US20190351108A1 - Multi-layered polymer film for sustained release of agents - Google Patents
Multi-layered polymer film for sustained release of agents Download PDFInfo
- Publication number
- US20190351108A1 US20190351108A1 US16/366,323 US201916366323A US2019351108A1 US 20190351108 A1 US20190351108 A1 US 20190351108A1 US 201916366323 A US201916366323 A US 201916366323A US 2019351108 A1 US2019351108 A1 US 2019351108A1
- Authority
- US
- United States
- Prior art keywords
- film
- layer
- antibiotic
- agent
- layers
- 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.)
- Abandoned
Links
- 238000013268 sustained release Methods 0.000 title claims 4
- 239000012730 sustained-release form Substances 0.000 title claims 4
- 229920006254 polymer film Polymers 0.000 title description 17
- 229920000642 polymer Polymers 0.000 claims abstract description 255
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 103
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 92
- 239000003795 chemical substances by application Substances 0.000 claims description 122
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 119
- 229960001225 rifampicin Drugs 0.000 claims description 118
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims description 116
- 229960004023 minocycline Drugs 0.000 claims description 111
- -1 cecropin-mellitin Proteins 0.000 claims description 83
- 239000013543 active substance Substances 0.000 claims description 47
- 238000002513 implantation Methods 0.000 claims description 34
- 229920002988 biodegradable polymer Polymers 0.000 claims description 24
- 239000004621 biodegradable polymer Substances 0.000 claims description 24
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 claims description 9
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 claims description 9
- 229960003722 doxycycline Drugs 0.000 claims description 9
- 229960004089 tigecycline Drugs 0.000 claims description 9
- 229930186147 Cephalosporin Natural products 0.000 claims description 7
- 239000004098 Tetracycline Substances 0.000 claims description 7
- 229940124587 cephalosporin Drugs 0.000 claims description 7
- 150000001780 cephalosporins Chemical class 0.000 claims description 7
- 150000003384 small molecules Chemical class 0.000 claims description 7
- 229960002180 tetracycline Drugs 0.000 claims description 7
- 229930101283 tetracycline Natural products 0.000 claims description 7
- 235000019364 tetracycline Nutrition 0.000 claims description 7
- 150000003522 tetracyclines Chemical class 0.000 claims description 7
- 229920001213 Polysorbate 20 Polymers 0.000 claims description 6
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 6
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 claims description 6
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 claims description 6
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 6
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 6
- 239000001818 polyoxyethylene sorbitan monostearate Substances 0.000 claims description 6
- 235000010989 polyoxyethylene sorbitan monostearate Nutrition 0.000 claims description 6
- 229940068977 polysorbate 20 Drugs 0.000 claims description 6
- 229940113124 polysorbate 60 Drugs 0.000 claims description 6
- 229920000053 polysorbate 80 Polymers 0.000 claims description 6
- 229940068968 polysorbate 80 Drugs 0.000 claims description 6
- 108700042778 Antimicrobial Peptides Proteins 0.000 claims description 5
- 102000044503 Antimicrobial Peptides Human genes 0.000 claims description 5
- GHXZTYHSJHQHIJ-UHFFFAOYSA-N Chlorhexidine Chemical compound C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 GHXZTYHSJHQHIJ-UHFFFAOYSA-N 0.000 claims description 5
- JUZNIMUFDBIJCM-ANEDZVCMSA-N Invanz Chemical compound O=C([C@H]1NC[C@H](C1)SC=1[C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)NC1=CC=CC(C(O)=O)=C1 JUZNIMUFDBIJCM-ANEDZVCMSA-N 0.000 claims description 5
- 108060003100 Magainin Proteins 0.000 claims description 5
- 229930182555 Penicillin Natural products 0.000 claims description 5
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 5
- XEFQLINVKFYRCS-UHFFFAOYSA-N Triclosan Chemical compound OC1=CC(Cl)=CC=C1OC1=CC=C(Cl)C=C1Cl XEFQLINVKFYRCS-UHFFFAOYSA-N 0.000 claims description 5
- 108010059993 Vancomycin Proteins 0.000 claims description 5
- 108060001132 cathelicidin Proteins 0.000 claims description 5
- 102000014509 cathelicidin Human genes 0.000 claims description 5
- POIUWJQBRNEFGX-XAMSXPGMSA-N cathelicidin Chemical compound C([C@@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(O)=O)NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C1=CC=CC=C1 POIUWJQBRNEFGX-XAMSXPGMSA-N 0.000 claims description 5
- 229960003260 chlorhexidine Drugs 0.000 claims description 5
- 108090000454 dermaseptin Proteins 0.000 claims description 5
- 229940049701 dermaseptin Drugs 0.000 claims description 5
- YFHLIDBAPTWLGU-CTKMSOPVSA-N dermaseptin Chemical compound C([C@@H](C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCC(N)=O)C(O)=O)[C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCSC)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCSC)NC(=O)[C@@H](NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)N)[C@@H](C)O)[C@@H](C)O)C1=CN=CN1 YFHLIDBAPTWLGU-CTKMSOPVSA-N 0.000 claims description 5
- 229960002770 ertapenem Drugs 0.000 claims description 5
- 229960002182 imipenem Drugs 0.000 claims description 5
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims description 5
- 239000003910 polypeptide antibiotic agent Substances 0.000 claims description 5
- 229960003500 triclosan Drugs 0.000 claims description 5
- 229960003165 vancomycin Drugs 0.000 claims description 5
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 claims description 5
- 102000018568 alpha-Defensin Human genes 0.000 claims description 4
- 108050007802 alpha-defensin Proteins 0.000 claims description 4
- 230000004962 physiological condition Effects 0.000 claims description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 4
- 210000001124 body fluid Anatomy 0.000 claims description 3
- 230000003444 anaesthetic effect Effects 0.000 claims 5
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims 3
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 claims 3
- 229940049954 penicillin Drugs 0.000 claims 3
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims 3
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 claims 3
- 230000003115 biocidal effect Effects 0.000 abstract description 218
- 239000000463 material Substances 0.000 abstract description 70
- 238000013270 controlled release Methods 0.000 abstract description 17
- 239000010410 layer Substances 0.000 description 458
- 229920001306 poly(lactide-co-caprolactone) Polymers 0.000 description 54
- 239000000203 mixture Substances 0.000 description 51
- 239000003814 drug Substances 0.000 description 48
- 229940079593 drug Drugs 0.000 description 45
- 238000013461 design Methods 0.000 description 42
- 229920001610 polycaprolactone Polymers 0.000 description 40
- 239000004632 polycaprolactone Substances 0.000 description 40
- 229920001577 copolymer Polymers 0.000 description 34
- 229920006210 poly(glycolide-co-caprolactone) Polymers 0.000 description 26
- 229920001606 poly(lactic acid-co-glycolic acid) Polymers 0.000 description 19
- 239000004599 antimicrobial Substances 0.000 description 18
- 239000002202 Polyethylene glycol Substances 0.000 description 16
- 208000015181 infectious disease Diseases 0.000 description 16
- 229920001223 polyethylene glycol Polymers 0.000 description 16
- 239000002356 single layer Substances 0.000 description 15
- 239000000243 solution Substances 0.000 description 11
- 239000011521 glass Substances 0.000 description 10
- 229920000071 poly(4-hydroxybutyrate) Polymers 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000011347 resin Substances 0.000 description 9
- 229920005989 resin Polymers 0.000 description 9
- 229920000954 Polyglycolide Polymers 0.000 description 8
- 230000000845 anti-microbial effect Effects 0.000 description 8
- 238000005266 casting Methods 0.000 description 8
- 238000007906 compression Methods 0.000 description 8
- 239000003102 growth factor Substances 0.000 description 8
- 238000013508 migration Methods 0.000 description 8
- 230000005012 migration Effects 0.000 description 8
- 239000005014 poly(hydroxyalkanoate) Substances 0.000 description 8
- 229920002463 poly(p-dioxanone) polymer Polymers 0.000 description 8
- 239000000622 polydioxanone Substances 0.000 description 8
- 229920000903 polyhydroxyalkanoate Polymers 0.000 description 8
- 239000002904 solvent Substances 0.000 description 8
- 229940008309 acetone / ethanol Drugs 0.000 description 7
- 229920002643 polyglutamic acid Polymers 0.000 description 7
- 239000011877 solvent mixture Substances 0.000 description 7
- 229960004022 clotrimazole Drugs 0.000 description 6
- VNFPBHJOKIVQEB-UHFFFAOYSA-N clotrimazole Chemical compound ClC1=CC=CC=C1C(N1C=NC=C1)(C=1C=CC=CC=1)C1=CC=CC=C1 VNFPBHJOKIVQEB-UHFFFAOYSA-N 0.000 description 6
- 239000002131 composite material Substances 0.000 description 6
- 230000006835 compression Effects 0.000 description 6
- 208000037765 diseases and disorders Diseases 0.000 description 6
- 238000003780 insertion Methods 0.000 description 6
- 230000037431 insertion Effects 0.000 description 6
- 229920002627 poly(phosphazenes) Polymers 0.000 description 6
- 229920000166 polytrimethylene carbonate Polymers 0.000 description 6
- 239000007921 spray Substances 0.000 description 6
- 238000005507 spraying Methods 0.000 description 6
- 239000000758 substrate Substances 0.000 description 6
- PAPBSGBWRJIAAV-UHFFFAOYSA-N ε-Caprolactone Chemical compound O=C1CCCCCO1 PAPBSGBWRJIAAV-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 5
- 229940121375 antifungal agent Drugs 0.000 description 5
- 230000001186 cumulative effect Effects 0.000 description 5
- 238000001704 evaporation Methods 0.000 description 5
- 230000008020 evaporation Effects 0.000 description 5
- 239000011159 matrix material Substances 0.000 description 5
- 150000003839 salts Chemical class 0.000 description 5
- RKDVKSZUMVYZHH-UHFFFAOYSA-N 1,4-dioxane-2,5-dione Chemical compound O=C1COC(=O)CO1 RKDVKSZUMVYZHH-UHFFFAOYSA-N 0.000 description 4
- JJTUDXZGHPGLLC-IMJSIDKUSA-N 4511-42-6 Chemical compound C[C@@H]1OC(=O)[C@H](C)OC1=O JJTUDXZGHPGLLC-IMJSIDKUSA-N 0.000 description 4
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 239000003429 antifungal agent Substances 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 229920000136 polysorbate Polymers 0.000 description 4
- 229950008882 polysorbate Drugs 0.000 description 4
- 239000000600 sorbitol Substances 0.000 description 4
- 235000010356 sorbitol Nutrition 0.000 description 4
- DOMXUEMWDBAQBQ-WEVVVXLNSA-N terbinafine Chemical compound C1=CC=C2C(CN(C\C=C\C#CC(C)(C)C)C)=CC=CC2=C1 DOMXUEMWDBAQBQ-WEVVVXLNSA-N 0.000 description 4
- 229920001817 Agar Polymers 0.000 description 3
- 102000008186 Collagen Human genes 0.000 description 3
- 108010035532 Collagen Proteins 0.000 description 3
- 229920001244 Poly(D,L-lactide) Polymers 0.000 description 3
- 239000008272 agar Substances 0.000 description 3
- 229940124326 anaesthetic agent Drugs 0.000 description 3
- 229940121363 anti-inflammatory agent Drugs 0.000 description 3
- 239000002260 anti-inflammatory agent Substances 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 229920001436 collagen Polymers 0.000 description 3
- YPHMISFOHDHNIV-FSZOTQKASA-N cycloheximide Chemical compound C1[C@@H](C)C[C@H](C)C(=O)[C@@H]1[C@H](O)CC1CC(=O)NC(=O)C1 YPHMISFOHDHNIV-FSZOTQKASA-N 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 229920001971 elastomer Polymers 0.000 description 3
- 239000000806 elastomer Substances 0.000 description 3
- 238000010828 elution Methods 0.000 description 3
- 239000003193 general anesthetic agent Substances 0.000 description 3
- 229920001982 poly(ester urethane) Polymers 0.000 description 3
- 229920000747 poly(lactic acid) Polymers 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 238000007789 sealing Methods 0.000 description 3
- 239000002344 surface layer Substances 0.000 description 3
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 description 2
- BLSQLHNBWJLIBQ-OZXSUGGESA-N (2R,4S)-terconazole Chemical compound C1CN(C(C)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2N=CN=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 BLSQLHNBWJLIBQ-OZXSUGGESA-N 0.000 description 2
- MQHLMHIZUIDKOO-OKZBNKHCSA-N (2R,6S)-2,6-dimethyl-4-[(2S)-2-methyl-3-[4-(2-methylbutan-2-yl)phenyl]propyl]morpholine Chemical compound C1=CC(C(C)(C)CC)=CC=C1C[C@H](C)CN1C[C@@H](C)O[C@@H](C)C1 MQHLMHIZUIDKOO-OKZBNKHCSA-N 0.000 description 2
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 description 2
- AFNXATANNDIXLG-SFHVURJKSA-N 1-[(2r)-2-[(4-chlorophenyl)methylsulfanyl]-2-(2,4-dichlorophenyl)ethyl]imidazole Chemical compound C1=CC(Cl)=CC=C1CS[C@H](C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 AFNXATANNDIXLG-SFHVURJKSA-N 0.000 description 2
- LEZWWPYKPKIXLL-UHFFFAOYSA-N 1-{2-(4-chlorobenzyloxy)-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound C1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 LEZWWPYKPKIXLL-UHFFFAOYSA-N 0.000 description 2
- QXHHHPZILQDDPS-UHFFFAOYSA-N 1-{2-[(2-chloro-3-thienyl)methoxy]-2-(2,4-dichlorophenyl)ethyl}imidazole Chemical compound S1C=CC(COC(CN2C=NC=C2)C=2C(=CC(Cl)=CC=2)Cl)=C1Cl QXHHHPZILQDDPS-UHFFFAOYSA-N 0.000 description 2
- VHVPQPYKVGDNFY-DFMJLFEVSA-N 2-[(2r)-butan-2-yl]-4-[4-[4-[4-[[(2r,4s)-2-(2,4-dichlorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N([C@H](C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@@H]3O[C@](CN4N=CN=C4)(OC3)C=3C(=CC(Cl)=CC=3)Cl)=CC=2)C=C1 VHVPQPYKVGDNFY-DFMJLFEVSA-N 0.000 description 2
- HUADITLKOCMHSB-AVQIMAJZSA-N 2-butan-2-yl-4-[4-[4-[4-[[(2s,4r)-2-(2,4-difluorophenyl)-2-(1,2,4-triazol-1-ylmethyl)-1,3-dioxolan-4-yl]methoxy]phenyl]piperazin-1-yl]phenyl]-1,2,4-triazol-3-one Chemical compound O=C1N(C(C)CC)N=CN1C1=CC=C(N2CCN(CC2)C=2C=CC(OC[C@H]3O[C@@](CN4N=CN=C4)(OC3)C=3C(=CC(F)=CC=3)F)=CC=2)C=C1 HUADITLKOCMHSB-AVQIMAJZSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- APKFDSVGJQXUKY-KKGHZKTASA-N Amphotericin-B Natural products O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1C=CC=CC=CC=CC=CC=CC=C[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-KKGHZKTASA-N 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 2
- 229920001661 Chitosan Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 208000036829 Device dislocation Diseases 0.000 description 2
- IIUZTXTZRGLYTI-UHFFFAOYSA-N Dihydrogriseofulvin Natural products COC1CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 IIUZTXTZRGLYTI-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- UXWOXTQWVMFRSE-UHFFFAOYSA-N Griseoviridin Natural products O=C1OC(C)CC=C(C(NCC=CC=CC(O)CC(O)C2)=O)SCC1NC(=O)C1=COC2=N1 UXWOXTQWVMFRSE-UHFFFAOYSA-N 0.000 description 2
- CTETYYAZBPJBHE-UHFFFAOYSA-N Haloprogin Chemical compound ClC1=CC(Cl)=C(OCC#CI)C=C1Cl CTETYYAZBPJBHE-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- BYBLEWFAAKGYCD-UHFFFAOYSA-N Miconazole Chemical compound ClC1=CC(Cl)=CC=C1COC(C=1C(=CC(Cl)=CC=1)Cl)CN1C=NC=C1 BYBLEWFAAKGYCD-UHFFFAOYSA-N 0.000 description 2
- DDUHZTYCFQRHIY-UHFFFAOYSA-N Negwer: 6874 Natural products COC1=CC(=O)CC(C)C11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-UHFFFAOYSA-N 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920000331 Polyhydroxybutyrate Polymers 0.000 description 2
- 229920001219 Polysorbate 40 Polymers 0.000 description 2
- 241000191963 Staphylococcus epidermidis Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 229960003204 amorolfine Drugs 0.000 description 2
- APKFDSVGJQXUKY-INPOYWNPSA-N amphotericin B Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/C=C/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 APKFDSVGJQXUKY-INPOYWNPSA-N 0.000 description 2
- 229960003942 amphotericin b Drugs 0.000 description 2
- 230000000844 anti-bacterial effect Effects 0.000 description 2
- 230000002421 anti-septic effect Effects 0.000 description 2
- 150000003851 azoles Chemical class 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 229960002962 butenafine Drugs 0.000 description 2
- ABJKWBDEJIDSJZ-UHFFFAOYSA-N butenafine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)CC1=CC=C(C(C)(C)C)C=C1 ABJKWBDEJIDSJZ-UHFFFAOYSA-N 0.000 description 2
- 229960005074 butoconazole Drugs 0.000 description 2
- SWLMUYACZKCSHZ-UHFFFAOYSA-N butoconazole Chemical compound C1=CC(Cl)=CC=C1CCC(SC=1C(=CC=CC=1Cl)Cl)CN1C=NC=C1 SWLMUYACZKCSHZ-UHFFFAOYSA-N 0.000 description 2
- 239000004202 carbamide Substances 0.000 description 2
- 229940041011 carbapenems Drugs 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 238000010382 chemical cross-linking Methods 0.000 description 2
- 229960003749 ciclopirox Drugs 0.000 description 2
- SCKYRAXSEDYPSA-UHFFFAOYSA-N ciclopirox Chemical compound ON1C(=O)C=C(C)C=C1C1CCCCC1 SCKYRAXSEDYPSA-UHFFFAOYSA-N 0.000 description 2
- 238000010276 construction Methods 0.000 description 2
- 238000006073 displacement reaction Methods 0.000 description 2
- 229960003913 econazole Drugs 0.000 description 2
- 239000013013 elastic material Substances 0.000 description 2
- 230000003628 erosive effect Effects 0.000 description 2
- NTNZTEQNFHNYBC-UHFFFAOYSA-N ethyl 2-aminoacetate Chemical compound CCOC(=O)CN NTNZTEQNFHNYBC-UHFFFAOYSA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 229960004884 fluconazole Drugs 0.000 description 2
- RFHAOTPXVQNOHP-UHFFFAOYSA-N fluconazole Chemical compound C1=NC=NN1CC(C=1C(=CC(F)=CC=1)F)(O)CN1C=NC=N1 RFHAOTPXVQNOHP-UHFFFAOYSA-N 0.000 description 2
- 229960004413 flucytosine Drugs 0.000 description 2
- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 239000004220 glutamic acid Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- DDUHZTYCFQRHIY-RBHXEPJQSA-N griseofulvin Chemical compound COC1=CC(=O)C[C@@H](C)[C@@]11C(=O)C(C(OC)=CC(OC)=C2Cl)=C2O1 DDUHZTYCFQRHIY-RBHXEPJQSA-N 0.000 description 2
- 229960002867 griseofulvin Drugs 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 229960001906 haloprogin Drugs 0.000 description 2
- 229920002674 hyaluronan Polymers 0.000 description 2
- 229960003160 hyaluronic acid Drugs 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 2
