CN117025127A - Hot-melt pressure-sensitive adhesive containing small molecular acid and salt thereof and application thereof - Google Patents
Hot-melt pressure-sensitive adhesive containing small molecular acid and salt thereof and application thereof Download PDFInfo
- Publication number
- CN117025127A CN117025127A CN202311129750.4A CN202311129750A CN117025127A CN 117025127 A CN117025127 A CN 117025127A CN 202311129750 A CN202311129750 A CN 202311129750A CN 117025127 A CN117025127 A CN 117025127A
- Authority
- CN
- China
- Prior art keywords
- sensitive adhesive
- melt pressure
- hot
- acid
- styrene
- 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
- 239000004820 Pressure-sensitive adhesive Substances 0.000 title claims abstract description 42
- 239000012943 hotmelt Substances 0.000 title claims abstract description 41
- 239000002253 acid Substances 0.000 title claims abstract description 20
- 150000003839 salts Chemical class 0.000 title claims abstract description 9
- 239000003814 drug Substances 0.000 claims abstract description 62
- 229940079593 drug Drugs 0.000 claims abstract description 56
- 239000011159 matrix material Substances 0.000 claims abstract description 53
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 68
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 35
- 239000003607 modifier Substances 0.000 claims description 23
- RSWGJHLUYNHPMX-UHFFFAOYSA-N Abietic-Saeure Natural products C12CCC(C(C)C)=CC2=CCC2C1(C)CCCC2(C)C(O)=O RSWGJHLUYNHPMX-UHFFFAOYSA-N 0.000 claims description 18
- KHPCPRHQVVSZAH-HUOMCSJISA-N Rosin Natural products O(C/C=C/c1ccccc1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 KHPCPRHQVVSZAH-HUOMCSJISA-N 0.000 claims description 18
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 18
- KHPCPRHQVVSZAH-UHFFFAOYSA-N trans-cinnamyl beta-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OCC=CC1=CC=CC=C1 KHPCPRHQVVSZAH-UHFFFAOYSA-N 0.000 claims description 18
- 229920000346 polystyrene-polyisoprene block-polystyrene Polymers 0.000 claims description 14
- 229920005989 resin Polymers 0.000 claims description 13
- 239000011347 resin Substances 0.000 claims description 13
- 239000002480 mineral oil Substances 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 11
- 235000010446 mineral oil Nutrition 0.000 claims description 11
- -1 fatty acid ester Chemical class 0.000 claims description 10
- 229960002373 loxoprofen Drugs 0.000 claims description 10
- 150000002148 esters Chemical class 0.000 claims description 8
- 125000005456 glyceride group Chemical group 0.000 claims description 8
- 229920002725 thermoplastic elastomer Polymers 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229920001577 copolymer Polymers 0.000 claims description 6
- 239000003921 oil Substances 0.000 claims description 6
- 229920001083 polybutene Polymers 0.000 claims description 6
- PRAKJMSDJKAYCZ-UHFFFAOYSA-N squalane Chemical compound CC(C)CCCC(C)CCCC(C)CCCCC(C)CCCC(C)CCCC(C)C PRAKJMSDJKAYCZ-UHFFFAOYSA-N 0.000 claims description 6
- 229920000468 styrene butadiene styrene block copolymer Polymers 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 5
- 230000003078 antioxidant effect Effects 0.000 claims description 5
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 4
- 125000001931 aliphatic group Chemical group 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 claims description 4
- 229940057995 liquid paraffin Drugs 0.000 claims description 4
- 239000003961 penetration enhancing agent Substances 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 4
- 150000003014 phosphoric acid esters Chemical class 0.000 claims description 4
- 150000003021 phthalic acid derivatives Chemical class 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920002367 Polyisobutene Polymers 0.000 claims description 3
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 claims description 3
- 229960001193 diclofenac sodium Drugs 0.000 claims description 3
- 239000004033 plastic Substances 0.000 claims description 3
- 229920003023 plastic Polymers 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 150000003384 small molecules Chemical class 0.000 claims description 3
- 239000001509 sodium citrate Substances 0.000 claims description 3
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 claims description 3
- 239000001488 sodium phosphate Substances 0.000 claims description 3
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 3
- 229960004025 sodium salicylate Drugs 0.000 claims description 3
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 claims description 3
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 3
- YYGNTYWPHWGJRM-UHFFFAOYSA-N (6E,10E,14E,18E)-2,6,10,15,19,23-hexamethyltetracosa-2,6,10,14,18,22-hexaene Chemical compound CC(C)=CCCC(C)=CCCC(C)=CCCC=C(C)CCC=C(C)CCC=C(C)C YYGNTYWPHWGJRM-UHFFFAOYSA-N 0.000 claims description 2
- ZJZLFDHSFOSUIJ-UHFFFAOYSA-N 4-methyl-3,4-dihydro-2,5-benzodioxocine-1,6-dione Chemical compound O=C1OC(C)COC(=O)C2=CC=CC=C21 ZJZLFDHSFOSUIJ-UHFFFAOYSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- BHEOSNUKNHRBNM-UHFFFAOYSA-N Tetramethylsqualene Natural products CC(=C)C(C)CCC(=C)C(C)CCC(C)=CCCC=C(C)CCC(C)C(=C)CCC(C)C(C)=C BHEOSNUKNHRBNM-UHFFFAOYSA-N 0.000 claims description 2
