总医院 | Painless vein plaster |
| CN211460793U (en) * | 2019-09-29 | 2020-09-11 | 深圳市萨米医疗中心(深圳市聚龙医院) | Medicinal phlebitis damp-heat application plaster |
| CN212037940U (en) * | 2019-12-25 | 2020-12-01 | 华中科技大学同济医学院附属协和医院 | Transparent visible aseptic dressing plaster with dyeing card |
| CN213285156U (en) * | 2020-04-23 | 2021-05-28 | 复旦大学附属儿科医院 | Local anesthesia plaster for skin |
| CN214342926U (en) * | 2020-07-27 | 2021-10-08 | 中国人民解放军联勤保障部队第九二〇医院 | Puncture anesthesia application plaster for dialysis internal fistula area |
| KR20220105560A (en) * | 2021-01-20 | 2022-07-27 | 박순용 | Smart dressing film body |
| CN218773998U (en) * | 2022-09-06 | 2023-03-31 | 车利 | Children venipuncture painless plaster |
| CN115887358A (en) * | 2022-11-29 | 2023-04-04 | 中国药科大学 | Gel based on temperature-sensitive drug-loaded alcohol carrier and preparation method and application thereof |
| US20230181373A1 (en) * | 2021-12-13 | 2023-06-15 | Stephen WELSH | Adhesive bandage system for medication delivery and indication of procedure location |
| CN219185462U (en) * | 2023-01-05 | 2023-06-16 | 深圳市儿童医院 | Local anesthesia adhesive tape for lumbar puncture |
-
2023
- 2023-12-26 CN CN202311799034.7A patent/CN117462836A/en active Pending
Patent Citations (27)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3814095A (en) * | 1972-03-24 | 1974-06-04 | H Lubens | Occlusively applied anesthetic patch |
| JPH06145051A (en) * | 1992-02-25 | 1994-05-24 | Nitto Denko Corp | Patch for application before treatment of centesis and method for alleviating pain during centesis |
| US5466465A (en) * | 1993-12-30 | 1995-11-14 | Harrogate Holdings, Limited | Transdermal drug delivery system |
| US6477410B1 (en) * | 2000-05-31 | 2002-11-05 | Biophoretic Therapeutic Systems, Llc | Electrokinetic delivery of medicaments |
| CN1479615A (en) * | 2000-11-16 | 2004-03-03 | 克里斯・利佩尔 | Medicuted tattoos |
| CN1543342A (en) * | 2001-06-11 | 2004-11-03 | 沙斯公司 | Controlled heat induced rapid delivery of pharmaceuticals from skin depot |
| CN101500640A (en) * | 2006-06-15 | 2009-08-05 | 海鸥Ip有限公司 | A delivery system and process |
| US20090123527A1 (en) * | 2006-07-24 | 2009-05-14 | Akorn, Inc. | Method of inducing topical anesthesia and transdermal patch |
| CN101744842A (en) * | 2008-12-01 | 2010-06-23 | 马德林 | Lipidosome Chinese traditional medicine membranous plaster |
| CN103505322A (en) * | 2012-06-26 | 2014-01-15 | 陕西远光高科技有限公司 | Functional dressing (film) |
| CN103505806A (en) * | 2012-12-27 | 2014-01-15 | 中国人民解放军第二军医大学 | Electret nanoparticle cutaneous penetration system |
| CN104367416A (en) * | 2014-11-07 | 2015-02-25 | 薛景 | Fast pain relieving method for children blood vessel puncture and pain relieving paste |
| CN106074849A (en) * | 2016-06-30 | 2016-11-09 | 柳州市妇幼保健院 | A kind of artery and vein puncture expansion blood vessel analgesic antiphlogistic patch |
| US20190224363A1 (en) * | 2016-09-08 | 2019-07-25 | Sefar Ag | Indicator dressing and method for indicating a contamination, in particular of a wound |
| CN107049994A (en) * | 2017-03-27 | 2017-08-18 | 华南农业大学 | A kind of multi-functional controlled release anti-inflammatory and antalgic patch and its preparation method and application |
| CN209137791U (en) * | 2018-01-18 | 2019-07-23 | 珠海全德科技有限公司 | A kind of ultrasound electro photoluminescence combination therapy instrument |
| CN209751381U (en) * | 2019-02-22 | 2019-12-10 | 临汾市中心医院 | Foam dressing for preventing phlebitis |
| CN210750879U (en) * | 2019-08-14 | 2020-06-16 | 中国人民解放军总医院 | Painless vein plaster |
| CN211460793U (en) * | 2019-09-29 | 2020-09-11 | 深圳市萨米医疗中心(深圳市聚龙医院) | Medicinal phlebitis damp-heat application plaster |