- 239000007943 implant Substances 0.000 description 2
- 229960004130 itraconazole Drugs 0.000 description 2
- 229960004125 ketoconazole Drugs 0.000 description 2
- JJTUDXZGHPGLLC-UHFFFAOYSA-N lactide Chemical compound CC1OC(=O)C(C)OC1=O JJTUDXZGHPGLLC-UHFFFAOYSA-N 0.000 description 2
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 229960002509 miconazole Drugs 0.000 description 2
- 150000002780 morpholines Chemical class 0.000 description 2
- 229960004313 naftifine Drugs 0.000 description 2
- OZGNYLLQHRPOBR-DHZHZOJOSA-N naftifine Chemical compound C=1C=CC2=CC=CC=C2C=1CN(C)C\C=C\C1=CC=CC=C1 OZGNYLLQHRPOBR-DHZHZOJOSA-N 0.000 description 2
- 229960000988 nystatin Drugs 0.000 description 2
- VQOXZBDYSJBXMA-NQTDYLQESA-N nystatin A1 Chemical compound O[C@H]1[C@@H](N)[C@H](O)[C@@H](C)O[C@H]1O[C@H]1/C=C/C=C/C=C/C=C/CC/C=C/C=C/[C@H](C)[C@@H](O)[C@@H](C)[C@H](C)OC(=O)C[C@H](O)C[C@H](O)C[C@H](O)CC[C@@H](O)[C@H](O)C[C@](O)(C[C@H](O)[C@H]2C(O)=O)O[C@H]2C1 VQOXZBDYSJBXMA-NQTDYLQESA-N 0.000 description 2
- 229960003483 oxiconazole Drugs 0.000 description 2
- QRJJEGAJXVEBNE-MOHJPFBDSA-N oxiconazole Chemical compound ClC1=CC(Cl)=CC=C1CO\N=C(C=1C(=CC(Cl)=CC=1)Cl)\CN1C=NC=C1 QRJJEGAJXVEBNE-MOHJPFBDSA-N 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 229920006209 poly(L-lactide-co-D,L-lactide) Polymers 0.000 description 2
- 229920001308 poly(aminoacid) Polymers 0.000 description 2
- 239000005015 poly(hydroxybutyrate) Substances 0.000 description 2
- 229920000515 polycarbonate Polymers 0.000 description 2
- 239000004417 polycarbonate Substances 0.000 description 2
- 239000004633 polyglycolic acid Substances 0.000 description 2
- 229920002959 polymer blend Polymers 0.000 description 2
- 239000000249 polyoxyethylene sorbitan monopalmitate Substances 0.000 description 2
- 235000010483 polyoxyethylene sorbitan monopalmitate Nutrition 0.000 description 2
- 229920001299 polypropylene fumarate Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229940101027 polysorbate 40 Drugs 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 108090000623 proteins and genes Proteins 0.000 description 2
- 102000004169 proteins and genes Human genes 0.000 description 2
- 150000007660 quinolones Chemical class 0.000 description 2
- 238000011084 recovery Methods 0.000 description 2
- 229950005137 saperconazole Drugs 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001179 sorption measurement Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960002607 sulconazole Drugs 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 229960002722 terbinafine Drugs 0.000 description 2
- 229960000580 terconazole Drugs 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 229920001169 thermoplastic Polymers 0.000 description 2
- 229920001187 thermosetting polymer Polymers 0.000 description 2
- 239000004416 thermosoftening plastic Substances 0.000 description 2
- 229960004214 tioconazole Drugs 0.000 description 2
- 229960004880 tolnaftate Drugs 0.000 description 2
- FUSNMLFNXJSCDI-UHFFFAOYSA-N tolnaftate Chemical compound C=1C=C2C=CC=CC2=CC=1OC(=S)N(C)C1=CC=CC(C)=C1 FUSNMLFNXJSCDI-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C([O-])=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 description 2
- 229960004740 voriconazole Drugs 0.000 description 2
- BCEHBSKCWLPMDN-MGPLVRAMSA-N voriconazole Chemical compound C1([C@H](C)[C@](O)(CN2N=CN=C2)C=2C(=CC(F)=CC=2)F)=NC=NC=C1F BCEHBSKCWLPMDN-MGPLVRAMSA-N 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- 238000002768 Kirby-Bauer method Methods 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- 206010041925 Staphylococcal infections Diseases 0.000 description 1
- 241001147736 Staphylococcus capitis Species 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000001195 anabolic effect Effects 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 230000000249 desinfective effect Effects 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 239000013536 elastomeric material Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 210000000416 exudates and transudate Anatomy 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 230000028744 lysogeny Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920001230 polyarylate Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000013047 polymeric layer Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000036515 potency Effects 0.000 description 1
- 238000004007 reversed phase HPLC Methods 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000008467 tissue growth Effects 0.000 description 1
- YFHICDDUDORKJB-UHFFFAOYSA-N trimethylene carbonate Chemical compound O=C1OCCCO1 YFHICDDUDORKJB-UHFFFAOYSA-N 0.000 description 1
- 210000001186 vagus nerve Anatomy 0.000 description 1
- 230000002861 ventricular Effects 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/65—Tetracyclines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/54—Biologically active materials, e.g. therapeutic substances
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
- A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L27/58—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/041—Mixtures of macromolecular compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/04—Macromolecular materials
- A61L31/06—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/148—Materials at least partially resorbable by the body
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
- A61N1/00—Electrotherapy; Circuits therefor
- A61N1/18—Applying electric currents by contact electrodes
- A61N1/32—Applying electric currents by contact electrodes alternating or intermittent currents
- A61N1/36—Applying electric currents by contact electrodes alternating or intermittent currents for stimulation
- A61N1/372—Arrangements in connection with the implantation of stimulators
- A61N1/375—Constructional arrangements, e.g. casings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/402—Anaestetics, analgesics, e.g. lidocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/602—Type of release, e.g. controlled, sustained, slow
- A61L2300/604—Biodegradation
Definitions
- the present invention relates to an antibiotic article that prevents infection associated with the implantation of medical devices.
- CIEDs cardiovascular implantable electronic devices
- a pouch to contain the CIED has been developed with the aim to create a stable environment when implanted in the body.
- a typical pouch used for this role is sealed at three sides and has a single opening for placing the device into said pouch.
- CMS Centers for Medicare & Medicaid Services
- An antimicrobial article that can be attached to, or wraps around the surface of, an implantable medical device may help to reduce, prevent, or mitigate infection by eluting antimicrobial agents over time into the surrounding environment of the medical device.
- the TYRX Absorbable Antibacterial Envelope is a mesh with large pores that is knitted from absorbable filaments (a polymer made of glycolide, caprolactone, and trimethylene carbonate) and is coated with an absorbable polyarylate polymer.
- absorbable filaments a polymer made of glycolide, caprolactone, and trimethylene carbonate
- the absorbable polymer coating contains two antimicrobial agents: minocycline and rifampicin.
- the envelope/pouch used in said devices has an opening that is usually bigger than the CIED to be inserted, which results in the potential risk of the CIED falling out.
- these devices are designed to cater to numerous sizes of CIED, which increases the risk of smaller CIEDs falling out due to the relative rigidity and inelasticity of the material. Hence, there is a need for a new and improved design and structure that can securely hold CIEDs of various sizes.
- the articles described above go some way to dealing with infections, there are issues with the use of these antimicrobial articles.
- the articles described above often coat both agents together on the surface, or impregnate both agents within a material, and cannot control the release of both agents together, especially when both agents have differing hydrophilicity values, as is the case with Rifampin and Minocycline.
- it is important to control the release of both agents so that they provide the required concentration of active agent over the required period of time.
- antimicrobial agents coated on the surface tend to be released easily, and thus there is minimal control on the rate of release of the antimicrobial agent over an extended period of time. Therefore, there is a need for an improved antibiotic article.
- a soft and elastic biodegradable controlled-release antibiotic socket e.g. a sleeve or band
- a socket i.e. a sleeve, band or pocket
- the socket and its openings can be stretched to a size larger than the object to be inserted to enable ease of insertion of said device.
- the elastic biodegradable controlled-release antibiotic socket is intended to hold a cardiac implantable electronic device (CIED) securely in order to provide a stable environment when implanted in the body; and reduce, prevent, or mitigate infection by releasing at least one antimicrobial agent during and/or after implantation in a controlled manner.
- the drug release is controlled by the choice of polymer, the addition of layers, tuning of the thickness of various layers, and the use of releasing agents.
- controlled-release antibiotic socket for securely holding an implantable medical device, comprising:
- At least one film made from at least one polymer layer, where the at least one film is formed into the socket;
- the at least one polymer layer comprises a biodegradable elastomeric polymeric material
- the at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- the socket may be in the form of a pocket with at least one opening or a sleeve/band with at least two openings. It will be further appreciated that for the socket to securely hold an implantable medical device, the socket made from the elastomeric material is smaller than the medical device to be inserted into it. This may result in the socket securely holding the medical device (e.g. a CIED device) by a resilient holding force generated from the elastomeric polymeric material that makes up the film.
- the medical device e.g. a CIED device
- a controlled-release antibiotic film made from at least one polymer layer for securely holding an implantable medical device, the film comprising at least one polymer layer that is made from a biodegradable elastomeric polymeric material; and at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- the socket (and hence the openings) are stretchable to at least 1.1 times (e.g. from 1.2 times to 10 times) to allow for insertion of the CIED into the socket, and can recover to more than 80% to securely hold the CIED within the socket and prevent fall off.
- a construction of the article that may be mentioned herein comprises at least one film, which itself comprises at least one polymer layer and at least one antimicrobial agent; and at least one opening and numerous holes on the surface.
- the term “at least one antibiotic” in relation to a film or socket made therefrom having more than one layer, it may refer to the use of the same (or same mixture of) antibiotic in all layers that contain an antibiotic, and/or to different antibiotics (and/or to different mixtures of antibiotics) in layers of the film or socket made therefrom.
- the implantable medical device may be a cardiovascular implantable electronic device (CIED).
- CIED cardiovascular implantable electronic device
- the film may be used to cover at least part of the surface of a medical device that is then implanted into a subject.
- an implantable medical device comprising a medical device and socket as set out in the first aspect of the invention (and its various embodiments, whether alone or in any suitable combination), wherein the film covers a part or the whole of the medical device and is suitable for reducing or preventing migration of the medical device within the body following implantation.
- the film may be provided in the shape of an envelope or pouch to surround part or whole of the medical device.
- the device may further comprise an additional active agent (e.g. a growth factor, an anti-inflammatory, or anaesthetic agent) coated onto whole or part of an exposed surface of the film.
- a process for making a socket or film as set out in the first and second aspects of the invention wherein when the socket is made from a film having two or more polymer layers or the film has two or more polymer layers, the film is prepared by the use of one or more of heat-melting, heat-compression, spray coating, dip coating, chemical grafting, electrostatic adsorption, chemical crosslinking to join the polymer layers together.
- FIGS. 1 to 3 depict schematic illustrations of an article designed according to an embodiment of the invention (a socket to surround a medical device) with holes.
- FIGS. 4A-4G depict examples of layered designs according to embodiments of the current invention.
- FIGS. 5A and 5B depict the cumulative release profile of minocycline ( 5 A) and rifampin ( 5 B) in the exemplified embodiments of the invention.
- FIG. 6 depicts the cumulative release profile of minocycline and rifampin in a single film according to an embodiment of the current invention.
- FIG. 7 depicts a tensile curve of an article.
- the antibiotic socket of the current invention relates to a socket made from an elastic film material (comprising one or more elastomeric polymer layers), with at least one opening in the socket.
- the socket is smaller than the objects it is intended to hold and so it is stretched to a size to permit the object to be inserted and then recovers towards its original size (due to the elastic material that is made from), such that it securely holds the object inserted thereto (e.g. resiliently engages, holds or secures the object).
- the secure/resilient securing of the object inserted significantly reduces the possibility of the CIED falling out.
- the socket (or the film the socket is made from) may also have a rough surface, which aids in securing the object to the socket and may also help the socket secure the object following implantation into the body.
- the rough surface may also prevent the film/socket made therefrom from becoming adhered to a surface (i.e. sticking to a surface), for example the roughness may ensure that the inner surfaces of the socket do not stick to each other and thereby enables easy opening of the socket to insert a device.
- the socket (or the film the socket is made from) may also contain numerous holes that may help to increase friction and reduce migration of the implant as well as allow outflow of exudates. The design of the socket is thus able to securely hold various sizes of medical devices (e.g. CIEDs) and prevent or reduce migration of the device during implantation, without risk of the device falling out of the socket.
- medical devices e.g. CIEDs
- the antibiotic socket of the current invention may comprise a single layer or multiple layers of a biodegradable/bioresorbable polymer film with at least one antibiotic agent contained within at least one of the polymer layers, or the antibiotic may be disposed as a separate layer encapsulated by at least two polymer layers to form a control-release matrix to provide a required eluting profile for the at least one antibiotic agent for a desired time period.
- the single layer or multilayer structure also can be incorporated with other functional agents, such as anti-inflammatory, or anaesthetic agents or a growth factor agent.
- a controlled-release antibiotic socket for securely holding an implantable medical device, comprising:
- At least one film made from at least one polymer layer, where the at least one film is formed into the socket;
- the at least one polymer layer comprises a biodegradable elastomeric polymeric material
- the at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- the term “socket” is intended to mean a device that is intended to securely hold a separate object by surrounding the whole or part of said separate object (e.g. the socket may leave parts of the object uncovered to enable further connectivity of the object).
- the socket is intended to be smaller than the object it is intended to hold and accomplishes the secure holding by its elastic nature, such that it may be stretched to a size larger than the object to be held and then recovers towards its original size once the object to be held has been placed within the socket.
- the socket requires at least one opening to permit an object to be inserted within it and so the socket may also be described as a pocket when it has a single opening.
- the socket may have two openings and so may also be called a sleeve or band. It will be appreciated that the socket may contain more than two openings too.
- the socket is made from at least one film.
- a film made from at least one polymer layer for securely holding an implantable medical device comprising:
- At least one polymer layer that is made from a biodegradable elastomeric polymeric material
- At least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- both the socket and film are elastic, in that they can be stretched/deformed in any direction and recover towards their original size and shape. This property enables the socket to securely hold an object placed therein. This may be accomplished by the resilient force applied to the object inserted into the socket by the elastomeric polymeric material that comprises the film.
- the socket or film can resiliently engage or resiliently hold a device inserted into a socket formed from the film after stretching.
- the socket or film can stretch from its original size to an expanded size and return to its original size or to a size no greater than the expanded size minus (80% of the difference between expanded size and original size), optionally wherein the socket or film can stretch from its original size to an expanded size and return to its original size or to a size no greater than the expanded size minus (90% of the difference between expanded size and original size).