- ZJCCRDAZUWHFQH-UHFFFAOYSA-N Trimethylolpropane Chemical class CCC(CO)(CO)CO ZJCCRDAZUWHFQH-UHFFFAOYSA-N 0.000 claims description 2
- 125000002723 alicyclic group Chemical group 0.000 claims description 2
- 229920006271 aliphatic hydrocarbon resin Polymers 0.000 claims description 2
- 229920006272 aromatic hydrocarbon resin Polymers 0.000 claims description 2
- 239000010692 aromatic oil Substances 0.000 claims description 2
- ZFMQKOWCDKKBIF-UHFFFAOYSA-N bis(3,5-difluorophenyl)phosphane Chemical compound FC1=CC(F)=CC(PC=2C=C(F)C=C(F)C=2)=C1 ZFMQKOWCDKKBIF-UHFFFAOYSA-N 0.000 claims description 2
- KGBXLFKZBHKPEV-UHFFFAOYSA-N boric acid Chemical compound OB(O)O KGBXLFKZBHKPEV-UHFFFAOYSA-N 0.000 claims description 2
- 239000004327 boric acid Substances 0.000 claims description 2
- 229920006026 co-polymeric resin Polymers 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- GQIDSVPVVYHXAP-UHFFFAOYSA-N dihexyl decanedioate Chemical compound CCCCCCOC(=O)CCCCCCCCC(=O)OCCCCCC GQIDSVPVVYHXAP-UHFFFAOYSA-N 0.000 claims description 2
- XWVQUJDBOICHGH-UHFFFAOYSA-N dioctyl nonanedioate Chemical compound CCCCCCCCOC(=O)CCCCCCCC(=O)OCCCCCCCC XWVQUJDBOICHGH-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 239000001530 fumaric acid Substances 0.000 claims description 2
- 229920006007 hydrogenated polyisobutylene Polymers 0.000 claims description 2
- 239000004310 lactic acid Substances 0.000 claims description 2
- 235000014655 lactic acid Nutrition 0.000 claims description 2
- CAAULPUQFIIOTL-UHFFFAOYSA-N methyl dihydrogen phosphate Chemical class COP(O)(O)=O CAAULPUQFIIOTL-UHFFFAOYSA-N 0.000 claims description 2
- JXTPJDDICSTXJX-UHFFFAOYSA-N n-Triacontane Natural products CCCCCCCCCCCCCCCCCCCCCCCCCCCCCC JXTPJDDICSTXJX-UHFFFAOYSA-N 0.000 claims description 2
- WXZMFSXDPGVJKK-UHFFFAOYSA-N pentaerythritol Chemical class OCC(CO)(CO)CO WXZMFSXDPGVJKK-UHFFFAOYSA-N 0.000 claims description 2
- UWJJYHHHVWZFEP-UHFFFAOYSA-N pentane-1,1-diol Chemical class CCCCC(O)O UWJJYHHHVWZFEP-UHFFFAOYSA-N 0.000 claims description 2
- 229940116351 sebacate Drugs 0.000 claims description 2
- 229940032094 squalane Drugs 0.000 claims description 2
- 229940031439 squalene Drugs 0.000 claims description 2
- TUHBEKDERLKLEC-UHFFFAOYSA-N squalene Natural products CC(=CCCC(=CCCC(=CCCC=C(/C)CCC=C(/C)CC=C(C)C)C)C)C TUHBEKDERLKLEC-UHFFFAOYSA-N 0.000 claims description 2
- 229920003048 styrene butadiene rubber Polymers 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 235000007586 terpenes Nutrition 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 229920005862 polyol Polymers 0.000 claims 2
- WORCCYVLMMTGFR-UHFFFAOYSA-M loxoprofen sodium Chemical group [Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 WORCCYVLMMTGFR-UHFFFAOYSA-M 0.000 claims 1
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical group [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims 1
- 125000002298 terpene group Chemical group 0.000 claims 1
- 230000001070 adhesive effect Effects 0.000 abstract description 11
- 239000000853 adhesive Substances 0.000 abstract description 8
- 238000013271 transdermal drug delivery Methods 0.000 abstract description 3
- 238000000034 method Methods 0.000 description 16
- 238000003756 stirring Methods 0.000 description 15
- 238000002474 experimental method Methods 0.000 description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 14
- 230000001186 cumulative effect Effects 0.000 description 10
- BAZQYVYVKYOAGO-UHFFFAOYSA-M loxoprofen sodium hydrate Chemical group O.O.[Na+].C1=CC(C(C([O-])=O)C)=CC=C1CC1C(=O)CCC1 BAZQYVYVKYOAGO-UHFFFAOYSA-M 0.000 description 10
- 238000009792 diffusion process Methods 0.000 description 8
- 238000000338 in vitro Methods 0.000 description 8
- 238000002360 preparation method Methods 0.000 description 8
- 238000010521 absorption reaction Methods 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- 238000002844 melting Methods 0.000 description 7
- 230000008018 melting Effects 0.000 description 7
- 229920006132 styrene block copolymer Polymers 0.000 description 7
- 238000012360 testing method Methods 0.000 description 6
- 229910019142 PO4 Inorganic materials 0.000 description 5
- 230000007423 decrease Effects 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 5
- 239000010452 phosphate Substances 0.000 description 5
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 238000004364 calculation method Methods 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 230000000875 corresponding effect Effects 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 238000005070 sampling Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 239000010410 layer Substances 0.000 description 3
- 230000035515 penetration Effects 0.000 description 3
- 229920002799 BoPET Polymers 0.000 description 2
- 241000699660 Mus musculus Species 0.000 description 2
- 239000004695 Polyether sulfone Substances 0.000 description 2
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 2
- 239000012790 adhesive layer Substances 0.000 description 2
- 238000003556 assay Methods 0.000 description 2