| CN212037940U (en) * | 2019-12-25 | 2020-12-01 | 华中科技大学同济医学院附属协和医院 | Transparent visible aseptic dressing plaster with dyeing card |
| CN213285156U (en) * | 2020-04-23 | 2021-05-28 | 复旦大学附属儿科医院 | Local anesthesia plaster for skin |
| CN214342926U (en) * | 2020-07-27 | 2021-10-08 | 中国人民解放军联勤保障部队第九二〇医院 | Puncture anesthesia application plaster for dialysis internal fistula area |
| KR20220105560A (en) * | 2021-01-20 | 2022-07-27 | 박순용 | Smart dressing film body |
| US20230181373A1 (en) * | 2021-12-13 | 2023-06-15 | Stephen WELSH | Adhesive bandage system for medication delivery and indication of procedure location |
| CN218773998U (en) * | 2022-09-06 | 2023-03-31 | 车利 | Children venipuncture painless plaster |
| CN115887358A (en) * | 2022-11-29 | 2023-04-04 | 中国药科大学 | Gel based on temperature-sensitive drug-loaded alcohol carrier and preparation method and application thereof |
| CN219185462U (en) * | 2023-01-05 | 2023-06-16 | 深圳市儿童医院 | Local anesthesia adhesive tape for lumbar puncture |
Non-Patent Citations (2)
| Title |
|---|
| 冯杨英凡;陈楷文;王华楠;陈陶;季平;: "生物功能化聚乙二醇基复合水凝胶的制备、性能研究及在感染创口修复中的初步应用", 华中科技大学学报(医学版), no. 04, 15 August 2020 (2020-08-15) * |
| 李和珂;李晓琴;曾瑜;肖静;万应伶;邓梦慧;郑蜀芳;: "减轻静脉穿刺疼痛方法的研究进展", 局解手术学杂志, no. 03, 25 March 2020 (2020-03-25) * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2661643T3 (en) | Dressing system | |
| JP6446035B2 (en) | Transdermal delivery system | |
| CN102871956B (en) | Propranolol hydrochloride gel for treating infant superficial hemangioma | |
| KR20070105331A (en) | Device method, and use for treatment of neuropathy involving nitric oxide | |
| CN109481148B (en) | A kind of moisture absorption vapor-permeable type wound dressing patch | |
| CN108785739A (en) | A kind of full-service fluid adhesive bandage and preparation method thereof | |
| CN113797155A (en) | Insoluble transdermal microneedle patch as well as preparation method and application thereof | |
| Long et al. | Microneedles for in situ tissue regeneration | |
| CN117462836A (en) | Functionalized ultrasonic controlled-release puncture dressing patch and preparation method thereof | |
| CN109550076B (en) | Medical silicone ozone oil vaseline dressing and wound care patch based on dressing | |
| CN102911378A (en) | Method for preparing hydrogel film for curing chemotherapeutic phlebitis | |
| CN112263777B (en) | Hydrogen molecule slow-release composite dressing and preparation method thereof | |
| CN108815182B (en) | Sterilized compound magnesium sulfate wet-dressing composition as well as preparation method and application thereof | |
| CN106562953A (en) | Application of hydroxysafflor yellow A in preparing medicine for treating diabetic foot ulceration, medicine and medicine preparation method | |
| CN109289095B (en) | Enteroscope gel containing lidocaine hydrochloride and preparation method thereof | |
| CN108721604B (en) | Thymosin beta-4 ethosome and preparation process thereof | |
| CN113694010A (en) | Production process of microneedle transdermal patch | |
| CN212816758U (en) | Dressing for venous indwelling needle | |
| US20220118237A1 (en) | Devices for topical delivery of active agents to a target site | |
| CN220090128U (en) | Novel indwelling needle infusion patch containing Miao medicine | |
| CN219148774U (en) | Catheter fixing dressing | |
| CN113143844B (en) | Polymer microneedle patch for treating acne and preparation method thereof | |
| RU206168U1 (en) | Atraumatic dressing for the treatment of wounds in animals | |
| CN113041237B (en) | Paracetamol abdominal navel patch and preparation method thereof | |
| CN212547765U (en) | Chitosan quaternary ammonium salt sterilization band-aid |
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 |