- the controlled release antibiotic socket of the current invention provides enhanced stability of the object (i.e. the CIED) within the socket, reducing the possibility of the object falling out of the socket, and is able to effectively achieve that for a wide range of objects (i.e. CIEDs of different sizes) with one size of socket.
- the selection of an elastic polymeric material is an intricate balance of elastic modulus and strain recovery. Certain polymers with high elasticity (low elastic modulus) have poor strain recovery, and would not be able to hold an object well. Other polymers that have relatively low elasticity (high elastic modulus) are not suitable for the construction of a sleeve that can securely hold different sizes of object.
- the design of the sleeve aids in enhancing the stability of the object (i.e. CIED) within. Thus care need to be exercised in selecting the materials used to form the polymer film.
- the controlled-release elastic biodegradable antibiotic film that makes up the socket in the first embodiment of the invention may comprise a single layer or multiple layers with at least one antibiotic agent contained within at least one of the layers to form a controlled-release matrix to provide a required eluting profile for the at least one antibiotic agent for a desired time period.
- One or more of the layers may contain a releasing agent to enhance control of release of at least one antibiotic agent within the same layer or at other layers of the film.
- the single layer or multilayer structure also can be incorporated with other functional agents, such as anti-inflammatory, or anaesthetic agents or a growth factor agent.
- a controlled-release antibiotic film made from at least one polymer layer for securely holding an implantable medical device, the film comprising at least one polymer layer that is made from a biodegradable elastomeric polymeric material; and at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- the controlled release antibiotic socket and films of the current invention provide enhanced control of drug eluting characteristics compared with previous drug eluting articles. This is achieved tuning of various factors, for example using additional layers (polymer layers or a layer of drug), where the active agent(s) are incorporated into different layer(s) (whether dispersed within a polymer layer, or forming a separate layer sandwiched between polymer layers), controlling the polymers used, controlling the thickness of the layers, the drug-polymer composite ratio, addition of releasing agent(s), and a layered structure designed to control the release rate of the active agent(s).
- antibiotic film and “antibiotic agent” may refer to an antimicrobial, an antifungal, an antiseptic or a disinfecting film and/or agent.
- antibiotic film and “antibiotic agent” may refer to an antimicrobial or antifungal agent.
- antimicrobial agents examples include tetracycline and its derivatives (such as minocycline, tigecycline and doxycycline), rifam pin, triclosan, chlorhexidine, penicillins, aminoglycides, quinolones, vancomycin, gentamycine, a cephalosporins (e.g. cephalosporin), carbapenems, imipenem, ertapenem, an antimicrobial peptide, cecropin-mellitin, magainin, dermaseptin, cathelicidin, ⁇ -defensins, ⁇ -protegrins, pharmaceutically acceptable salts thereof and combinations thereof.
- tetracycline and its derivatives such as minocycline, tigecycline and doxycycline
- rifam pin such as minocycline, tigecycline and doxycycline
- triclosan such as minocycline, tigecycline and doxycycline
- chlorhexidine penicillin
- antimicrobial agents include a combination of rifampin and another antimicrobial agent, such as a combination of rifampin and a tetracycline derivative (e.g. minocycline, doxycycline, and tigecycline, such combinations including rifampin and doxycycline, rifampin and tigecycline or, more particularly, rifampin and minocycline).
- a combination of rifampin and another antimicrobial agent such as a combination of rifampin and a tetracycline derivative (e.g. minocycline, doxycycline, and tigecycline, such combinations including rifampin and doxycycline, rifampin and tigecycline or, more particularly, rifampin and minocycline).
- the antimicrobial agent is a combination of rifampin and minocycline
- the ratio of rifampin to minocycline is from 1:10 to 10:1 (wt/wt) (e.g. from 2:5 to 5:2(wt/wt)).
- rifampicin and “rifampin” are used interchangeably herein to refer to the active agent having CAS number 13292-46-1, or salts and/or solvates thereof.
- antifungal agents examples include azoles (such as ketoconazole,clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, voriconazole, clotrimazole), allylamines(such as terbinafine), morpholines(such as amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafin, amphotericin B and pharmaceutically acceptable salts thereof.
- azoles such as ketoconazole,clotrimazole, miconazole, econazole, itraconazole, fluconazole, b
- releasing agent or “hydrophilic small molecules” may refer to natural or synthetic chemical compounds with a molecular weight of less than 2000 Daltons, which are able to dissolve or dislodge from a matrix when in contact with water or in physiological conditions.
- releasing agents include sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number average molecular weight of from 200 to 2000 Daltons, polysorbate and urea or any molecule (e.g. one that has a molecular weight of less than 2000 Daltons) with a hydrophobic-lipophilic balance of greater than 6.
- the term “polymer layer” may refer to a formulated composition which forms a solid or semi-solid film, with/without an antibiotic agent (as defined herein), with a controlled thickness.
- the combination of polymer layers may serve as a drug reservoir exhibiting drug control-release behaviour.
- the polymeric material when an antibiotic agent is present in the polymeric layer, may comprise at least 1 wt % (e.g. at least 2 wt %, such as at least 5 wt %) of the polymer layer.
- antibiotic layer may refer to a defined layer of an antibiotic layer laid on the surface of a polymer layer and comprising at least one or more antibiotic materials, but which is substantially free of a polymeric material (i.e. there may be less than 0.5 wt % of a polymeric material as a minor impurity in said layer), or more particularly, there is an absence of polymeric material in the antibiotic layer.
- the antibiotic layer cannot be on a surface of a polymer layer that is directly in contact with the environment in a completed film, that is, each antibiotic layer is ultimately encapsulated between two polymer layers. This encapsulation may be direct (e.g. an antibiotic layer is sandwiched between two polymer layers) or indirect (e.g.
- the antibiotic layers may be continuous or discontinuous, such that the antibiotic layer can be encapsulated within the polymer layers (e.g. the footprint of the antibiotic layer is adjusted so that it is smaller than the footprint of the polymer layers that encapsulate it).
- the antibiotic layer may take the form of a particulate layer on the surface of a polymeric substrate layer.
- the film of the current invention may provide beneficial effects as a single layer of film
- particular embodiments of the invention relate to a film has at least two polymer layers.
- the film may have from two to nine layers, such as from three to seven layers (e.g. from three to five layers), whether polymer layers only or a combination of polymer layers and antibiotic layers, provided that the antibiotic layers are not the outer layers of the film.
- the film may have from two to nine polymer layers, such as from three to seven polymer layers (e.g. from three to five polymer layers).
- bioresorbable polymer and “biodegradable polymer” refers to a material that can be at least partially broken down or, more particularly, fully degraded by contact with a bodily fluid, with the breakdown products being either eliminated from the body as waste or used by the body in further metabolic processes (e.g. anabolic processes).
- bioresorbable polymers include poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, poly(lactide-co-caprolactone) (PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), poly(phosphate ester), poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide) (PLG L), poly(D,L-lactide-co-glycoli
- Particular bioresorbable polymers include poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), PEG and its derivatives, and their copolymers (e.g. selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and their copolymers) .
- PCL poly(DL-lactide-co-caprolactone)
- PGA polyglycolide
- PLA poly(L-lactic acid)
- PEG and its derivatives and their copolymers e.g. selected from one or more of the group consist
- poly(ester-urethane)s include, poly(diol citrates), poly(4-hydroxybutyrate)s, poly(glycerol sebacate), and star-poly(c-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) and other biodegradable elastomer prepared through synthesis of di-, tri-, or multi-polymers, architecturally arranged in block, star, or linear structures, and prepared as thermoplastics or thermosets, their co-polymers, and mixtures or blends.
- Particular polymers that may be mentioned herein include DL-PLCL, PGCL and PLCL, their copolymers, and mixtures or blends thereof.
- the term “elastic polymer” refers to a material that can resist a distorting influence or stress and can return to towards its original size and shape when the stress is removed.
- the elastic polymer may be stretched up to 10 times its original size in any direction (e.g. from 1.1 times to 4 times its original size) and may then recover at least to 80%, such as at least 90% of its original size following release of the stretch.
- a film to size B a difference of size C
- C is B ⁇ A, such as a maximum size of B ⁇ (0.9 ⁇ C).
- the antibiotic film can be prepared as a single polymer, a polymer blend or copolymer, with one or more layers.
- Particular polymers that may be mentioned herein include PLCL, DL-PLCL and PGCL.
- polymer layers described above may be combined to form a single multilayer film.
- This film may only have polymer layers, or may also have antibiotic layers interspersed between the polymer layers, provided that the antibiotic layers are ultimately encapsulated between two polymer layers.
- the number average molecular weight of the polymer may be greater than or equal to 5,000 Daltons, such as greater than 5000 Daltons (e.g. from 5,000 to 500,000 Daltons).
- the antibiotic film include may include a releasing agent in at least one layer of the film or the film that comprises a component part of the socket.
- the releasing agent may be present in at least one of the at least one layers of the film, whether the layer is a polymer layer or an antibiotic layer, or may be present in more than one of the layers that make up the film, up to the total number of layers in the film. It will be appreciated, that when present, the releasing agent may be a single releasing agent or may be more than one releasing agent. When there is more than one releasing agent (e.g. 2 to 10 releasing agents), the releasing agents may be mixed together to form a blend that may be applied to one or more of the layers of the film as described above.
- each releasing agent may be applied to separate layers of the film, provided that more than two layers of the film are intended to contain a releasing agent.
- at least three releasing agents e.g. 4 to 10 releasing agents
- at least two blends e.g. 3 to 9 blends
- the releasing agent may be present in an amount from 0.1 wt % to 50 wt % of said layer.
- the antibiotic film includes at least one antibiotic agent which is distributed in at least one layer of polymer.
- the antibiotic agent may be distributed within one or more polymer layers of the antibiotic film (e.g. heterogeneously or, more particularly homogeneously distributed). Therefore, while not necessary, in particular embodiments of the current invention the at least one antibiotic agent is miscible with the bioresorbable polymer of each polymer layer in which it is present. For example:
- the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 99 wt %, such as from 0.1 wt % to 95 wt % of said polymer layer (e.g.
- the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 30 wt % of said polymer layer, optionally wherein said polymer layer is solvent cast and/or in the at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of from 10 wt % to 95 wt % (e.g.
- the antibiotic film can be formed as a single layer film or a multilayer film composite.
- the composite consists of at least one type of biodegradable polymer and at least one antibiotic agent.
- Each polymer layer can be formed from one biodegradable polymer or polymer blends.
- the outer layer of biodegradable polymer film incorporated with or without an agent to encourage tissue growth on the surface, such as collagen, a middle layer of biodegradable polymer incorporated with an antibiotic agent, and a third layer of biodegradable polymer, with no active agent.
- Another multilayer film composite can be a layer of biodegradable polymer with or without a growth factor agent, three layers of a biodegradable polymer composite comprising an antibiotic agent, and followed by a layer of biodegradable polymer film with or without a growth factor agent.
- the antibiotic agents in the three layers can be the same or different in content and concentration distribution.
- antibiotic film examples include:
- the at least one antibiotic agent is present in an amount of from 0.1 wt % to 99 wt %, such as from 0.1 wt % to 95 wt % of said polymer layer (e.g. from 0.1 wt % to 90 wt % or from 0.1 wt % to 80 wt %, from 0.1 wt % to 60 wt %, such as from 0.1 wt % to 30 wt % or from 10 wt % to 60 wt %).
- the actual amount present within each polymer layer may vary depending on the way that the layer of film was prepared.
- the at least one antibiotic agent when the polymer layer is solvent cast the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 30 wt % of said polymer layer, and when the polymer layer was formed by spray coating it onto a substrate, the at least one antibiotic agent may be present in an amount of from 10 wt % to 95 wt % (e.g. from 10 wt % to 60 wt %, or from 30 wt % to 95 wt %, such as from 40 wt % to 80 wt %).
- 10 wt % to 95 wt % e.g. from 10 wt % to 60 wt %, or from 30 wt % to 95 wt %, such as from 40 wt % to 80 wt %.
- the film and sockets made therefrom may contain one or more layers of the one or more antibiotic agent that are ultimately encapsulated between two polymer layers.
- the at least one antibiotic agent may be present in an amount of from 10 wt % to 100 wt % of said layer.
- Said layer may further comprise releasing agent or other pharmaceutically acceptable adjuvants, diluents or disperants.
- the at least one antibiotic agent may make up from 0.001 wt % to 30 wt %, or more particularly 0.001 wt % to 20 wt %, such as 0.001 wt % to 20 wt % (e.g. from 0.01 wt % to 5 wt %, or from 0.5 wt % to 5 wt %) of the weight of the entire film (i.e. all layers of the film).
- the film/socket has to release the one or more antibiotic agents over an extended period of time in a controlled manner.
- the at least one antibiotic agent is released from the antibiotic film over a period of from 1 to 30 days following implantation or, more particularly, over a period of from 3 to 14 days following implantation.
- Particular films and sockets made therefrom that may be mentioned herein include an antibiotic film/socket where more than 10 wt % of the at least one antibiotic agent is released within 24 hours of implantation, with the entirety of the at least one antibiotic agent being released from the antibiotic film over a period of from 3 to 14 days following implantation.
- the antibiotic films and the sockets made therefrom of the current invention can be used in medicine.
- the antibiotic films mentioned herein can be used in treating or preventing infection and associated diseases and disorders.
- the films mentioned herein may be used in:
- the antibiotic films and sockets made therefrom mentioned herein may be used to cover at least part of the surface of a medical device that is then implanted into a subject, as described in more detail below.
- the films and the sockets made therefrom may be applied to an implantable medical device, where the resulting device comprises a medical device and an antibiotic film in the form of a socket as described herein, wherein the socket covers a part or the whole of the medical device and is suitable for reducing or preventing migration of the medical device within the body following implantation.
- the sockets made from the film may be provided in the shape of an envelope, pouch, pocket, sleeve or band to surround part or whole of the medical device.
- the device may further comprise an additional active agent (e.g. a growth factor) coated onto whole or part of an exposed surface of the film. An embodiment of the device is described below in relation to FIG. 1 .
- implantable medical device refers to a medical device that can be implanted transdermally, or to any indwelling medical device that includes a transdermal component.
- implantable medical device examples include arteriovenous shunts, left ventricular assist devices, cardiovascular implantable electronic devices (CIEDs), tissue expanders, gastric lap bands, spinal cord stimulators, intrathecal infusion pumps, deep brain stimulators, gastric electrical stimulators, sacral nerve stimulators, and vagus nerve stimulators, amongst others.
- FIG. 1 is a schematic illustration of an antibiotic film shaped into an article substrate that can be coupled to an implantable medical device for implantation into a site of subject's body.
- the article may be used to secure an implantable device at the desired site within the subject's body, by helping to anchor the device into the surrounding tissue or part of the tissue.
- the article is also able to inhibit bacterial growth due to the presence of the antibiotic agent within the film.
- the socket 100 comprising a controlled-release antimicrobial film 110 as hereinbefore defined, has two openings 120 and 130 that may be fully or partially open, and so may be described as a band or sleeve, as well as a socket.
- the socket itself and hence the openings 120 / 130 are smaller than the object to be inserted into and held by the socket.
- the socket may also, as illustrated, contain a plurality of holes 140 in the film 110 .
- the socket is made from a single film and so only requires a single side-seal 150 and may also comprise curved seal corners 160 . It will be appreciated that the socket may be manufactured using more than one film, which may then result in additional side-seals being required.
- the openings 120 / 130 may be of the same size. However, it is specifically contemplated that the openings may also be of different sizes. In certain embodiments, the holes may be from 0.1 mm to 5 mm (e.g. from 0.3 mm to 2 mm or from 0.3 mm to 1 mm). As shown in FIG. 1 , the holes may have a uniform shape and size (e.g. all are circular in shape of the same size). However, it is specifically contemplated that the holes may be irregular in shape (each hole being of an undefined shape) or be of any shape (e.g. random defined shapes) and that the size of the holes may not be uniform. The holes may be focused in the middle (avoiding seals and openings) as shown in FIGS.
- the sleeve may be formed by sealing at one end, as shown in FIG. 1 , or sealed at multiple ends.
- the corner seals may be curved, as shown in FIG. 1 , angled or squared.
- the socket 200 is made from a controlled-release antimicrobial film 210 (i.e. any film as defined hereinbefore), with two openings 220 and 230 , a plurality of holes (e.g. one or more holes) 240 , two-side seals 250 and angled sealed corners 260 .
- the socket is smaller than the object to be inserted therein (i.e. a CIED) and may be capable of housing a range of different sizes of CIED.
- the openings may be of different sizes; however it is specifically contemplated that the openings may also be of the same size.
- the holes may be from 0.1 mm to 5 mm (e.g.
- the socket of FIG. 2 may be formed by sealing two films together at two ends, as shown in FIG. 2 to form a sleeve or band-like structure.
- the corner seals may be angled, as shown in FIG. 2 , or curved or squared. It is also contemplated that the corner seals may be angled in any technically suitable manner.
- a socket in the form of a pocket 300 comprising a controlled-release antimicrobial film 310 (i.e. any film described hereinbefore), with one opening 320 , a plurality of holes (e.g. one or more holes) 330 , a three-side seal 340 , curved sealed corners 350 and angled sealed corners 360 .