- 230000005540 biological transmission Effects 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000008367 deionised water Substances 0.000 description 2
- 229910021641 deionized water Inorganic materials 0.000 description 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000004907 flux Effects 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 238000011068 loading method Methods 0.000 description 2
- 238000003760 magnetic stirring Methods 0.000 description 2
- 239000012528 membrane Substances 0.000 description 2
- 230000000051 modifying effect Effects 0.000 description 2
- 239000004745 nonwoven fabric Substances 0.000 description 2
- 238000011580 nude mouse model Methods 0.000 description 2
- 230000010355 oscillation Effects 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920006393 polyether sulfone Polymers 0.000 description 2
- 159000000000 sodium salts Chemical class 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 238000002834 transmittance Methods 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 1
- GXFCDCCXXUOPDE-UHFFFAOYSA-N C(C=C)(=O)OCC.CN(C)C.C(C(=C)C)(=O)OC Chemical compound C(C=C)(=O)OCC.CN(C)C.C(C(=C)C)(=O)OC GXFCDCCXXUOPDE-UHFFFAOYSA-N 0.000 description 1
- MQIUGAXCHLFZKX-UHFFFAOYSA-N Di-n-octyl phthalate Natural products CCCCCCCCOC(=O)C1=CC=CC=C1C(=O)OCCCCCCCC MQIUGAXCHLFZKX-UHFFFAOYSA-N 0.000 description 1
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- ULFUTCYGWMQVIO-PCVRPHSVSA-N [(6s,8r,9s,10r,13s,14s,17r)-17-acetyl-6,10,13-trimethyl-3-oxo-2,6,7,8,9,11,12,14,15,16-decahydro-1h-cyclopenta[a]phenanthren-17-yl] acetate;[(8r,9s,13s,14s,17s)-3-hydroxy-13-methyl-6,7,8,9,11,12,14,15,16,17-decahydrocyclopenta[a]phenanthren-17-yl] pentano Chemical compound C1CC2=CC(O)=CC=C2[C@@H]2[C@@H]1[C@@H]1CC[C@H](OC(=O)CCCC)[C@@]1(C)CC2.C([C@@]12C)CC(=O)C=C1[C@@H](C)C[C@@H]1[C@@H]2CC[C@]2(C)[C@@](OC(C)=O)(C(C)=O)CC[C@H]21 ULFUTCYGWMQVIO-PCVRPHSVSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- 238000010539 anionic addition polymerization reaction Methods 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 1
- 238000006735 epoxidation reaction Methods 0.000 description 1
- 125000003700 epoxy group Chemical group 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229960004211 loxoprofen sodium dihydrate Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 238000002464 physical blending Methods 0.000 description 1
- 238000000053 physical method Methods 0.000 description 1
- 229920001195 polyisoprene Polymers 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 150000003505 terpenes Chemical group 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
- C09J11/02—Non-macromolecular additives
- C09J11/06—Non-macromolecular additives organic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
- A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
- A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
- A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
- A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
- A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
- C09J11/02—Non-macromolecular additives
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J11/00—Features of adhesives not provided for in group C09J9/00, e.g. additives
- C09J11/02—Non-macromolecular additives
- C09J11/04—Non-macromolecular additives inorganic
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J125/00—Adhesives based on homopolymers or copolymers of compounds having one or more unsaturated aliphatic radicals, each having only one carbon-to-carbon double bond, and at least one being terminated by an aromatic carbocyclic ring; Adhesives based on derivatives of such polymers
- C09J125/02—Homopolymers or copolymers of hydrocarbons
- C09J125/04—Homopolymers or copolymers of styrene
- C09J125/08—Copolymers of styrene
- C09J125/10—Copolymers of styrene with conjugated dienes
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09J—ADHESIVES; NON-MECHANICAL ASPECTS OF ADHESIVE PROCESSES IN GENERAL; ADHESIVE PROCESSES NOT PROVIDED FOR ELSEWHERE; USE OF MATERIALS AS ADHESIVES
- C09J7/00—Adhesives in the form of films or foils
- C09J7/30—Adhesives in the form of films or foils characterised by the adhesive composition
- C09J7/38—Pressure-sensitive adhesives [PSA]
- C09J7/381—Pressure-sensitive adhesives [PSA] based on macromolecular compounds obtained by reactions involving only carbon-to-carbon unsaturated bonds
- C09J7/387—Block-copolymers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
A hot-melt pressure-sensitive adhesive containing small molecular acid and salt thereof and application thereof belong to the technical field of hot-melt pressure-sensitive adhesives. The hydrophilicity of the matrix is improved by adding small molecular acid and salt thereof into a hot-melt pressure-sensitive adhesive system, so that the solubility and compatibility of hydrophilic drugs to the matrix are improved, and the modified HMPSA matrix is used as a pressure-sensitive adhesive of a transdermal drug delivery system, so that good release of the hydrophilic drugs can be realized, the adhesive performance of the hydrophilic drugs is ensured to be acceptable, and the modified HMPSA matrix can be used as a drug-carrying matrix of a transdermal patch.