- the pocket may be formed by sealing at least two films together at three ends, leaving a single end open to act as an opening. It will be appreciated that all of the ends may be sealed together and a new opening created by cutting an opening of suitable dimensions into the sealed film (this may apply using a single film as well as more than two films).
- the term “article” may refer to the overall medical device unit, that is the film and implantable medical device, or it may refer to the film shaped as a socket (i.e. a mesh, pouch, bag, envelope, sleeve, band, pocket or receptacle (all of which may be with or without holes)), that can fully or partially cover an implantable medical device.
- a socket i.e. a mesh, pouch, bag, envelope, sleeve, band, pocket or receptacle (all of which may be with or without holes)
- the socket (e.g. 300 of FIG. 3 ) may be in the form of an envelope with an opening 320 to allow insertion of an implantable device into the film and to permit insertion of accessories, such as leads or wires.
- the surface of the article 300 may also contain holes 330 within the film 310 , with all possible shapes and dimensions to reduce mass of pouch and to enhance the release of the active agent into the surrounding tissue efficiently. It will be appreciated that this is generically applicable to other forms of sockets described or contemplated herein.
- the size, shape and weight of the article can vary according to the implantation requirement.
- the film may be cut into strips an applied piece-meal so as to cover whole or part of the medical device.
- the film may be applied by any method of bonding, such as by the use of an adhesive, heat bonding or adhesion caused by the nature of the film itself (e.g. in the manner of attaching a plastic paraffin film to an object).
- the sockets of FIGS. 1-3 are configured to (1) reduce device migration or erosion; (2) securely hold the implanted medical device within the article to reduce the risk of it falling out; (3) securely hold various sizes of medical device to reduce the risk of it falling out; (4) eliminate direct contact between the implanted medical device and the tissue layer; and (5) release antibiotic agent within a desired period at the required eluting rate. This is achieved by the properties of the socket and the antibiotic film(s) that form the socket of the current invention.
- the antibiotic article is a versatile platform, which can be capable of different functions.
- the controlled release of the antibiotic agent is sufficient to prevent or reduce bacteria colonization on the surface of the implantable medical device.
- the device can also be incorporated with other functions, such as the enhancement of tissue attachment on the outer surface of the envelope by coating the surface of the film in direct contact with body tissue with one or more growth factors.
- the article can be designed to have any shape and size according to the needs of the medical device to be implanted.
- the film of the article described in FIG. 1 can be formed by at least one layer or several layers of biodegradable polymer film. At least one of said polymers layers contains an antibiotic agent. However, different layers may have different functions, such as a drug incorporation layer, a drug release control layer, a layer to promote tissue-ingrowth after implantation etc.
- FIG. 4 provides various multilayer films according to aspects of the invention.
- the single layer to multiple layer films may have a total thickness of the film is from 1 ⁇ m to 2000 ⁇ m (e.g. from 10 ⁇ m to 500 ⁇ m, such as from 40 ⁇ m to 300 ⁇ m).
- the thickness of each layer of the polymer film may be from 0.01 ⁇ m to 1000 ⁇ m (e.g. from 0.01 ⁇ m to 200 ⁇ m).
- FIGS. 4A-4G The multilayer designs of various embodiments of the invention are depicted in FIGS. 4A-4G .
- the design shown in FIG. 4A (also referred to herein as “design 4 - 1 ” shows a 3-layer film, in which the middle layer may be a piece of drug-containing biodegradable polymer film with at least one or more drugs 1 , the outer two layers 2 may be biodegradable polymer films further comprising a releasing agent blend, but without any active agent which can be formed by the same or different polymer materials.
- FIG. 4A also referred to herein as “design 4 - 1 ” shows a 3-layer film, in which the middle layer may be a piece of drug-containing biodegradable polymer film with at least one or more drugs 1 , the outer two layers 2 may be biodegradable polymer films further comprising a releasing agent blend, but without any active agent which can be formed by the same or different polymer materials.
- FIG. 4A also referred to herein as “design
- FIG. 4B depicts a 3-layer film, in which the middle layer is a piece of drug-containing biodegradable polymer film with at least one or more drugs 3 , the surface of this film (3) is coated with a layer of drug-containing biodegradable polymer layers with one or more drugs 4 .
- the design shown in FIG. 4C depicts a 5-layer film, in which the middle three layers are similar to design 4-2, with the outer two surface layers being biodegradable polymer layers that may contain a releasing agent and are with/without drug 5 .
- FIG. 4D shows a 4-layer film, in which the middle two layers 6 contain a drug, with the films in the outer surfaces 5 are biodegradable polymer layers that may contain a releasing agent and are with/without drug.
- FIG. 4E shows a 2-layer film, in which both layers are with one or two drugs 7 .
- 4F (also referred to herein as “design 4-6”) shows a 5-layer film, in which the middle layer may be a piece of biodegradable elastic polymer film without any active agent or releasing agent 8 , the surface of this film (8) is coated with a layer of drug-containing biodegradable polymer layers with one or more drugs 4 , and the two outer surface layers are a blend of polymer and releasing agent that may or may not contain a drug 9 .
- 4G shows a 7-layer film in which the middle layer may be a piece of biodegradable elastic polymer film without any active agent or releasing agent 8 , the surface of this film (8) is coated with a layer of drug-containing biodegradable polymer layers with one or more drugs 4 , the two layers immediately after is a blend of polymer with or without releasing agent 10 , and the outer surface layer is a blend of polymer and releasing agent that may or may not contain a drug 9 .
- films may be prepared by making each layer separately and stacking these individual film layers together through heat-melting, heat-compression, chemical grafting, electrostatic adsorption, chemical crosslinking etc.
- a film layer may also be used as a substrate and be spray- or dip-coated on one or both surfaces to form a further polymer layer (or layers).
- the preferred film preparation methods are film casting, spray coating and heat compression.
- the various embodiments described above are not intended to be limiting and the principles provided can be used to generate, further designs having different drug or polymer compositions and/or different film properties that do not departs from the spirit and scope of the current invention (e.g. that do not depart from the scope of the currently claimed invention). Designs that may be mentioned herein include those where the film comprises at least 2-layers.
- the main purpose of the invention is to be able to control the drug release profile of one or more active agents independently in a drug-polymer matrix for different drugs. As different active agents have different potencies and different hydrophilicity, it is rather challenging to control the drug release profile by using one polymer formulation for each drug.
- the designs shown in FIG. 4 enable one to control the drug release profile of different active agents separately to achieve a desired drug release profile for both agents.
- the antibiotic article can be tailored to different shapes and dimension to partially cover or fully wrap an implantable medical device.
- the thickness of each layer ranges from 0.01 ⁇ m to 1000 ⁇ m (e.g. from 0.01 ⁇ m to 200 ⁇ m).
- the antibiotic article is bioabsorable, which can provide a temporary anchorage for implantable medical device and gradually be absorbed/excreted by the body to provide comfort to patient.
- the article eliminates direct contact between the implanted medical device and tissue layer and may reduce the implanted device's migration or erosion.
- the article is fully resorbable with good mechanical strength.
- the growth of tissue on the surface of the antibiotic article can be controlled by incorporating a layer of growth factor on the surface according to surgeons' needs.
- the sockets and/or films of the current invention provide the following advantages:
- a sample of the film was cut into a 2 cm ⁇ 2 cm size, which was immersed in a vial containing 4 mL of PBS buffer (as the elution medium) for continuous drug elution testing.
- the vial was placed in a 37° C. incubator shaker. At periodic intervals, the elution medium was withdrawn for reverse phase HPLC analysis to determine the eluted amount of rifampicin and minocycline and replaced with fresh PBS solution (4 mL). The cumulative drug release was calculated and plotted (see FIGS. 4-6 ).
- Table 1 and FIG. 4 list a series of designs that were used in the examples.
- the table lists a number of polymers that can be used to generate compositions according to the current invention (whether alone or in combination), as well as antibiotics. It will be understood that alternative polymers and antibiotics may be used.
- PLCL resin 700 mg of sorbitol and 160 mg of minocycline (film code 1-1; rifampicin for film code 1-2) were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- 1.8 g PLCL resin and 50 mg sorbitol were dissolved in 10 mL of acetone.
- a homogeneous solution was poured onto a glass plate and drawn by a film applicator to form a film following evaporation of the solvent. The film was then removed from the glass plate.
- composition according to design 4-1 was prepared using two films according to 1-B sandwiching a film according to 1-A.
- the resulting stack of films were aligned and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- the middle three layers were prepared by following procedure in Example 2.
- the two outer layers were prepared by following Example 1-B.
- the stack of 5 layers of films were aligned properly and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- the outer two layers were prepared by following Example 1-B.
- the two middle drug-polymer layers were prepared by following Example 2-B.
- the resulting films were aligned properly and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- the two layers were prepared by following Example 1-A and 2-A.
- Film compression procedure is the same as 1-C.
- PLCL resin was heat compressed at 150° C., 60 Mpa for 1 minute.
- PLCL resin 250 mg of polysorbate and 160 mg of minocycline(film code 1-1; rifampicin for film code 1-2) were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- a composition according to design 4-6 was prepared using two films according to 6-C sandwiching a film 6-A coated according to 6-B. The resulting stack of films were aligned and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- 1.8 g PLCL resin and 50 mg of polysorbate were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- a composition according to design 4-7 was prepared using two films according to 7-A sandwiching a film 6-A coated according to 6-B. The stack is further sandwiched between two films according to 6-C. The resulting stack of films were aligned and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- Film preparation procedure is the same as Example 1-A to prepare a single layer.
- PLCL resin and 160 mg of minocycline(film code 1-1; rifampicin for film code 1-2) were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- the film was prepared by following the protocol in Example 3.
- the middle layer was prepared by using a drug mixture of 120 mg minocycline and 160 mg rifampin.
- the two intermittent layers were prepared by spray coating of minocycline by following Example 2-B.
- the outer two layers were prepared by following Example 1-B.
- the stack of 5 layers of films were aligned properly and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- the cumulative releasing profiles of two antibiotics are shown in FIG. 6 .
- FIGS. 5A-5B show the cumulative release of two antibiotics from different layered film designs and single films prepared in Examples 1 to 9 (film codes 1-1 to 1-18).
- the drug density of both antibiotics is between 0.05 mg to 0.1 mg/cm 2 .
- the absence of releasing agent results in a film with very slow release, while the presence of releasing agent gives a high initial burst with a fast releasing profile.
- minocycline is more hydrophilic than rifampin, minocycline releases much faster.
- the release profile and initial burst rate of rifampin and minocycline are tuned and well-controlled through the different designs.
- the zone-of-inhibition (ZOI) for the film was determined according to the Kirby-Bauer method.
- the study chose to test Escherisia coli ( E. coli ) and S. aureus, S. epidermidisas demonstration.
- E. coli has the highest minimum inhibitory concentration (MIC) among the other bacteria that are commonly found in humans.
- the MIC of E. coli is 20 times higher than S. aureus, S. epidermidis , MRSA, S. capitis etc.
- E. coli were inoculated into Lysogeny broth (LB broth) from a stock solution and incubated at 37° C. and then evenly spread over the entirety of an agar plate by a disposable spreader. A 15 mm diameter film was firmly pressed into the center of an agar plate and incubated at 37° C. Pieces were transferred to other fresh agar plates using sterile forceps every 24 hr. The diameter of the ZOI was measured and recorded every day.
- Lysogeny broth LB broth
- the elasticity and fit of the socket was tested using different socket sizes and CIED sizes. A good fit is when the CIED could be easily inserted into the socket, and does not fall out when overturned and held by the socket.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Vascular Medicine (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Molecular Biology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oral & Maxillofacial Surgery (AREA)
- Dermatology (AREA)
- Transplantation (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Radiology & Medical Imaging (AREA)
- Medicinal Preparation (AREA)
- Materials For Medical Uses (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Electrotherapy Devices (AREA)
Abstract
Description
- The present application is a continuation of U.S. application Ser. No. 15/563,527, filed Sep. 29, 2017, which is a 371 of PCT Patent Application No. PCT/SG2016/050158, filed Mar. 31, 2016, which claims priority to foreign application GB 1505527.0, filed Mar. 31, 2015, all of which are incorporated herein by reference in their entirety.
- The present invention relates to an antibiotic article that prevents infection associated with the implantation of medical devices.
- Over the past decade, the usage of cardiovascular implantable electronic devices (CIEDs) has expanded dramatically, driven mostly by the increase in defibrillator therapy. Since the introduction of CIEDs, there have been numerous cases of complications, like generator migration, lead displacement and Twindler's syndrome, which are all related to the migration or displacement of the implant which leads to further intervention being necessary. A pouch to contain the CIED has been developed with the aim to create a stable environment when implanted in the body. A typical pouch used for this role is sealed at three sides and has a single opening for placing the device into said pouch.
- Moreover, with the increased rate at which CIEDs are being implanted, there has been an associated increase in the number of CIED infections (Voigt et al. PACE. 2010; 33(4):414-419). Inpatient mortality associated with a CIED infection ranges from 8.4% to 11.6% (Tarakjiet al. Heart Rhythm. 2010; 7(8):1043-1047). The average cost to treat a CIED infection is very expensive, around US $146,000. However, since 2013 in US, the Centers for Medicare & Medicaid Services (CMS) have ceased to reimburse hospitals for the costs associated with treating infections acquired as a result of the surgical implantation of a medical device, such as a CIED, (http://www.cms.gov/newsroom/mediareleasedatabase/fact-sheets/2013-fact-sheets-items/2013-08-02-3.html). Therefore, there is a significant economic impact on both the patient and the hospital in treating a hospital-acquired CIED infection. An antimicrobial article that can be attached to, or wraps around the surface of, an implantable medical device may help to reduce, prevent, or mitigate infection by eluting antimicrobial agents over time into the surrounding environment of the medical device.
- A number of antimicrobial articles disclosed in International patent application publication Nos. WO 2008/127411, WO 2008/136856, WO 2009/113972, WO 2012/064963 and WO 2013/013123, have sought to address the issues associated with CIED migration and infections caused by its implantation. This Absorbable Antibacterial Envelope, developed by TYRX, Inc. (a medical device company acquired by Medtronic), is a fully absorbable sterile prosthesis designed to hold a pacemaker pulse generator or defibrillator to help create a stable environment when implanted in the body. The TYRX Absorbable Antibacterial Envelope is a mesh with large pores that is knitted from absorbable filaments (a polymer made of glycolide, caprolactone, and trimethylene carbonate) and is coated with an absorbable polyarylate polymer. The absorbable polymer coating contains two antimicrobial agents: minocycline and rifampicin.
- While this system, and others like it have been proven effective for their intended use, these devices present new challenges and problems. Firstly, the envelope/pouch used in said devices has an opening that is usually bigger than the CIED to be inserted, which results in the potential risk of the CIED falling out. Moreover, these devices are designed to cater to numerous sizes of CIED, which increases the risk of smaller CIEDs falling out due to the relative rigidity and inelasticity of the material. Hence, there is a need for a new and improved design and structure that can securely hold CIEDs of various sizes.
- Moreover, while the articles above go some way to dealing with infections, there are issues with the use of these antimicrobial articles. For example, the articles described above often coat both agents together on the surface, or impregnate both agents within a material, and cannot control the release of both agents together, especially when both agents have differing hydrophilicity values, as is the case with Rifampin and Minocycline. In situations where it is advisable to use more than one antimicrobial agent, it is important to control the release of both agents so that they provide the required concentration of active agent over the required period of time. Further, antimicrobial agents coated on the surface tend to be released easily, and thus there is minimal control on the rate of release of the antimicrobial agent over an extended period of time. Therefore, there is a need for an improved antibiotic article.
- In the present invention, there is provided a soft and elastic biodegradable controlled-release antibiotic socket (e.g. a sleeve or band) which is designed to be able to securely hold different sizes of CIEDs. As such a socket (i.e. a sleeve, band or pocket) is constructed of an elastic material with at least one opening, in which the device and therefore all of the openings are smaller than the object to be inserted. The socket and its openings can be stretched to a size larger than the object to be inserted to enable ease of insertion of said device. Once said device has been inserted, the socket, which is made of an elastomeric polymeric material, is allowed to recover towards its original size, thereby holding the device inserted thereto securely. The elastic biodegradable controlled-release antibiotic socket is intended to hold a cardiac implantable electronic device (CIED) securely in order to provide a stable environment when implanted in the body; and reduce, prevent, or mitigate infection by releasing at least one antimicrobial agent during and/or after implantation in a controlled manner. The drug release is controlled by the choice of polymer, the addition of layers, tuning of the thickness of various layers, and the use of releasing agents.
- Thus, in a first aspect of the invention, there is provided controlled-release antibiotic socket for securely holding an implantable medical device, comprising:
- at least one film made from at least one polymer layer, where the at least one film is formed into the socket;
- at least one antibiotic agent; and
- at least one opening in the socket, wherein
- the at least one polymer layer comprises a biodegradable elastomeric polymeric material; and
- the at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- It will be appreciated that in embodiments of the socket, the socket may be in the form of a pocket with at least one opening or a sleeve/band with at least two openings. It will be further appreciated that for the socket to securely hold an implantable medical device, the socket made from the elastomeric material is smaller than the medical device to be inserted into it. This may result in the socket securely holding the medical device (e.g. a CIED device) by a resilient holding force generated from the elastomeric polymeric material that makes up the film.
- In a second aspect of the invention there is provided a controlled-release antibiotic film made from at least one polymer layer for securely holding an implantable medical device, the film comprising at least one polymer layer that is made from a biodegradable elastomeric polymeric material; and at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- The socket (and hence the openings) are stretchable to at least 1.1 times (e.g. from 1.2 times to 10 times) to allow for insertion of the CIED into the socket, and can recover to more than 80% to securely hold the CIED within the socket and prevent fall off. A construction of the article that may be mentioned herein comprises at least one film, which itself comprises at least one polymer layer and at least one antimicrobial agent; and at least one opening and numerous holes on the surface.
- In certain embodiments of the socket and/or film of the invention:
-
- (a) the film may have at least two polymer layers. For example, the film may have from two to ten polymer layers (e.g. from two to nine polymer layers, such as from three to seven polymer layers);
- (b) the film applies a resilient force onto an object inserted into the socket;
- (c) the socket or film can resiliently engage (or resiliently hold) a device after stretching or can stretch from its original size to an expanded size and return to its original size or to a size no greater than the expanded size minus (80% of the difference between expanded size and original size), optionally wherein the socket or film can stretch from its original size to an expanded size and return to its original size or to a size no greater than the expanded size minus (90% of the difference between expanded size and original size);
- (d) the bioresorbable polymer of the at least one polymer layer may be selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PH B), polyhydroxyalkanoates (PHA), poly(phosphazene), poly(phosphate ester), poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate), poly(glycolide-co-carolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate,
poly 1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone co-butylacrylate, a copolymer of polyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer of poly(trimethylene carbonate), polyethylene glycol (PEG), hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides (such as hyaluronic acid, chitosan and starch), proteins (such as gelatin and collagen) or PEG derivatives and copolymers thereof (e.g. the bioresorbable polymer of the at least one polymer layer may be selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), PEG and its derivatives, and their copolymers (such as selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) copolymer, or more preferably, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and their copolymers. Particlar polymers that may be mentioned include polycaprolactone (PCL), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(glycolide-co-caprolactone) (PGCL), poly(lactide-co-caprolactone) (PLCL)and its derivatives and their copolymers)); - (e) the bioresorbable polymer of the at least one polymer layer may be selected from one or more of the group consisting of poly(ester-urethane)s, poly(diol citrates), and poly(4-hydroxybutyrate)s, poly(glycerol sebacate), and star-poly(c-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(DL-lactide-co-caprolactone) (DL-PLCL), poly(glycolide-co-caprolactone) (PGCL) and other biodegradable elastomer prepared through synthesis of di-, tri-, or multi-polymers, architecturally arranged in block, star, or linear structures, and prepared as thermoplastics or thermosets, their co-polymers, and mixtures or blends (e.g. PLCL, DL-PLCL and PGCL, its copolymers, and mixtures or blends, such as PLCL, its copolymers, and mixtures or blends);
- (f) at least one of the at least one polymer layers may further comprise a releasing agent that is composed of one or more biocompatible hydrophilic small molecules with a hydrophobic-lipophilic balance of greater than 6 (e.g. the releasing agent is selected from one or more of the group consisting of sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number average molecular weight of from 200 to 2000, polysorbate and urea (e.g. selected from one or more of
polysorbate 40, or more particularly,polysorbate 20,polysorbate 60 and polysorbate 80)); - (g) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be poly(lactide-co-caprolactone) (PLCL) (e.g. having a PLA to PCL ratio of from 90:10 to 60:40) or its derivatives and copolymers thereof, and/or the bioresorbable elastomeric polymeric material of one of the at least one polymer layers is poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g. having a DL-PLA to PCL ratio of from 90:10 to 50:50) or its derivatives and copolymers thereof, and/or the bioresorbable elastomeric polymeric material of one of the at least one polymer layers is poly(glycolide-co-caprolactone) (PGCL) (e.g. having a PGA to PCL ratio of from 90:10 to 10:90) or its derivatives and copolymers thereof, or, more particularly, the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be a blend of PCL and PLA (e.g. a ratio blend of PCL and PLA having a wt:wt ratio of 1:9 to 9:1);
- (h) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be a blend of DL-PLCL or PGCL or, more particularly, PLCL with a releasing agent selected from one or more of the group selected from
polysorbate 20,polysorbate 60,polysorbate 80, or polyethyleneglycol having a molecular weight of 200 to 2000 Daltons in a wt:wt ratio of PLCL to releasing agent of from 25:1 to 1:9; - (i) the bioresorbable polymer of one of the at least one polymer layers may be PCL or PLA;
- (j) the bioresorbable polymer of one of the at least one polymer layers may be a copolymer of poly(D,L-lactide/glycolide), such as PLGA (e.g. having a PLA to PGA ratio of from 1:9 to 9:1);
- (k) the number average molecular weight of the polymer may be greater than or equal to 5,000 Daltons (e.g. from 5,000 to 500,000 Daltons or between 5,000 Daltons and 500,000 Daltons);
- (l) the at least one antibiotic agent may be miscible with the bioresorbable polymer of each polymer layer in which it is present;
- (m) in at least one layer of the polymer film, the at least one antibiotic agent may be homogeneously distributed within at least one of the polymer layers in which it is present (e.g. when the at least one antibiotic agent is distributed within a polymer layer, it is homogeneously distributed within said polymer layer);
- (n) when the film has at least two polymer layers, the at least one antibiotic agent is distributed within at least two of the polymer layers;
- (o) when the film has at least two polymer layers, the at least one antibiotic agent forms a separate layer sandwiched between the two polymer layers;
- (p) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a first antibiotic agent layer is sandwiched between two layers of a second antibiotic agent or between a layer of a second antibiotic agent and layer of a third antibiotic agent;
- (q) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least two antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a first antibiotic agent layer is sandwiched between a polymer layer and a second antibiotic layer;
- (r) in at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of 0.1 wt to 99 wt %, such as from 0.1 wt % to 95 wt % of said polymer layer (e.g. from 0.1 wt % to 90 wt % or from 0.1 wt % to 80 wt %, such as from 0.1 wt % to 60 wt %), for example, in at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 30 wt % (e.g. from 1 wt % to 25 wt %) of said polymer layer, optionally wherein said polymer layer is solvent cast and/or in the at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of from 10 wt % to 95 wt % (e.g. from 10 wt % to 60 wt %, or from 30 wt % to 95 wt %, such as from 40 wt % to 80 wt %) of said polymer layer, optionally wherein said polymer layer was spray coated onto a substrate;
- (s) the film may further comprise holes, for example the diameter of each of the holes may be from 0.1 mm to 5 mm (e.g. from 0.3 mm to 2 mm or, more particularly, from 0.3 mm to 1 mm) or from 0.5 mm to 15 mm (e.g. from 1 mm to 20 mm), optionally:
- (i) the shape of the holes may not be uniform or the holes may be circular; and/or
- (ii) the size of the holes may not be uniform; and/or
- (iii) the holes on the socket constructed from the film may be evenly distributed throughout the film, or focused in the middle of the film (to avoid seals), or nearer to the seals;
- (t) the total thickness of the film may be from 1 μm to 2000 μm (e.g. from 10 μm to 500 μm, such as from 40 μm to 300 μm).
- (u) the thickness of each layer of the polymer film may be from 0.01 μm to 1000 μm (e.g. from 0.01 μm to 200 μm);
- (v) the at least one antibiotic agent may be an antiseptic, a disinfectant, or, more particularly, an antimicrobial agent or an antifungal agent (e.g. the antimicrobial agent may be selected from one or more of the group consisting of tetracycline and its derivatives (such as minocycline, tigecycline and doxycycline), rifampin, triclosan, chlorhexidine, penicillins, aminoglycides, quinolones, vancomycin, gentamycine, a cephalosporin (e.g. cephalosporin), carbapenems, imipenem, ertapenem, an antimicrobial peptide, cecropin-mellitin, magainin, dermaseptin, cathelicidin, a-defensins, a-protegrins and pharmaceutically acceptable salts thereof (e.g. a combination of rifampin and another antimicrobial agent, such as a combination of rifampin and a tetracycline derivative), the antimicrobial agent may be a combination of rifampin and one or more of the group selected from minocycline, doxycycline, and tigecycline (e.g. rifampin and doxycycline, rifampin and tigecycline or, more particularly, rifampin and minocycline, such as a combination of rifampin and/or minocycline, for example, a combination of rifampin and minocycline, the ratio of rifampin to minocycline is from 1:10 to 10:1 (wt/wt) (e.g. from 2:5 to 5:2 (wt/wt)), the antifungal agent may be selected from one or more of the group consisting of azoles (such as ketoconazole, clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, voriconazole, clotrimazole), allylamines (such as terbinafine), morpholines (such as amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cycloheximide, ciclopirox, flucytosine, terbinafin, amphotericin B and pharmaceutically acceptable salts thereof.
- (w) the at least one antibiotic agent may be released from the antibiotic film over a period of from 1 to 30 days following implantation, for example
- (i) the at least one antibiotic agent may be released from the antibiotic film over a period of from 3 to 14 days following implantation;
- (ii) more than 10 wt % of the at least one antibiotic agent may be released within 24 h of implantation, and the remainder of the at least one antibiotic agent is released from the antibiotic film over a period of from 3 to 14 days following implantation.
- (x) the film may have a single polymer layer and contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (y) the film may have three polymer layers, with the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (z) the film may have three polymer layers, with the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline or rifampicin) and the outer layers containing a further antibiotic (e.g. the further antibiotic is minocycline or rifampicin, provided that when the at least one antibiotic of the middle layer is minocycline, the further antibiotic of the outer layers is rifampicin and vice versa).
- (aa) the film may have five polymer layers, with the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline or rifampicin) and the layers immediately on top and bottom of the middle layer containing a further antibiotic (e.g. the further antibiotic is minocycline or rifampicin, provided that when the at least one antibiotic of the middle layer is minocycline, the further antibiotic of the outer layers is rifampicin and vice versa);
- (bb) the film may have five polymer layers, where the layers immediately on top and bottom of the middle layer contain an antibiotic (e.g. the antibiotic is minocycline and/or rifampicin;
- (cc) the film may have four polymer layers, with the middle two layers containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (dd) the film may have two polymer layers, with the two layers each containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (ee) the amount of the at least one antibiotic compared to the total weight of the film may be from 0.001 wt % to 30 wt %, or more particularly 0.001 wt % to 20 wt %, such as 0.001 wt % to 20 wt % (e.g. from 0.01 wt % to 5 wt %, or from 0.5 wt % to 5 wt %);
- (ff) the film has two outer layers and the outer layers may have a rough and non-smooth surface.
- In embodiments of the film and/or socket that may be mentioned herein:
- (i) the film is a single polymer layer that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein; or
- (ii) the film is a single polymer layer that comprises a polymeric material and a releasing agent that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein; or
- (iii) the film has three polymer layers, such that there is a top, middle and bottom layer, where the middle layer consists only of polymeric material, and the top and bottom layers each contain at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein; or
- (iv) the film has three polymer layers, such that there is a top, middle and bottom layer, where the middle layer consists only of polymeric material, and the top and bottom polymer layers each comprise a polymeric material and a releasing agent that further contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein; or
- (v) the film has five layers, such that there is a top, top-intermediate, middle, bottom-intermediate and bottom layer, where the middle layer consists only of polymeric material, the top-intermediate and bottom-intermediate layers contain at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom polymer layers contain at least one further antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-intermediate and bottom-intermediate layers contain rifampicin and the top and bottom layers contain minocycline dispersed therein or vice versa; or
- (vi) the film has five layers, comprising a central polymer layer, and two outer polymers layers that contain at least one antibiotic dispersed therein (e.g. the at least one antibiotic is minocycline and/or rifampicin), with an antibiotic layer (e.g. the antibiotic layers comprise minocycline and/or rifampicin) sandwiched between the central layer and each of the outer polymer layers; or
- (vii) the film has five layers, such that there is a top, top-intermediate, middle, bottom-intermediate and bottom layer, where the middle layer consists only of polymeric material, the top-intermediate and bottom-intermediate polymer layers each comprise a polymeric material and a releasing agent that further contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom polymer layers each comprise a polymeric material and a releasing agent that contains at least one further antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-intermediate and bottom-intermediate polymer layers contain rifampicin and the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (viii) the film has seven layers, such that there is a top, top-intermediate, top-middle-intermediate, middle, bottom-middle-intermediate, bottom-intermediate and bottom polymer layer, where the middle layer consists only of polymeric material, the top-middle-intermediate and bottom-middle-intermediate polymer layers each comprise a polymeric material that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, the top-intermediate and bottom-intermediate polymer layers each comprise a polymeric material and a releasing agent, and the top and bottom polymer layers each further contain at least one further antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-middle-intermediate and bottom-middle-intermediate polymer layers contain rifampicin, the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (ix) the film has seven layers, such that there is a top, top-intermediate, top-middle-intermediate, middle, bottom-middle-intermediate, bottom-intermediate and bottom polymer layer, where the middle layer consists only of polymeric material, the top-middle-intermediate and bottom-middle-intermediate layers consist of at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin), the top-intermediate and bottom-intermediate layers comprise a polymeric material and a releasing agent, and the top and bottom layers each comprise a polymeric material and at least one further antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-middle-intermediate and bottom-middle-intermediate polymer layers contain rifampicin, the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (x) the film has seven layers, such that there is a top, top-intermediate, top-middle-intermediate, middle, bottom-middle-intermediate, bottom-intermediate and bottom polymer layer, where the middle layer consists only of polymeric material, the top-middle-intermediate and bottom-middle-intermediate polymer layers each comprise a polymeric material that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, the top-intermediate and bottom-intermediate polymer layers each comprise a polymeric material and a releasing agent, and the top and bottom polymer layers each comprise a polymeric material and a releasing agent and each further contain at least one further antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-middle-intermediate and bottom-middle-intermediate polymer layers contain rifampicin, the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (xi) the film has seven layers, such that there is a top, top-intermediate, top-middle-intermediate, middle, bottom-middle-intermediate, bottom-intermediate and bottom polymer layer, where the middle, top-intermediate and bottom-intermediate polymer layers consists only of polymeric material, the top-middle-intermediate and bottom-middle-intermediate polymer layers each comprise a polymeric material that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom polymer layers each contain at least one further antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-middle-intermediate and bottom-middle-intermediate polymer layers contain rifampicin, the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (xii) the film has seven layers, with the middle layer being a biodegradable elastic polymer layer, the layers immediately on top and bottom of the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin), the layers on top of the antibiotic layers are polymer layers, and the outer layers are each comprise a polymeric material and a further antibiotic (e.g. the further antibiotic is minocycline or rifampicin, provided that when the at least one antibiotic of the intermediate layer is minocycline, the further antibiotic of the outer layers is rifampicin and vice versa); or
- (xiii) the film has seven layers, such that there is a top, top-intermediate, top-middle-intermediate, middle, bottom-middle-intermediate, bottom-intermediate and bottom polymer layer, where the middle, top-intermediate and bottom-intermediate polymer layers consists only of polymeric material, the top-middle-intermediate and bottom-middle-intermediate polymer layers each comprise a polymeric material that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom polymer layers each comprise a polymeric material and a releasing agent and each contain at least one further antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-middle-intermediate and bottom-middle-intermediate polymer layers contain rifampicin, the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (xiv) the film has three polymer layers, where the middle polymer layer contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein; or
- (xv) the film has three polymer layers, where the middle polymer layer contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom layers contain at least one further antibiotic (e.g. the at least one further antibiotic is minocycline or rifampicin; optionally wherein, when the at least one antibiotic of the middle layer is minocycline, the at least one further antibiotic of the outer layers is rifampicin and vice versa) dispersed therein; or
- (xvi) the film has three polymer layers, where the middle polymer layer comprises a polymeric material and a releasing agent that contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom layers each comprise a polymeric material and a releasing agent that contains at least one further antibiotic dispersed therein (e.g. the at least one further antibiotic is minocycline or rifampicin; optionally wherein, when the at least one antibiotic of the middle layer is minocycline, the at least one further antibiotic of the outer layers is rifampicin and vice versa); or
- (xvii) the film has five polymer layers, such that there is a top, top-intermediate, middle, bottom-intermediate and bottom layer, where the middle layer contains at least one antibiotic (e.g. the at least one antibiotic is minocycline or rifampicin) dispersed therein, and the top-intermediate and bottom-intermediate polymer layers contain at least one further antibiotic dispersed therein (e.g. the at least one further antibiotic is minocycline or rifampicin, optionally wherein that when the at least one antibiotic of the middle layer is minocycline, the at least one further antibiotic of the top-intermediate and bottom-intermediate layers is rifampicin and vice versa); or
- (xviii) the film has five polymer layers, such that there is a top, top-intermediate, middle, bottom-intermediate and bottom layer, where the middle layer contains at least one antibiotic (e.g. the at least one antibiotic is minocycline or rifampicin) dispersed therein, and the top-intermediate and bottom-intermediate polymer layers contain at least one further antibiotic dispersed therein (e.g. the at least one further antibiotic is minocycline or rifampicin, provided that when the at least one antibiotic of the middle layer is minocycline, the at least one further antibiotic of the top-intermediate and bottom-intermediate layers is rifampicin and vice versa), and the top and bottom layers each comprise a polymeric material and a releasing agent; or
- (xix) the film has five polymer layers, such that there is a top, top-intermediate, middle, bottom-intermediate and bottom layer, where the top-intermediate and bottom-intermediate polymer layers contain at least one antibiotic ((e.g. the further antibiotic is minocycline and/or rifampicin); or
- (xx) the film has four polymer layers, where the middle two polymer layers containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin); or
- (xxi) the film has four polymer layers, where the middle two polymer layers containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the two outermost layers comprise a polymeric material and a releasing agent; or
- (xxii) the film has two polymer layers, where the two polymer layers each contain at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin); or
- (xxiii) the film has two polymer layers, where one of the polymers layers further comprises at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) and the other polymer layer further comprises at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) and a releasing agent, optionally the antibiotic in the layer also containing the releasing agent is minocycline and the other layer contains rifampicin or vice versa; or
- (xxiv) the film has five layers, such that there is a top, top-intermediate, middle, bottom-intermediate and bottom layer, where the middle layer consists only of polymeric material, the top-intermediate and bottom-intermediate polymer layers each comprise a polymeric material and at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin) dispersed therein, and the top and bottom polymer layers each comprise a polymeric material, a releasing agent and at least one further antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin) dispersed therein, optionally wherein, when the top-intermediate and bottom-intermediate polymer layers contain rifampicin the top and bottom polymer layers contain minocycline dispersed therein or vice versa; or
- (xxv) the film has four layers, such that there is a top, top-middle, bottom-middle and bottom layer, where the top layer comprises a polymeric material, a releasing agent and at least one antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin), the top-middle layer consists of at least one antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin), the bottom-middle layer comprises a polymeric material and at least one antibiotic (e.g. the at least one further antibiotic is minocycline and/or rifampicin), and the bottom layer consists only of polymeric material.