Description
Technical Field
The invention belongs to the technical field of hot-melt pressure-sensitive adhesives, and mainly relates to a method for improving hydrophilic drug release by using a hot-melt pressure-sensitive adhesive containing small molecular acid and salt thereof.
Background
The Hot Melt Pressure Sensitive Adhesive (HMPSA) has wide application in various fields because it does not contain volatile organic substances, has lower cost and is environment-friendly. HMPSA is typically made from a combination of thermoplastic elastomer, tackifier, plastic modifier, antioxidant, etc., and is applied in the molten state (typically 120-150 ℃) and the hot melt remains thermoplastic throughout the process without chemical reaction. Most hot melt pressure sensitive adhesives are based on styrene block copolymers SBC, which have permanent surface tack at room temperature and provide good adhesion at light finger pressure.
Styrene-isoprene-styrene block copolymers (SIS) are the most commonly used styrene block copolymers. The polyisoprene block of SIS has a lateral methyl structure, and has the advantages of good cohesion and strength, lower modulus, smaller melt viscosity and easy production and processing. However, because of the small polarity of the SIS-based hot-melt pressure-sensitive adhesive molecules, polar drugs are difficult to release well, so that the SIS-based hot-melt pressure-sensitive adhesive has a great defect as a matrix of a transdermal patch.
Some research has been directed to improving the polarity of HMPSA, mainly by modifying SIS-HMPSA by physical and chemical methods. Physical methods are generally performed by changing the structure of the copolymer, blending the copolymer, and controlling the reaction conditions. For example, by adding ethyl acrylate-methyl methacrylate-trimethylamine (RLPO), the proportion of the hot-melt pressure-sensitive adhesive matrix is optimized, and the release rate of the hydrophilic medicament is improved. Adding acrylic resinEPO and SIS are blended to form a bicontinuous structure, and the amphiphilic pH-sensitive hot-melt pressure-sensitive adhesive is prepared. The physical blending process, while simple, requires clear knowledge of the compatibility between the blends. Chemical modification methods are generally carried out by increasing the polarityThe radical and the reduction of the number of unsaturated double bonds are achieved, for example, by preparing epoxidized SIS (ESIS). And synthesizing polyethylene glycol segments at one end of an SIS molecular chain by adopting an anionic polymerization method to prepare the amphiphilic hot-melt pressure-sensitive adhesive.
The above method improves the hydrophilicity of SIS-HMPSA to some extent, but the preparation operation is complex and has defects. For example, the effect of loading hydrophilic drugs is still not ideal when ESIS is prepared by epoxidation, and the adhesive properties of the corresponding patches are poor because of poor compatibility between the epoxy groups and the tackifying resin, which can affect the adhesive properties of HMPSA.
Therefore, there is a need for a hydrophilic drug loaded HMPSA that is simple to prepare and maintains adhesive properties for application in the field of transdermal drug delivery.
Disclosure of Invention
The present inventors have also tried to solve the above-mentioned problems, and as a result, have found that the addition of a small molecule acid during the preparation of HMPSA can improve the hydrophilicity and flowability of HMPSA, and the solubility and thermodynamic activity of the supported hydrophilic drug in the matrix can be improved, and the supported hydrophilic drug can move more easily in the matrix, thereby improving the release rate and permeability of the drug.
The technical scheme of the invention is as follows: a modified hot-melt pressure-sensitive adhesive, which is prepared by taking small molecular acid and corresponding medical acceptable salt thereof as a modifier, wherein the modifier is used for improving the hydrophilic performance of the hot-melt pressure-sensitive adhesive; and the hot-melt pressure-sensitive adhesive is used as a matrix to increase the release of the loaded hydrophilic drugs; the molecular weight of the small molecular acid is less than 1000Da.
The small molecule acid is selected from one or more of phosphoric acid, boric acid, citric acid, tartaric acid, acetic acid, fumaric acid and lactic acid. The hot-melt pressure-sensitive adhesive comprises thermoplastic elastomer, tackifier, plasticity regulator, mineral oil and modifier, and comprises the following components in percentage by mass:
the thermoplastic elastomer is selected from the group consisting of styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers including styrene-isoprene-styrene block copolymers and styrene-isoprene copolymers, and styrene-butadiene-styrene block copolymers including styrene-butadiene-styrene block copolymers and styrene-butadiene copolymers; the amount of the copolymer is not particularly limited, but is preferably 15 to 25% by weight, particularly preferably 18 to 23% by weight, based on the total amount of the compounds contained in the adhesive matrix.
The tackifier is selected from terpene resin, rosin, petroleum resin or rosin resin, wherein the rosin resin comprises rosin glyceride, hydrogenated rosin, polymerized rosin and hydrogenated rosin glyceride, and the petroleum resin comprises C5 resin, C9 resin, alicyclic resin or C5/C9 copolymer resin; the above tackifiers may be used singly or in combination. The amount of the compound to be formulated is not particularly limited, but is preferably 10 to 30% by weight, particularly preferably 15 to 20% by weight, based on the total amount of the compound contained in the adhesive matrix.
The mineral oil is selected from liquid paraffin, squalane, squalene, naphthenic oil, aromatic oil, polyethylene glycol, and liquid fatty acid ester. The amount of the compound to be formulated is not particularly limited, and is preferably 30 to 50% by weight, particularly preferably 40 to 50% by weight, based on the total amount of the compound contained in the adhesive matrix.