- It will be appreciated that when the term “at least one antibiotic” is used above in relation to a film or socket made therefrom having more than one layer, it may refer to the use of the same (or same mixture of) antibiotic in all layers that contain an antibiotic, and/or to different antibiotics (and/or to different mixtures of antibiotics) in layers of the film or socket made therefrom.
- In embodiments of the socket described herein, the implantable medical device may be a cardiovascular implantable electronic device (CIED).
- In further aspects of the invention, there is provided:
-
- (i) a socket or film as set out in the first and second aspects of the invention (and their various embodiments, whether alone or in any suitable combination) for use in treating or preventing infection and associated diseases and disorders;
- (ii) a socket or film as set out in the first and second aspects of the invention (and their various embodiments, whether alone or in any suitable combination), in the manufacture of a medicament for use in the treatment or prevention of infection and associated diseases and disorders; or
- (iii) a method of treatment comprising the step of placing at least part of an implantable medical device into a socket as set out in the first aspect of the invention (and its various embodiments, whether alone or in any suitable combination) to provide a coated implantable medical device and placing the coated implanted medical device into a subject to treat or prevent infection and associated diseases and disorders arising from said implantation.
- In embodiments of the above aspects, the film may be used to cover at least part of the surface of a medical device that is then implanted into a subject.
- In a further aspect of the invention, there is provided an implantable medical device comprising a medical device and socket as set out in the first aspect of the invention (and its various embodiments, whether alone or in any suitable combination), wherein the film covers a part or the whole of the medical device and is suitable for reducing or preventing migration of the medical device within the body following implantation. For example, the film may be provided in the shape of an envelope or pouch to surround part or whole of the medical device. In certain embodiments, the device may further comprise an additional active agent (e.g. a growth factor, an anti-inflammatory, or anaesthetic agent) coated onto whole or part of an exposed surface of the film.
- In yet a further aspect of the invention, there is provided a process for making a socket or film as set out in the first and second aspects of the invention (and their various embodiments, whether alone or in any suitable combination), wherein when the socket is made from a film having two or more polymer layers or the film has two or more polymer layers, the film is prepared by the use of one or more of heat-melting, heat-compression, spray coating, dip coating, chemical grafting, electrostatic adsorption, chemical crosslinking to join the polymer layers together.
-
FIGS. 1 to 3 depict schematic illustrations of an article designed according to an embodiment of the invention (a socket to surround a medical device) with holes. -
FIGS. 4A-4G depict examples of layered designs according to embodiments of the current invention. -
FIGS. 5A and 5B depict the cumulative release profile of minocycline (5A) and rifampin (5B) in the exemplified embodiments of the invention. -
FIG. 6 depicts the cumulative release profile of minocycline and rifampin in a single film according to an embodiment of the current invention. -
FIG. 7 depicts a tensile curve of an article. - The antibiotic socket of the current invention relates to a socket made from an elastic film material (comprising one or more elastomeric polymer layers), with at least one opening in the socket. The socket is smaller than the objects it is intended to hold and so it is stretched to a size to permit the object to be inserted and then recovers towards its original size (due to the elastic material that is made from), such that it securely holds the object inserted thereto (e.g. resiliently engages, holds or secures the object). The secure/resilient securing of the object inserted significantly reduces the possibility of the CIED falling out. In addition, the socket (or the film the socket is made from) may also have a rough surface, which aids in securing the object to the socket and may also help the socket secure the object following implantation into the body. In addition, the rough surface may also prevent the film/socket made therefrom from becoming adhered to a surface (i.e. sticking to a surface), for example the roughness may ensure that the inner surfaces of the socket do not stick to each other and thereby enables easy opening of the socket to insert a device. Further, the socket (or the film the socket is made from) may also contain numerous holes that may help to increase friction and reduce migration of the implant as well as allow outflow of exudates. The design of the socket is thus able to securely hold various sizes of medical devices (e.g. CIEDs) and prevent or reduce migration of the device during implantation, without risk of the device falling out of the socket.
- In addition, the antibiotic socket of the current invention may comprise a single layer or multiple layers of a biodegradable/bioresorbable polymer film with at least one antibiotic agent contained within at least one of the polymer layers, or the antibiotic may be disposed as a separate layer encapsulated by at least two polymer layers to form a control-release matrix to provide a required eluting profile for the at least one antibiotic agent for a desired time period. The single layer or multilayer structure also can be incorporated with other functional agents, such as anti-inflammatory, or anaesthetic agents or a growth factor agent.
- Thus there is provided a controlled-release antibiotic socket for securely holding an implantable medical device, comprising:
- at least one film made from at least one polymer layer, where the at least one film is formed into the socket;
- at least one antibiotic agent; and
- at least one opening in the socket, wherein
- the at least one polymer layer comprises a biodegradable elastomeric polymeric material; and
- the at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- When used herein, the term “socket” is intended to mean a device that is intended to securely hold a separate object by surrounding the whole or part of said separate object (e.g. the socket may leave parts of the object uncovered to enable further connectivity of the object). It will be appreciated from the context of the invention, that the socket is intended to be smaller than the object it is intended to hold and accomplishes the secure holding by its elastic nature, such that it may be stretched to a size larger than the object to be held and then recovers towards its original size once the object to be held has been placed within the socket. As will be apparent, the socket requires at least one opening to permit an object to be inserted within it and so the socket may also be described as a pocket when it has a single opening. In alternative arrangements, the socket may have two openings and so may also be called a sleeve or band. It will be appreciated that the socket may contain more than two openings too.
- The socket is made from at least one film. Thus, there is also provided a film made from at least one polymer layer for securely holding an implantable medical device, the film comprising:
- at least one polymer layer that is made from a biodegradable elastomeric polymeric material; and
- at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- As is apparent, both the socket and film are elastic, in that they can be stretched/deformed in any direction and recover towards their original size and shape. This property enables the socket to securely hold an object placed therein. This may be accomplished by the resilient force applied to the object inserted into the socket by the elastomeric polymeric material that comprises the film. Thus, the socket or film can resiliently engage or resiliently hold a device inserted into a socket formed from the film after stretching. In addition or alternatively, the socket or film can stretch from its original size to an expanded size and return to its original size or to a size no greater than the expanded size minus (80% of the difference between expanded size and original size), optionally wherein the socket or film can stretch from its original size to an expanded size and return to its original size or to a size no greater than the expanded size minus (90% of the difference between expanded size and original size).
- The controlled release antibiotic socket of the current invention provides enhanced stability of the object (i.e. the CIED) within the socket, reducing the possibility of the object falling out of the socket, and is able to effectively achieve that for a wide range of objects (i.e. CIEDs of different sizes) with one size of socket. The selection of an elastic polymeric material is an intricate balance of elastic modulus and strain recovery. Certain polymers with high elasticity (low elastic modulus) have poor strain recovery, and would not be able to hold an object well. Other polymers that have relatively low elasticity (high elastic modulus) are not suitable for the construction of a sleeve that can securely hold different sizes of object. The design of the sleeve aids in enhancing the stability of the object (i.e. CIED) within. Thus care need to be exercised in selecting the materials used to form the polymer film.
- The controlled-release elastic biodegradable antibiotic film that makes up the socket in the first embodiment of the invention may comprise a single layer or multiple layers with at least one antibiotic agent contained within at least one of the layers to form a controlled-release matrix to provide a required eluting profile for the at least one antibiotic agent for a desired time period. One or more of the layers may contain a releasing agent to enhance control of release of at least one antibiotic agent within the same layer or at other layers of the film. The single layer or multilayer structure also can be incorporated with other functional agents, such as anti-inflammatory, or anaesthetic agents or a growth factor agent.
- Thus, there is provided a controlled-release antibiotic film made from at least one polymer layer for securely holding an implantable medical device, the film comprising at least one polymer layer that is made from a biodegradable elastomeric polymeric material; and at least one antibiotic agent is dispersed within at least one of the at least one polymer layers and/or, when the film comprises at least two polymer layers, the at least one antibiotic agent is disposed as a separate layer between two polymer layers.
- The controlled release antibiotic socket and films of the current invention provide enhanced control of drug eluting characteristics compared with previous drug eluting articles. This is achieved tuning of various factors, for example using additional layers (polymer layers or a layer of drug), where the active agent(s) are incorporated into different layer(s) (whether dispersed within a polymer layer, or forming a separate layer sandwiched between polymer layers), controlling the polymers used, controlling the thickness of the layers, the drug-polymer composite ratio, addition of releasing agent(s), and a layered structure designed to control the release rate of the active agent(s). It will be appreciated that these features allow for the design of a polymer film where the release profile of two or more active agents, having different release profiles from a polymer film, can be independently controlled. This allows for the active agents to be released at the same time, or to have one or other of the active agents release more quickly in comparison to other active agents etc.
- When used herein, the terms “antibiotic film” and “antibiotic agent” may refer to an antimicrobial, an antifungal, an antiseptic or a disinfecting film and/or agent. In particular examples, “antibiotic film” and “antibiotic agent” may refer to an antimicrobial or antifungal agent.
- Examples of antimicrobial agents that may be mentioned herein include tetracycline and its derivatives (such as minocycline, tigecycline and doxycycline), rifam pin, triclosan, chlorhexidine, penicillins, aminoglycides, quinolones, vancomycin, gentamycine, a cephalosporins (e.g. cephalosporin), carbapenems, imipenem, ertapenem, an antimicrobial peptide, cecropin-mellitin, magainin, dermaseptin, cathelicidin, α-defensins, α-protegrins, pharmaceutically acceptable salts thereof and combinations thereof. Particular combinations of antimicrobial agents that may be mentioned include a combination of rifampin and another antimicrobial agent, such as a combination of rifampin and a tetracycline derivative (e.g. minocycline, doxycycline, and tigecycline, such combinations including rifampin and doxycycline, rifampin and tigecycline or, more particularly, rifampin and minocycline).
- For example, when the antimicrobial agent is a combination of rifampin and minocycline, the ratio of rifampin to minocycline is from 1:10 to 10:1 (wt/wt) (e.g. from 2:5 to 5:2(wt/wt)).
- When used herein “rifampicin” and “rifampin” are used interchangeably herein to refer to the active agent having CAS number 13292-46-1, or salts and/or solvates thereof.
- Examples of antifungal agents that may be mentioned herein include azoles (such as ketoconazole,clotrimazole, miconazole, econazole, itraconazole, fluconazole, bifoconazole, terconazole, butaconazole, tioconazole, oxiconazole, sulconazole, saperconazole, clotrimazole, voriconazole, clotrimazole), allylamines(such as terbinafine), morpholines(such as amorolfine and naftifine), griseofulvin, haloprogin, butenafine, tolnaftate, nystatin, cyclohexamide, ciclopirox, flucytosine, terbinafin, amphotericin B and pharmaceutically acceptable salts thereof.
- When used herein, the term “releasing agent” or “hydrophilic small molecules” may refer to natural or synthetic chemical compounds with a molecular weight of less than 2000 Daltons, which are able to dissolve or dislodge from a matrix when in contact with water or in physiological conditions. Examples of releasing agents that may be mentioned herein include sorbitol, xylitol, glycerin, mannitol, polyethylene glycol (PEG) having a number average molecular weight of from 200 to 2000 Daltons, polysorbate and urea or any molecule (e.g. one that has a molecular weight of less than 2000 Daltons) with a hydrophobic-lipophilic balance of greater than 6.
- When used herein, the term “polymer layer” may refer to a formulated composition which forms a solid or semi-solid film, with/without an antibiotic agent (as defined herein), with a controlled thickness. The combination of polymer layers may serve as a drug reservoir exhibiting drug control-release behaviour. In certain embodiments of the invention that may be mentioned herein, when an antibiotic agent is present in the polymeric layer, the polymeric material may comprise at least 1 wt % (e.g. at least 2 wt %, such as at least 5 wt %) of the polymer layer.
- When used herein “antibiotic layer” may refer to a defined layer of an antibiotic layer laid on the surface of a polymer layer and comprising at least one or more antibiotic materials, but which is substantially free of a polymeric material (i.e. there may be less than 0.5 wt % of a polymeric material as a minor impurity in said layer), or more particularly, there is an absence of polymeric material in the antibiotic layer. For the avoidance of doubt, the antibiotic layer cannot be on a surface of a polymer layer that is directly in contact with the environment in a completed film, that is, each antibiotic layer is ultimately encapsulated between two polymer layers. This encapsulation may be direct (e.g. an antibiotic layer is sandwiched between two polymer layers) or indirect (e.g. where two antibiotic layers are laid on top of each other and encapsulated between two polymer layers, such that each antibiotic layer is in direct contact with one of the polymer layers). It will be appreciated that the antibiotic layers may be continuous or discontinuous, such that the antibiotic layer can be encapsulated within the polymer layers (e.g. the footprint of the antibiotic layer is adjusted so that it is smaller than the footprint of the polymer layers that encapsulate it). In addition, it will be appreciated that the antibiotic layer may take the form of a particulate layer on the surface of a polymeric substrate layer.
- While it is possible for the film of the current invention to provide beneficial effects as a single layer of film, particular embodiments of the invention relate to a film has at least two polymer layers. For example, the film may have from two to nine layers, such as from three to seven layers (e.g. from three to five layers), whether polymer layers only or a combination of polymer layers and antibiotic layers, provided that the antibiotic layers are not the outer layers of the film. In embodiments that may be mentioned herein, the film may have from two to nine polymer layers, such as from three to seven polymer layers (e.g. from three to five polymer layers).
- When used herein, the terms “bioresorbable polymer” and “biodegradable polymer” refers to a material that can be at least partially broken down or, more particularly, fully degraded by contact with a bodily fluid, with the breakdown products being either eliminated from the body as waste or used by the body in further metabolic processes (e.g. anabolic processes).
- Examples of bioresorbable polymers include poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, poly(lactide-co-caprolactone) (PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), poly(trimethylene carbonate) (PTMC), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), poly(phosphazene), poly(phosphate ester), poly(amino acid), polydepsipeptides, poly(butylene succinate) (PBS), polyethylene oxide, polypropylene fumarate, polyiminocarbonates, poly(D,L-lactic acid), polyglycolic acid, poly(L-lactide-co-D,L-lactide), poly(L-lactide-co-glycolide) (PLG L), poly(D,L-lactide-co-glycolide), poly(gycolide-trimethylene carbonate), poly(glycolide-co-caprolactone) (PGCL), poly(ethyl glutamate-co-glutamic acid), poly(tert-butyloxy-carbonylmethyl glutamate), poly(glycerol sebacate), tyrosine-derived polycarbonate, poly 1,3-bis-(p-carboxyphenoxy) hexane-co-sebacic acid, polyphosphazene, ethyl glycinate polyphosphazene, polycaprolactone co-butylacrylate, a copolymer of polyhydroxybutyrate, a copolymer of maleic anhydride, a copolymer of poly(trimethylene carbonate), polyethylene glycol, hydroxypropylmethylcellulose and cellulose derivatives, polysaccharides, such as hyaluronic acid, chitosan, starch, proteins such as gelatin, collagen or PEG derivatives and combinations thereof.
- Particular bioresorbable polymers that may be mentioned include poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly, polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), polydioxanone (PDO), poly(4-hydroxy butyrate) (PHB), polyhydroxyalkanoates (PHA), PEG and its derivatives, and their copolymers (e.g. selected from one or more of the group consisting of poly(DL-lactide-co-caprolactone) (DL-PLCL), polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and their copolymers) . Further polymers that may be mentioned herein include, poly(ester-urethane)s, poly(diol citrates), poly(4-hydroxybutyrate)s, poly(glycerol sebacate), and star-poly(c-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) and other biodegradable elastomer prepared through synthesis of di-, tri-, or multi-polymers, architecturally arranged in block, star, or linear structures, and prepared as thermoplastics or thermosets, their co-polymers, and mixtures or blends. Particular polymers that may be mentioned herein include DL-PLCL, PGCL and PLCL, their copolymers, and mixtures or blends thereof.
- When used herein, the term “elastic polymer” refers to a material that can resist a distorting influence or stress and can return to towards its original size and shape when the stress is removed. For example, the elastic polymer may be stretched up to 10 times its original size in any direction (e.g. from 1.1 times to 4 times its original size) and may then recover at least to 80%, such as at least 90% of its original size following release of the stretch. For example, when stretching a film to size B (a difference of size C) from size A results in the film returning to a maximum size of B−(0.8×C) following stretching and release, where C is B−A, such as a maximum size of B−(0.9×C). That is, if one stretches a film from 0.1 cm to 0.11 cm (difference of 0.01 cm), the resulting film will have maximum size of 0.11−(0.8×0.01)=0.102 cm if the film recovers at least to 80% of its original size or will have a maximum size of 0.101 cm if the film recovers to at least 90% of its original size following stretching. It will be appreciated that the film may recover to its original size or almost to its original size.
- The antibiotic film can be prepared as a single polymer, a polymer blend or copolymer, with one or more layers. In particular embodiments of the film or socket made therefrom:
-
- (a) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be a blend of PCL and PLA (e.g. a ratio blend of PCL and PLA having a wt:wt ratio of 1:9 to 9:1), or a blend of PCL and PGA (e.g. a ratio blend of PCL and PGA having a wt:wt ratio of 1:9 to 9:1); or
- (b) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be PCL, or a copolymer of poly(DL-lactide/caprolactone), such as DL-PLCL (e.g. having a DL-PLA to PCL ratio of from 1:9 to 9:1) , or a copolymer of poly(lactide/caprolactone) such as PLCL (e.g. having a PLA to PCL ratio of from 1:9 to 9:1), or a copolymer of poly(glycolide/caprolactone) such as PGCL (e.g. having a PCL to PGA ratio of from 1:9 to 9:1), ; or
- (c) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be poly(DL-lactide-co-caprolactone) (DL-PLCL), or more particularly a blend of PCL and PLA (e.g. a ratio blend of PCL and PLA having a wt:wt ratio of 1:9 to 9:1), poly(ester-urethane)s, poly(diol citrates), and poly(4-hydroxybutyrate)s, poly(glycerol sebacate), star-poly(ε-caprolactone-co-D,L-lactide), poly(lactide-co-caprolactone) (PLCL), poly(glycolide-co-caprolactone) (PGCL) or other biodegradable elastomer; or
- (d) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be one or more copolymers (such as selected from one or more of the group consisting of polycaprolactone (PCL), polyglycolide (PGA), poly(L-lactic acid) (PLA), PEG and its derivatives and their copolymers)), such as a copolymer of poly (glycolide/caprolactone) or poly (lactide/caprolactone) (e.g. having a PLA to PCL ratio of from 9:1 to 6:4) or its derivatives and copolymers thereof; or
- (e) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers may be a blend of PLCL and PCL (e.g. a ratio blend of PLCL and PCL having a wt:wt ratio of 1:9 to 9:1).
- Further polymeric elastomeric materials that may be mentioned herein include:
-
- a) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers is poly(lactide-co-caprolactone) (PLCL) (e.g. having a PLA to PCL ratio of from 90:10 to 60:40) or its derivatives and copolymers thereof; and/or
- b) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers is poly(DL-lactide-co-caprolactone) (DL-PLCL) (e.g. having a DL-PLA to PCL ratio of from 90:10 to 50:50) or its derivatives and copolymers thereof; and/or
- c) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers is poly(glycolide-co-caprolactone) (PGCL) (e.g. having a PGA to PCL ratio of from 90:10 to 10:90) or its derivatives and copolymers thereof; and/or
- d) the bioresorbable elastomeric polymeric material of one of the at least one polymer layers is a blend of PLCL or DL-PLCL or PGCL with a releasing agent selected from one or more of the group selected from
polysorbate 20,polysorbate 40,polysorbate 60,polysorbate 80, or polyethyleneglycol having a molecular weight of 200 to 2000 Daltons in a wt:wt ratio of PLCL or DL-PLCL or PGCL to releasing agent of from 25:1 to 1:9.
- Particular polymers that may be mentioned herein include PLCL, DL-PLCL and PGCL.
- It will be appreciated, that the polymer layers described above may be combined to form a single multilayer film. This film may only have polymer layers, or may also have antibiotic layers interspersed between the polymer layers, provided that the antibiotic layers are ultimately encapsulated between two polymer layers.
- In particular embodiments of the invention as disclosed herein, the number average molecular weight of the polymer may be greater than or equal to 5,000 Daltons, such as greater than 5000 Daltons (e.g. from 5,000 to 500,000 Daltons).
- The antibiotic film include may include a releasing agent in at least one layer of the film or the film that comprises a component part of the socket. The releasing agent may be present in at least one of the at least one layers of the film, whether the layer is a polymer layer or an antibiotic layer, or may be present in more than one of the layers that make up the film, up to the total number of layers in the film. It will be appreciated, that when present, the releasing agent may be a single releasing agent or may be more than one releasing agent. When there is more than one releasing agent (e.g. 2 to 10 releasing agents), the releasing agents may be mixed together to form a blend that may be applied to one or more of the layers of the film as described above. Alternatively, when there are at least two releasing agents (e.g. 3 to 9 releasing agents), each releasing agent may be applied to separate layers of the film, provided that more than two layers of the film are intended to contain a releasing agent. Yet further alternatively, when there are at least three releasing agents (e.g. 4 to 10 releasing agents), at least two blends (e.g. 3 to 9 blends) of releasing agents may be prepared and each blend may be applied to separate layers of the film, provided that more than two layers of the film are intended to contain a releasing agent. When present in a layer, the releasing agent may be present in an amount from 0.1 wt % to 50 wt % of said layer.
- The antibiotic film includes at least one antibiotic agent which is distributed in at least one layer of polymer. The antibiotic agent may be distributed within one or more polymer layers of the antibiotic film (e.g. heterogeneously or, more particularly homogeneously distributed). Therefore, while not necessary, in particular embodiments of the current invention the at least one antibiotic agent is miscible with the bioresorbable polymer of each polymer layer in which it is present. For example:
-
- (i) when the film has at least two polymer layers, the at least one antibiotic agent is distributed within at least two of the polymer layers; and/or
- (ii) when the film has at least two polymer layers, the at least one antibiotic agent forms a separate layer sandwiched between the two polymer layers; and/or
- (ii) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least three antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a first antibiotic agent layer is sandwiched between two layers of a second antibiotic agent or between a layer of a second antibiotic agent and layer of a third antibiotic agent; and/or
- (iii) when the film has at least two polymer layers and the at least one antibiotic agent is present as at least two antibiotic layers, the antibiotic layers are sandwiched between the polymer layers and a first antibiotic agent layer is sandwiched between a polymer layer and a second antibiotic layer.
- In at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 99 wt %, such as from 0.1 wt % to 95 wt % of said polymer layer (e.g. from 0.1 wt % to 90 wt % or from 0.1 wt % to 80 wt %, such as from 0.1 wt % to 60 wt %), for example, in at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 30 wt % of said polymer layer, optionally wherein said polymer layer is solvent cast and/or in the at least one layer of the polymer film, the at least one antibiotic agent may be present in an amount of from 10 wt % to 95 wt % (e.g. from 10 wt % to 60 wt %, or from 30 wt % to 95 wt %, such as from 40 wt % to 80 wt %) of said polymer layer, optionally wherein said polymer layer was spray coated onto a substrate.
- The antibiotic film can be formed as a single layer film or a multilayer film composite. The composite consists of at least one type of biodegradable polymer and at least one antibiotic agent. Each polymer layer can be formed from one biodegradable polymer or polymer blends. For example, the outer layer of biodegradable polymer film incorporated with or without an agent to encourage tissue growth on the surface, such as collagen, a middle layer of biodegradable polymer incorporated with an antibiotic agent, and a third layer of biodegradable polymer, with no active agent. Another multilayer film composite can be a layer of biodegradable polymer with or without a growth factor agent, three layers of a biodegradable polymer composite comprising an antibiotic agent, and followed by a layer of biodegradable polymer film with or without a growth factor agent. The antibiotic agents in the three layers can be the same or different in content and concentration distribution.
- Further examples of the antibiotic film include:
-
- (a) a film having a single polymer layer and contains at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (b) a film having three polymer layers, with the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (c) a film having three polymer layers, with the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline or rifampicin) and the outer layers containing a further antibiotic (e.g. the further antibiotic is minocycline or rifampicin, provided that when the at least one antibiotic of the middle layer is minocycline, the further antibiotic of the outer layers is rifampicin and vice versa);
- (d) a film having five polymer layers, with the middle layer containing at least one antibiotic (e.g. the at least one antibiotic is minocycline or rifampicin) and the layers immediately on top and bottom of the middle layer containing a further antibiotic (e.g. the further antibiotic is minocycline or rifampicin, provided that when the at least one antibiotic of the middle layer is minocycline, the further antibiotic of the outer layers is rifampicin and vice versa);
- (e) a film having five polymer layers, where the layers immediately on top and bottom of the middle layer contain an antibiotic (e.g. the further antibiotic is minocycline and/or rifampicin;
- (f) a film having four polymer layers, with the middle two layers containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin);
- (g) a film having two polymer layers, with the two layers each containing at least one antibiotic (e.g. the at least one antibiotic is minocycline and/or rifampicin).
- Yet further examples are provided as embodiments (i) to (xxv) in the summary of invention section hereinabove and are omitted in full here for brevity. It will be noted from these examples that while the layering design may be symmetrical, it does not need to be. That is, the layering design may be asymmetrical in nature and an example of this is provided as example (xxv) in the summary of invention section hereinabove.
- In at least one layer of the antibiotic polymer film and sockets made therefreom, the at least one antibiotic agent is present in an amount of from 0.1 wt % to 99 wt %, such as from 0.1 wt % to 95 wt % of said polymer layer (e.g. from 0.1 wt % to 90 wt % or from 0.1 wt % to 80 wt %, from 0.1 wt % to 60 wt %, such as from 0.1 wt % to 30 wt % or from 10 wt % to 60 wt %). The actual amount present within each polymer layer may vary depending on the way that the layer of film was prepared. For example, when the polymer layer is solvent cast the at least one antibiotic agent may be present in an amount of from 0.1 wt % to 30 wt % of said polymer layer, and when the polymer layer was formed by spray coating it onto a substrate, the at least one antibiotic agent may be present in an amount of from 10 wt % to 95 wt % (e.g. from 10 wt % to 60 wt %, or from 30 wt % to 95 wt %, such as from 40 wt % to 80 wt %).
- As noted hereinbefore, the film and sockets made therefrom, may contain one or more layers of the one or more antibiotic agent that are ultimately encapsulated between two polymer layers. In such separate antibiotic layers, the at least one antibiotic agent may be present in an amount of from 10 wt % to 100 wt % of said layer. Said layer may further comprise releasing agent or other pharmaceutically acceptable adjuvants, diluents or disperants.
- The at least one antibiotic agent may make up from 0.001 wt % to 30 wt %, or more particularly 0.001 wt % to 20 wt %, such as 0.001 wt % to 20 wt % (e.g. from 0.01 wt % to 5 wt %, or from 0.5 wt % to 5 wt %) of the weight of the entire film (i.e. all layers of the film).
- It will be appreciated that for the film/socket to prove effective, it has to release the one or more antibiotic agents over an extended period of time in a controlled manner. For example, the at least one antibiotic agent is released from the antibiotic film over a period of from 1 to 30 days following implantation or, more particularly, over a period of from 3 to 14 days following implantation.
- Particular films and sockets made therefrom that may be mentioned herein include an antibiotic film/socket where more than 10 wt % of the at least one antibiotic agent is released within 24 hours of implantation, with the entirety of the at least one antibiotic agent being released from the antibiotic film over a period of from 3 to 14 days following implantation.
- It will be appreciated that the antibiotic films and the sockets made therefrom of the current invention can be used in medicine. For example, the antibiotic films mentioned herein can be used in treating or preventing infection and associated diseases and disorders. In addition, the films mentioned herein may be used in:
-
- (a) the manufacture of a medicament for use in the treatment or prevention of infection and associated diseases and disorders; and
- (b) a method of treatment comprising the step of applying the controlled-release antibiotic film to a subject to treat or prevent infection and associated diseases and disorders.
- The antibiotic films and sockets made therefrom mentioned herein may be used to cover at least part of the surface of a medical device that is then implanted into a subject, as described in more detail below.
- As mentioned hereinbefore, the films and the sockets made therefrom may be applied to an implantable medical device, where the resulting device comprises a medical device and an antibiotic film in the form of a socket as described herein, wherein the socket covers a part or the whole of the medical device and is suitable for reducing or preventing migration of the medical device within the body following implantation. For example, the sockets made from the film may be provided in the shape of an envelope, pouch, pocket, sleeve or band to surround part or whole of the medical device. The device may further comprise an additional active agent (e.g. a growth factor) coated onto whole or part of an exposed surface of the film. An embodiment of the device is described below in relation to
FIG. 1 . - The term “implantable medical device”, when used herein refers to a medical device that can be implanted transdermally, or to any indwelling medical device that includes a transdermal component. Examples of an implantable medical device that may be mentioned herein include arteriovenous shunts, left ventricular assist devices, cardiovascular implantable electronic devices (CIEDs), tissue expanders, gastric lap bands, spinal cord stimulators, intrathecal infusion pumps, deep brain stimulators, gastric electrical stimulators, sacral nerve stimulators, and vagus nerve stimulators, amongst others.
-
FIG. 1 is a schematic illustration of an antibiotic film shaped into an article substrate that can be coupled to an implantable medical device for implantation into a site of subject's body. The article may be used to secure an implantable device at the desired site within the subject's body, by helping to anchor the device into the surrounding tissue or part of the tissue. The article is also able to inhibit bacterial growth due to the presence of the antibiotic agent within the film. - In
FIG. 1 , thesocket 100 according to the current invention, comprising a controlled-release antimicrobial film 110 as hereinbefore defined, has twoopenings openings 120/130 are smaller than the object to be inserted into and held by the socket. The socket may also, as illustrated, contain a plurality ofholes 140 in thefilm 110. As depicted, the socket is made from a single film and so only requires a single side-seal 150 and may also comprisecurved seal corners 160. It will be appreciated that the socket may be manufactured using more than one film, which may then result in additional side-seals being required. As shown inFIG. 1 , theopenings 120/130 may be of the same size. However, it is specifically contemplated that the openings may also be of different sizes. In certain embodiments, the holes may be from 0.1 mm to 5 mm (e.g. from 0.3 mm to 2 mm or from 0.3 mm to 1 mm). As shown inFIG. 1 , the holes may have a uniform shape and size (e.g. all are circular in shape of the same size). However, it is specifically contemplated that the holes may be irregular in shape (each hole being of an undefined shape) or be of any shape (e.g. random defined shapes) and that the size of the holes may not be uniform. The holes may be focused in the middle (avoiding seals and openings) as shown inFIGS. 2 and 3 , or evenly distributed throughout the band or nearer to the seals and openings as shown inFIG. 1 . According to certain embodiments of the invention, the sleeve may be formed by sealing at one end, as shown inFIG. 1 , or sealed at multiple ends. The corner seals may be curved, as shown inFIG. 1 , angled or squared. - In
FIG. 2 , thesocket 200 according to the current invention is made from a controlled-release antimicrobial film 210 (i.e. any film as defined hereinbefore), with twoopenings side seals 250 and angled sealedcorners 260. It will be appreciated that the socket is smaller than the object to be inserted therein (i.e. a CIED) and may be capable of housing a range of different sizes of CIED. As shown inFIG. 2 , the openings may be of different sizes; however it is specifically contemplated that the openings may also be of the same size. In certain embodiments, the holes may be from 0.1 mm to 5 mm (e.g. from 0.3 mm to 2 mm). The socket ofFIG. 2 may be formed by sealing two films together at two ends, as shown inFIG. 2 to form a sleeve or band-like structure. According to further embodiments of the invention, the corner seals may be angled, as shown inFIG. 2 , or curved or squared. It is also contemplated that the corner seals may be angled in any technically suitable manner. - In
FIG. 3 , there is provided a socket in the form of apocket 300 according to the current invention, comprising a controlled-release antimicrobial film 310 (i.e. any film described hereinbefore), with oneopening 320, a plurality of holes (e.g. one or more holes) 330, a three-side seal 340, curved sealedcorners 350 and angled sealedcorners 360. As shown inFIG. 3 , the pocket may be formed by sealing at least two films together at three ends, leaving a single end open to act as an opening. It will be appreciated that all of the ends may be sealed together and a new opening created by cutting an opening of suitable dimensions into the sealed film (this may apply using a single film as well as more than two films). - When used herein, the term “article” may refer to the overall medical device unit, that is the film and implantable medical device, or it may refer to the film shaped as a socket (i.e. a mesh, pouch, bag, envelope, sleeve, band, pocket or receptacle (all of which may be with or without holes)), that can fully or partially cover an implantable medical device.