The plastic modifier is selected from polybutene oils, phthalic acid esters, phosphoric acid esters, aliphatic dibasic acid esters, polyhydric alcohol esters, wherein the polybutene oils comprise polybutene, polyisobutene, hydrogenated polyisobutene or polyisobutenyl glyceride, the phthalic acid esters comprise dibutyl phthalate, dioctyl phthalate or propylene phthalate, the phosphoric acid esters comprise phosphoric acid triesters or methyl phosphoric acid esters, the aliphatic dibasic acid esters comprise dioctyl adipate, dioctyl azelate, dihexyl sebacate or di (2-ethyl) hexyl sebacate, the polyhydric alcohol esters comprise pentanediol esters, trimethylolpropane esters or pentaerythritol esters; the above-mentioned plasticity-adjusting agents may be used alone or in combination. The amount of the compound to be formulated is not particularly limited, but is preferably 10 to 30% by weight, particularly preferably 15 to 20% by weight, based on the total amount of the compound contained in the adhesive matrix.
The modifier is phosphoric acid, citric acid, sodium phosphate or sodium citrate.
The mass percentage of the modifier is 0.5-2%
The hot-melt pressure-sensitive adhesive also comprises an antioxidant, a penetration enhancer and a filler.
A modified transdermal patch adopts the modified hot-melt pressure-sensitive adhesive as a matrix, and hydrophilic drugs are loaded on the matrix.
The modified transdermal patch comprises the following components in percentage by mass:
the hydrophilic medicine is loxoprofen sodium, diclofenac sodium or sodium salicylate.
The invention relates to a transdermal absorption preparation taking modified HMPSA as a matrix.
The modified HMPSA of the present invention may further contain an antioxidant, a permeation enhancer, and a filler.
As the matrix-supported drug, hydrophilic drugs commonly used in the field of transdermal administration are mentioned alkali metal salts (sodium salt, potassium salt and calcium salt), sulfate, hydrochloride and the like, such as loxoprofen sodium, diclofenac sodium, sodium salicylate and the like.
The hot-melt pressure-sensitive adhesive can be prepared by a solvent method or a melt blending method.
The hot-melt pressure-sensitive adhesive is applied to the transdermal patch, namely comprises a release layer, a back lining layer and the hot-melt pressure-sensitive adhesive coated on the back lining layer. An antioxidant, a penetration enhancer and a filler are also required to be added into the hot-melt pressure-sensitive adhesive for the transdermal patch.
Preparation of HMPSA: HMPSA is prepared by melt blending: adding the styrene segmented copolymer, tackifier, plasticity regulator and mineral oil into a stirring kettle according to the formula amount, melting and stirring the mixture to transparent liquid at the temperature of 120-160 ℃, and removing bubbles in a vacuum environment (-80 mPa).
Preparation of modified/drug-loaded HMPSA: the preparation method is the same as the HMPSA method, and the modifier and/or the drug are added before the bubble removing step.
Preparation of transdermal patch: after the modified HMPSA matrix was obtained, it was coated on a PET film by a coater at 130 ℃ to a coating thickness of 100 μm to obtain an adhesive layer. The nonwoven fabric was then laminated as a backing. A transdermal patch was obtained.
In the present invention, the acrylic non-steroidal anti-inflammatory drug loxoprofen sodium dihydrate (C 15 H 17 NaO 3 ·2H 2 O, MW=304.31, logP= -0.19, melting point 202 ℃ as hydrophilic model drug, phosphoric acid as modifier to prepare modified SIS-HMPSA drug-carrying matrix.
In vitro release rate assay: the effective diffusion area is 1.767cm by adopting a vertical Franz diffusion cell 2 A0.22 μm polyethersulfone filter was immobilized in the supply and receiving wells. The die-cut patch is torn off from the release film, the drug release surface is attached to the filter film, the receiving solution is 10mL of physiological saline, the magnetic stirring rotating speed is 600rpm, and the temperature is kept at 32+/-0.2 ℃. 0.2mL was sampled from the receiving tank at predetermined times (1, 2,4,6,8, 10, 12, 24 h) and an equal amount of receiving solution was added. The calculation formula of the accumulated drug release rate is as follows:
wherein R is t Is the cumulative transmittance; m is M 0 Is the initial drug content; v is the volume (mL) of the receiving liquid; c (C) n Concentration (μg/mL) for the nth sample; v (V) n Is the sampling volume (mL).
In vitro permeation experiments: the model skin is the skin of nude mice (200 mu m plus or minus 20 mu m) instead of the filter membrane, and the rest of the experimental process and the analysis conditions are the same as the in vitro release experimental method. The calculation formula of the accumulated permeation flux of the medicine is as follows:
in which Q t Cumulative transmission amount at time t (. Mu.g/cm) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the V is the volume (mL) of the receiving liquid; c (C) n Concentration (μg/mL) for the nth sample; v (V) n Is the sampling volume; a is the effective diffusion area (cm) of the diffusion cell 2 )。
Contact angle experiments: contact angle was used to test the surface polarity of SIS-HMPSA, the sample was peeled off the release film, placed on a tester, distilled water (about 5 μl) was dropped on the surface of the film, and the contact angle of the water drop on the surface of the sample was measured by the protractor method for not less than 1min.
Water absorption experiments: the sample was removed from the release film, weighed, placed in a test tube, and deionized water was added. After 24h, the surface of the patch was carefully dried with filter paper, each sample was again weighed and the water uptake was calculated over 24 h.
Rheological property test: SIS-HMPSA samples with a thickness of 1000 μm were prepared and placed on a parallel plate of a rotary rheometer, which was subjected to oscillation frequency sweep at a temperature of 32℃in a frequency sweep range of 0.1rad/s to 100rad/s.
Adhesion experiments: the adhesive holding force and the peel strength of the patch were tested, and experiments were carried out with reference to national standards GB/T4852-98 and GB 2792-81, respectively.
Differential calorimetric scanning (DSC) is used to analyze the compatibility of a drug with a matrix.
Fourier transform infrared (FT-IR) was used to analyze the groups and chemical reactions of the components.
By adding phosphoric acid to SIS-HMPSA, the hydrophilicity of the matrix is improved, as evidenced by an increase in water absorption and a decrease in contact angle values, and a positive correlation with the amount of phosphoric acid obtained. The addition of phosphoric acid also changes the rheological properties of the matrix, which is manifested by a decrease in the elastic modulus G', a steeper rise in SIS-HMPSA with phosphoric acid, and an increase in the flowability of the matrix as the frequency increases.
The beneficial effects of the invention are as follows:
the solubility and compatibility of hydrophilic drugs on the matrix are improved by adding small molecular acid and salt thereof into a hot-melt pressure-sensitive adhesive system to improve the hydrophilicity and fluidity, and the modified HMPSA matrix is used as a pressure-sensitive adhesive of a transdermal drug delivery system, so that good release of the hydrophilic drugs can be realized, the adhesive performance is ensured to be acceptable, and the modified HMPSA matrix can be used as a drug-carrying matrix of a transdermal patch
(1) The contact angle of the small molecular acid is continuously reduced and the water absorption is improved along with the continuous increase of the dosage of the small molecular acid, which proves that the hydrophilicity and the fluidity of the hot-melt pressure-sensitive adhesive system are increased.
(2) In the sample DSC graph of the drug-loaded matrix (phosphoric acid) sample, the endothermic peaks at 70℃and 200℃disappeared, indicating that the drug was changed from crystalline to amorphous and no significant endothermic peak was observed. It was demonstrated that the compatibility of the drug with the matrix was improved due to the presence of phosphoric acid.
(3) Fourier transform infrared analysis, loxoprofen sodium and SIS-HMPSA matrix produced a new peak signal (1250 cm -1 、1091cm -1 And 1016cm -1 ) There is some binding, presumably the LOX carboxyl group and the hydroxyl group in the hydrogenated rosin glycerol ester form an ester. In the spectrogram of the drug-loaded matrix (containing phosphoric acid), the C-H stretching vibration signal is obviously enhanced, the C=O stretching vibration is obviously weakened, and the length of 1547cm is obviously reduced -1 The COO-antisymmetric expansion of the carboxylate radical is obviously enhanced, and the addition of phosphoric acid is presumed to dissociate the ester radical and reform the free carboxylate radical.
Drawings
FIG. 1 is a graph showing the change in water absorption and contact angle values of SIS-HMPSA.
FIG. 2 is a frequency sweep plot of SIS-HMPSA.
Figure 3 is the cumulative release rate of loxoprofen sodium in SIS-HMPSA.
Figure 4 is the cumulative permeation of loxoprofen sodium in SIS-HMPSA.
Figure 5 is the change in tack time and peel strength of SIS-HMPSA.
Fig. 6 is a DSC thermogram of the patch.
Fig. 7 is a FTIR spectrum of the patch.
Detailed Description
The present invention will be described in further detail with reference to specific examples, but is not limited to these examples. Unless otherwise specified, "%" means "wt%".
Example 1: blank SIS-HMPSA patch
HMPSA is prepared by melt blending: adding styrene block copolymer, tackifier, plasticity regulator and mineral oil in the amount of formula into a stirring kettle, melting and stirring to transparent liquid at 130 ℃, adding phosphoric acid, stirring for 3min, and removing bubbles in vacuum environment (-80 mPa).
Wherein the tackifier is hydrogenated rosin glyceride, the plasticity regulator is polyisobutylene, the mineral oil is liquid paraffin, and the modifier is phosphoric acid.
TABLE 1 comparison of the Properties of different matrices
Contact angle experiments: contact angle was used to test the surface polarity of SIS-HMPSA, the sample was peeled off the release film, placed on a tester, distilled water (about 5 μl) was dropped on the surface of the film, and the contact angle of the water drop on the surface of the sample was measured by the protractor method for not less than 1min.
Water absorption experiments: the sample was removed from the release film, weighed, placed in a test tube, and deionized water was added. After 24h, the surface of the patch was carefully dried with filter paper, each sample was again weighed and the water uptake was calculated over 24 h.
Rheological property test: SIS-HMPSA samples with a thickness of 1000 μm were prepared and placed on a parallel plate of a rotary rheometer, which was subjected to oscillation frequency sweep at a temperature of 32℃in a frequency sweep range of 0.1rad/s to 100rad/s.
Adhesion experiments: the adhesive holding force and the peel strength of the patch were tested, and experiments were carried out with reference to national standards GB/T4852-98 and GB 2792-81, respectively.
As can be seen from Table 1, the increase in the phosphoric acid content resulted in a concomitant decrease in the antenna value and a concomitant increase in 24h water absorption (FIG. 1), indicating a gradual transition of the matrix from hydrophobic to hydrophilic, which favors the loading of hydrophilic drugs.
Frequency scanning (FIG. 2) was performed on the different formulations of example 1, and it can be seen that the elastic modulus G' was always kept at the highest value without adding phosphoric acid (NO. 1-1), indicating that the matrix was more rigid. And as the concentration of phosphoric acid increases, the G' curve gradually decreases, and the curve change amplitude is more obvious, which indicates that the fluidity of the matrix is enhanced and the rigidity is relatively reduced. The drug is more easily moved in the phosphate-containing matrix.
Fig. 5 shows the change in holding time and 180 ° peel strength of the substrate. The substrate holding time and peel strength of the phosphoric acid addition tended to decrease, but there was no significant difference, compared to No.1-1, and the mechanical properties of the patch were still acceptable.
Example 2: drug-containing SIS-HMPSA patch
Adding styrene block copolymer, tackifier, plasticity regulator and mineral oil into stirring kettle, melting and stirring at 130deg.C to obtain transparent liquid, adding phosphoric acid, stirring for 3min, adding LOX, stirring for 5min, and removing bubbles under vacuum (-80 mPa).
Preparation of transdermal patch: after the modified HMPSA matrix was obtained, it was coated on a PET film by a coater at 130 ℃ to a coating thickness of 100 μm to obtain an adhesive layer. The nonwoven fabric was then laminated as a backing. A transdermal patch was obtained.
Table 2 comparison of patch performance with different formulations
In example 2 above, the effect of the amounts of the components of SIS-HMPSA on the drug release rate was compared, and the results showed that the drug was released well over 24 hours within the preferred ranges given in the present invention. No.2-5 because the dosage of liquid paraffin is less, and SIS and hydrogenated rosin glyceride content is higher, the mobility of the matrix is poor, and the drug release is difficult.
Example 3: influence of different modifiers
Adding styrene block copolymer, tackifier, plasticity regulator and mineral oil into stirring kettle, melting and stirring at 130deg.C to obtain transparent liquid, adding phosphoric acid, citric acid, sodium phosphate and sodium citrate as modifier, stirring for 3min, adding medicine LOX, stirring for 5min, and removing air bubbles under vacuum (-80 mPa).
TABLE 3 influence of different modifiers on patch properties
In example 3 above, the effect of different modifiers on drug release was compared, and each modifier had a significant enhancement on drug release compared to control No.3-1, where the acid modification was better than the corresponding medically approved salts (phosphoric acid and citric acid were better than the corresponding sodium salts) and the enhancement of phosphoric acid was the best.
Example 4: comparison of different thermoplastic elastomers, tackifiers, plasticity regulators, mineral oils
Adding styrene block copolymer, tackifier, plasticity regulator and mineral oil into stirring kettle, melting and stirring at 130deg.C to obtain transparent liquid, adding phosphoric acid and LOX, and removing bubbles under vacuum (-80 mPa).
Table 4 comparison of patch performance with different formulations
In the above example 4, the effect of the commonly used thermoplastic elastomer, tackifier, plasticity modifier and mineral oil components on release of LOX (loxoprofen sodium) is compared, and the orthogonal experiment shows that phosphoric acid has good modifying effect on hot-melt pressure-sensitive adhesive composed of different components, and LOX has better release within 24 hours.
Example 5: in vitro Release and permeation experiments of patches
TABLE 5 permeation Properties of drug-containing patches with different content of modifier
In vitro release rate assay: the effective diffusion area is 1.767cm by adopting a vertical Franz diffusion cell 2 A0.22 μm polyethersulfone filter was immobilized in the supply and receiving wells. The die-cut patch is torn off from the release film, the drug release surface is attached to the filter film, the receiving solution is 10mL of physiological saline, the magnetic stirring rotating speed is 600rpm, and the temperature is kept at 32+/-0.2 ℃. 0.2mL was sampled from the receiving tank at predetermined times (1, 2,4,6,8, 10, 12, 24 h) and an equal amount of receiving solution was added. The calculation formula for calculating the cumulative drug release rate according to the formula 1.1 is:
wherein R is t Is the cumulative transmittance; m is M 0 Is the initial drug content; v is the volume (mL) of the receiving liquid; c (C) n Concentration (μg/mL) for the nth sample; v (V) n Is the sampling volume (mL).
In vitro permeation experiments: the model skin is the skin of nude mice (200 mu m plus or minus 20 mu m) instead of the filter membrane, and the rest of the experimental process and the analysis conditions are the same as the in vitro release experimental method. The calculation formula of the accumulated permeation flux of the medicine is as follows:
in which Q t Cumulative transmission amount at time t (. Mu.g/cm) 2 ) The method comprises the steps of carrying out a first treatment on the surface of the V is the volume (mL) of the receiving liquid; c (C) n Concentration (. Mu.g/m) for the nth sampleL)；V n Is the sampling volume; a is the effective diffusion area (cm) of the diffusion cell 2 )。
In example 5 above, the in vitro release and penetration of patches of different phosphate content were compared (fig. 3 and 4), and it can be seen that the cumulative release rate and cumulative penetration of the drug were positively correlated with the phosphate content. The 4% phosphate content had the greatest cumulative release rate, but did not further increase the penetration, probably because the drug released from the matrix was sufficient for skin transport.
FIG. 6 is a DSC chart of the drug-containing matrix (containing phosphoric acid) of No.1-3, the drug-containing matrix (containing no phosphoric acid) of No.1-1, the blank matrix and loxoprofen sodium, in which: it can be seen that the drug has two endothermic peaks, 70 ℃ (moisture in the drug) and 200 ℃ (melting endothermic peak). In the drug-loaded matrix (without phosphoric acid) samples, an endothermic peak at 70 ℃ from the drug was observed, and in the high temperature region, there was also a jagged weak endothermic peak, indicating poor compatibility of the drug with the matrix. In the drug-loaded matrix (phosphate-containing) samples, the endothermic peaks at 70 ℃ and 200 ℃ disappeared, indicating that the drug was changed from crystalline to amorphous and no significant endothermic peak was observed. It was demonstrated that the compatibility of the drug with the matrix was improved due to the presence of phosphoric acid.
FIG. 7 is a Fourier transform infrared ray ordinary plot of the drug-containing matrix (containing phosphoric acid) of No.1-3, the drug-containing matrix (not containing phosphoric acid) of No.1-1, blank matrix and loxoprofen sodium, showing that loxoprofen sodium and SIS-HMPSA matrix generate new peak signals (1250 cm -1 、1091cm -1 And 1016cm -1 ) There is some binding, presumably the LOX carboxyl group and the hydroxyl group in the hydrogenated rosin glycerol ester form an ester. In the spectrogram of the drug-loaded matrix (containing phosphoric acid), the C-H stretching vibration signal is obviously enhanced, the C=O stretching vibration is obviously weakened, the COO-antisymmetric stretching of the carboxylate radical at 1547cm < -1 > is obviously enhanced, and the addition of phosphoric acid is presumed to dissociate the ester radical and reform the free carboxylate radical.
Claims (10)
1. A modified hot-melt pressure-sensitive adhesive is characterized in that: preparing a hot-melt pressure-sensitive adhesive by using small molecular acid and salt thereof as a modifier, wherein the modifier is used for improving the hydrophilic performance of the hot-melt pressure-sensitive adhesive; and the hot-melt pressure-sensitive adhesive is used as a matrix to increase the release of the loaded hydrophilic drugs; the molecular weight of the small molecular acid is less than 1000Da.
2. The modified hot-melt pressure-sensitive adhesive according to claim 1, wherein: the small molecule acid is selected from one or more of phosphoric acid, boric acid, citric acid, tartaric acid, acetic acid, fumaric acid and lactic acid.
3. The modified hot-melt pressure-sensitive adhesive according to claim 2, wherein: the hot-melt pressure-sensitive adhesive comprises thermoplastic elastomer, tackifier, plasticity regulator, mineral oil and modifier, and comprises the following components in percentage by mass:
4. a modified hot melt pressure sensitive adhesive as claimed in claim 3, wherein:
the thermoplastic elastomer is selected from the group consisting of styrene-isoprene-styrene block copolymers, styrene-butadiene-styrene block copolymers, styrene-isoprene-styrene block copolymers including styrene-isoprene-styrene block copolymers and styrene-isoprene copolymers, and styrene-butadiene-styrene block copolymers including styrene-butadiene-styrene block copolymers and styrene-butadiene copolymers;
the tackifier is selected from terpene resin, rosin, petroleum resin or rosin resin, wherein the rosin resin comprises rosin glyceride, hydrogenated rosin, polymerized rosin and hydrogenated rosin glyceride, and the petroleum resin comprises C5 resin, C9 resin, alicyclic resin or C5/C9 copolymer resin;
the mineral oil is selected from liquid paraffin, squalane, squalene, naphthenic oil, aromatic oil, polyethylene glycol and liquid fatty acid ester;
the plastic modifier is selected from polybutene oils, phthalic acid esters, phosphoric acid esters, aliphatic dibasic acid esters, polyol esters, wherein the polybutene oils comprise polybutene, polyisobutene, hydrogenated polyisobutene or polyisobutenyl glycerides, the phthalic acid esters comprise dibutyl, dioctyl or propylene phthalate, the phosphoric acid esters comprise phosphoric acid triesters or methyl phosphoric acid esters, the aliphatic dibasic acid esters comprise dioctyl adipate, dioctyl azelate, dihexyl sebacate or di (2-ethyl) hexyl sebacate, the polyol esters comprise pentanediol esters, trimethylolpropane esters and pentaerythritol esters.
5. The modified hot-melt pressure-sensitive adhesive of claim 4, wherein: the modifier is one or more of phosphoric acid, sodium phosphate, citric acid and sodium citrate.
6. The modified hot-melt pressure-sensitive adhesive of claim 5, wherein: the mass percentage of the modifier is 0.5% -2%.
7. The modified hot-melt pressure-sensitive adhesive of claim 4, wherein: the hot-melt pressure-sensitive adhesive also comprises an antioxidant, a penetration enhancer and a filler.
8. A modified transdermal patch characterized by: the patch adopts the modified hot-melt pressure-sensitive adhesive as a matrix, and hydrophilic drugs are loaded in the matrix.
9. The modified transdermal patch of claim 8, wherein the components comprise the following components in mass percent:
10. a modified transdermal patch according to claim 9, wherein: the hydrophilic medicine is loxoprofen sodium, diclofenac sodium or sodium salicylate.
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| CN202311129750.4A CN117025127A (en) | 2023-09-04 | 2023-09-04 | Hot-melt pressure-sensitive adhesive containing small molecular acid and salt thereof and application thereof |
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| CN202311129750.4A CN117025127A (en) | 2023-09-04 | 2023-09-04 | Hot-melt pressure-sensitive adhesive containing small molecular acid and salt thereof and application thereof |
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