- As noted above, the socket (e.g. 300 of
FIG. 3 ) may be in the form of an envelope with anopening 320 to allow insertion of an implantable device into the film and to permit insertion of accessories, such as leads or wires. The surface of thearticle 300 may also containholes 330 within thefilm 310, with all possible shapes and dimensions to reduce mass of pouch and to enhance the release of the active agent into the surrounding tissue efficiently. It will be appreciated that this is generically applicable to other forms of sockets described or contemplated herein. The size, shape and weight of the article can vary according to the implantation requirement. Alternatively, the film may be cut into strips an applied piece-meal so as to cover whole or part of the medical device. In such examples, the film may be applied by any method of bonding, such as by the use of an adhesive, heat bonding or adhesion caused by the nature of the film itself (e.g. in the manner of attaching a plastic paraffin film to an object). - The sockets of
FIGS. 1-3 , are configured to (1) reduce device migration or erosion; (2) securely hold the implanted medical device within the article to reduce the risk of it falling out; (3) securely hold various sizes of medical device to reduce the risk of it falling out; (4) eliminate direct contact between the implanted medical device and the tissue layer; and (5) release antibiotic agent within a desired period at the required eluting rate. This is achieved by the properties of the socket and the antibiotic film(s) that form the socket of the current invention. - The antibiotic article is a versatile platform, which can be capable of different functions. For example, the controlled release of the antibiotic agent is sufficient to prevent or reduce bacteria colonization on the surface of the implantable medical device. In addition, the device can also be incorporated with other functions, such as the enhancement of tissue attachment on the outer surface of the envelope by coating the surface of the film in direct contact with body tissue with one or more growth factors.
- It will be appreciated that the article can be designed to have any shape and size according to the needs of the medical device to be implanted.
- The film of the article described in
FIG. 1 can be formed by at least one layer or several layers of biodegradable polymer film. At least one of said polymers layers contains an antibiotic agent. However, different layers may have different functions, such as a drug incorporation layer, a drug release control layer, a layer to promote tissue-ingrowth after implantation etc. -
FIG. 4 provides various multilayer films according to aspects of the invention. The single layer to multiple layer films may have a total thickness of the film is from 1 μm to 2000 μm (e.g. from 10 μm to 500 μm, such as from 40 μm to 300 μm). In general, for a multilayer film (or a single layer film), the thickness of each layer of the polymer film may be from 0.01 μm to 1000 μm (e.g. from 0.01 μm to 200 μm). - The multilayer designs of various embodiments of the invention are depicted in
FIGS. 4A-4G . The design shown inFIG. 4A (also referred to herein as “design 4-1” shows a 3-layer film, in which the middle layer may be a piece of drug-containing biodegradable polymer film with at least one ormore drugs 1, the outer twolayers 2 may be biodegradable polymer films further comprising a releasing agent blend, but without any active agent which can be formed by the same or different polymer materials. The design shown inFIG. 4B (also referred to herein as “design 4-2”) depicts a 3-layer film, in which the middle layer is a piece of drug-containing biodegradable polymer film with at least one ormore drugs 3, the surface of this film (3) is coated with a layer of drug-containing biodegradable polymer layers with one ormore drugs 4. The design shown inFIG. 4C (also referred to herein as “design 4-3”) depicts a 5-layer film, in which the middle three layers are similar to design 4-2, with the outer two surface layers being biodegradable polymer layers that may contain a releasing agent and are with/withoutdrug 5. The design shown inFIG. 4D (also referred to herein as “design 4-4”) shows a 4-layer film, in which the middle twolayers 6 contain a drug, with the films in theouter surfaces 5 are biodegradable polymer layers that may contain a releasing agent and are with/without drug. The design shown inFIG. 4E (also referred to herein as “design 4-5”) shows a 2-layer film, in which both layers are with one or twodrugs 7. The design shown inFIG. 4F (also referred to herein as “design 4-6”) shows a 5-layer film, in which the middle layer may be a piece of biodegradable elastic polymer film without any active agent or releasingagent 8, the surface of this film (8) is coated with a layer of drug-containing biodegradable polymer layers with one ormore drugs 4, and the two outer surface layers are a blend of polymer and releasing agent that may or may not contain adrug 9. The design shown inFIG. 4G (also referred to herein as “design 4-7”) shows a 7-layer film in which the middle layer may be a piece of biodegradable elastic polymer film without any active agent or releasingagent 8, the surface of this film (8) is coated with a layer of drug-containing biodegradable polymer layers with one ormore drugs 4, the two layers immediately after is a blend of polymer with or without releasingagent 10, and the outer surface layer is a blend of polymer and releasing agent that may or may not contain adrug 9. - These films may be prepared by making each layer separately and stacking these individual film layers together through heat-melting, heat-compression, chemical grafting, electrostatic adsorption, chemical crosslinking etc. Alternatively or additionally, a film layer may also be used as a substrate and be spray- or dip-coated on one or both surfaces to form a further polymer layer (or layers). The preferred film preparation methods are film casting, spray coating and heat compression.
- The various embodiments described above are not intended to be limiting and the principles provided can be used to generate, further designs having different drug or polymer compositions and/or different film properties that do not departs from the spirit and scope of the current invention (e.g. that do not depart from the scope of the currently claimed invention). Designs that may be mentioned herein include those where the film comprises at least 2-layers. The main purpose of the invention is to be able to control the drug release profile of one or more active agents independently in a drug-polymer matrix for different drugs. As different active agents have different potencies and different hydrophilicity, it is rather challenging to control the drug release profile by using one polymer formulation for each drug. The designs shown in
FIG. 4 enable one to control the drug release profile of different active agents separately to achieve a desired drug release profile for both agents. - The antibiotic article can be tailored to different shapes and dimension to partially cover or fully wrap an implantable medical device. The thickness of each layer ranges from 0.01 μm to 1000 μm (e.g. from 0.01 μm to 200 μm).
- The antibiotic article is bioabsorable, which can provide a temporary anchorage for implantable medical device and gradually be absorbed/excreted by the body to provide comfort to patient. The article eliminates direct contact between the implanted medical device and tissue layer and may reduce the implanted device's migration or erosion. The article is fully resorbable with good mechanical strength.
- The growth of tissue on the surface of the antibiotic article can be controlled by incorporating a layer of growth factor on the surface according to surgeons' needs.
- The sockets and/or films of the current invention provide the following advantages:
-
- (1) the elastic socket can hold the device tightly to prevent medical device from dropping-off when implanted—especially when used to fit various sizes of CIED;
- (2) the socket can secularly hold a medical device and prevent or reduce migration of device during implantation;
- (3) drug release control can be tuned independently according to desired drug release profile for each drug within the film—a particular challenge when there is more than one antibiotic agent to be released;
- (4) the antibiotic agents are distributed throughout the polymer layers to which they form an integral part, making the antibiotic agent more stable and reducing fragility problems associated with coating a layer of drug onto a polymer surface;
- (5) the burst phase of the antibiotic agent(s) are easier to control using the film technology of the current invention, allowing more consistent control of the delivery of the antibiotic agents initially and in the subsequent controlled release phase.
- General Preparation
- To illustrate the kinetics of drug release, a sample of the film was cut into a 2 cm×2 cm size, which was immersed in a vial containing 4 mL of PBS buffer (as the elution medium) for continuous drug elution testing. The vial was placed in a 37° C. incubator shaker. At periodic intervals, the elution medium was withdrawn for reverse phase HPLC analysis to determine the eluted amount of rifampicin and minocycline and replaced with fresh PBS solution (4 mL). The cumulative drug release was calculated and plotted (see
FIGS. 4-6 ). - Table 1 and
FIG. 4 list a series of designs that were used in the examples. The table lists a number of polymers that can be used to generate compositions according to the current invention (whether alone or in combination), as well as antibiotics. It will be understood that alternative polymers and antibiotics may be used. -
TABLE 1 Film matrix with rifampin (R) and minocycline (M) Film code Design Polymer Antibiotics 1-1 4-1 PLCL, PLA, PLGA M 1-2 4-1 PLCL, PLA, PLGA R 1-3 4-2 PLCL, PLA, PLGA M 1-4 4-2 PLCL, PLA, PLGA R 1-5 4-3 PLCL, PLA, PLGA M 1-6 4-3 PLCL, PLA, PLGA R 1-7 4-4 PLCL, PLA, PLGA M 1-8 4-4 PLCL, PLA, PLGA R 1-9 4-5 PLCL, PLA, PLGA M 1-10 4-5 PLCL, PLA, PLGA R 1-11 4-6 PLCL, PLA, PLGA M 1-12 4-6 PLCL, PLA, PLGA R 1-13 4-7 PLCL, PLA, PLGA M 1-14 4-7 PLCL, PLA, PLGA R 1-15 Single Layer, PLCL M with releasing agent 1-16 Single Layer, PLCL R with releasing agent 1-17 Single Layer, PLCL M without releasing agent 1-18 Single Layer, PLCL R without releasing agent - 1-A Film Casting for Drug-Resorable Film
- 1.8 g PLCL resin, 700 mg of sorbitol and 160 mg of minocycline (film code 1-1; rifampicin for film code 1-2) were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- 1-B Film Casting for Control Layer Film
- Similarly, 1.8 g PLCL resin and 50 mg sorbitol were dissolved in 10 mL of acetone. A homogeneous solution was poured onto a glass plate and drawn by a film applicator to form a film following evaporation of the solvent. The film was then removed from the glass plate.
- 1-C Films Compression
- A composition according to design 4-1 was prepared using two films according to 1-B sandwiching a film according to 1-A. The resulting stack of films were aligned and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- 2-A Film Casting for Drug-Biodegradable Film
- 1.8 g PLCL/PLC resin (2:8 weight ratio) and 160 mg of minocycline (film code 1-3; rifampicin for film code 1-4) were dissolved in 10 mL acetone/ethanol solvent mixture having a ratio of 5:5 v/v. The film casting procedure was the same as described in Example 1-A.
- 2-B Spray Coating of Drug-PLGA Mixture
- Similarly, 180 mg PLGA resin and 20 mg of minocycline (film code 1-3; rifampicin for film code 1-4) were dissolved in 10 mL acetone/ethanol solvent mixture having the ratio of 5:5 v/v. The mixture was spray coated onto the film prepared in 2-A, using 2 mL of the prepared solution, by repeatedly passing the spray nozzle over both sides of film 2A with the same number of passes.
- The middle three layers were prepared by following procedure in Example 2. The two outer layers were prepared by following Example 1-B. The stack of 5 layers of films were aligned properly and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- The outer two layers were prepared by following Example 1-B. The two middle drug-polymer layers were prepared by following Example 2-B. The resulting films were aligned properly and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- The two layers were prepared by following Example 1-A and 2-A. Film compression procedure is the same as 1-C.
- 6-A Film Compression for Elastic Biodegradable Polymer Film
- PLCL resin was heat compressed at 150° C., 60 Mpa for 1 minute.
- 6-B Spray Coating of Drug-PLGA Mixture
- 180 mg PLGA resin and 20 mg of minocycline (film code 1-11; rifampicin for film code 1-12) were dissolved in 10 mL acetone/ethanol solvent mixture having the ratio of 5:5 v/v. The mixture was spray coated onto the film prepared in 6-A, using 2 mL of the prepared solution, by repeatedly passing the spray nozzle over both sides of film 6A with the same number of passes.
- 6-C Film Casting for Blend of Small Molecules Drug Film
- 1.8 g PLCL resin, 250 mg of polysorbate and 160 mg of minocycline(film code 1-1; rifampicin for film code 1-2) were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- 6-D Films Compression
- A composition according to design 4-6 was prepared using two films according to 6-C sandwiching a film 6-A coated according to 6-B. The resulting stack of films were aligned and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- 7-A Film Casting for Blend of Small Molecule Control Film
- 1.8 g PLCL resin and 50 mg of polysorbate were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- 7-B Films Compression
- A composition according to design 4-7 was prepared using two films according to 7-A sandwiching a film 6-A coated according to 6-B. The stack is further sandwiched between two films according to 6-C. The resulting stack of films were aligned and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds.
- Film preparation procedure is the same as Example 1-A to prepare a single layer.
- 9-A Film Casting for Drug-Resorbable Film
- 0.5 g PLCL resin and 160 mg of minocycline(film code 1-1; rifampicin for film code 1-2) were dissolved in 10 mL acetone/ethanol solvent mixture of the ratio of 5:5 v/v. The mixture was mixed evenly for more than 4 hours. After the mixing, the solution was homogeneous and 5 mL of the solution was then poured onto a glass plate and drawn by a film applicator to form a film upon drying. The film was removed from the glass plate after the film was completely dry, following evaporation of the solvent.
- The film was prepared by following the protocol in Example 3. The middle layer was prepared by using a drug mixture of 120 mg minocycline and 160 mg rifampin. The two intermittent layers were prepared by spray coating of minocycline by following Example 2-B. The outer two layers were prepared by following Example 1-B. The stack of 5 layers of films were aligned properly and compressed by a heat compressor at 60° C., 6 MPa for 50 seconds. The cumulative releasing profiles of two antibiotics are shown in
FIG. 6 . -
FIGS. 5A-5B show the cumulative release of two antibiotics from different layered film designs and single films prepared in Examples 1 to 9 (film codes 1-1 to 1-18). The drug density of both antibiotics is between 0.05 mg to 0.1 mg/cm2. As shown inFIGS. 5A-B , for single drug film, the absence of releasing agent results in a film with very slow release, while the presence of releasing agent gives a high initial burst with a fast releasing profile. Because minocycline is more hydrophilic than rifampin, minocycline releases much faster. For the layered film designs, the release profile and initial burst rate of rifampin and minocycline are tuned and well-controlled through the different designs. - This result shows that by knowing the releasing behaviour of each drug in the different designs, the releasing profile of a drug mixture can be tuned to provide a desired releasing profile. This can be clearly seen from
FIG. 6 , which shows a significant improvement from literature data where rifampin always has a lower initial burst and slower releasing profile than the other hydrophilic counterpart (in this case minocycline). - The zone-of-inhibition (ZOI) for the film was determined according to the Kirby-Bauer method. The study chose to test Escherisia coli (E. coli) and S. aureus, S. epidermidisas demonstration. E. coli has the highest minimum inhibitory concentration (MIC) among the other bacteria that are commonly found in humans. The MIC of E. coli is 20 times higher than S. aureus, S. epidermidis, MRSA, S. capitis etc.
- E. coli were inoculated into Lysogeny broth (LB broth) from a stock solution and incubated at 37° C. and then evenly spread over the entirety of an agar plate by a disposable spreader. A 15 mm diameter film was firmly pressed into the center of an agar plate and incubated at 37° C. Pieces were transferred to other fresh agar plates using sterile forceps every 24 hr. The diameter of the ZOI was measured and recorded every day.
-
TABLE 2 ZOI of layer-by-layer composite film with minocycline and rifampicin. E. Coli S. epidermidis S. aureus Day 1/mm 30.0 47.3 37.3 Day 2/mm25.8 41.0 37.0 Day 3/mm23.8 39.0 36.3 Day 4/mm21.5 42.0 33.3 Day 5/mm18.3 34.0 31.3 Day 6/mm16.4 34.0 27.5 Day 7/mm15.8 33.8 26.8 Day 8/mmNo Zone 32.4 26.3 Day 9/mm31.0 26.8 Day 10/mm29.9 25.8 Day 11/mm 28.7 25.0 Day 12/mm 26.5 24.5 Day 13/mm 25.0 21.0 Day 14/mm 23.9 20.3 - The elasticity and fit of the socket was tested using different socket sizes and CIED sizes. A good fit is when the CIED could be easily inserted into the socket, and does not fall out when overturned and held by the socket.
-
Socket CIED Size* Stretch Width Seal to Seal Width Width Depth for Insertion length after (mm) (mm) (mm) (mm) Insertion Fit 50 43 8 80 51 Yes 50 48 7.5 80 55.5 Yes 50 53 7.5 85 60.5 Yes 50 58 7.5 85 65.5 Yes 60 51 15 85 66 Yes 60 60 15 90 75 Yes 60 75 9.9 90 84.9 Yes *A CIED size is an addition of the width and depth, taking into consideration the volume of space it occupies. As such, the width of the socket is smaller than the size of the CIED (width and depth).
Claims (49)
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US16/366,323 US20190351108A1 (en) | 2015-03-31 | 2019-03-27 | Multi-layered polymer film for sustained release of agents |
US17/305,851 US11964076B2 (en) | 2015-03-31 | 2021-07-15 | Multi-layered polymer film for sustained release of agents |
US18/609,954 US20240226394A1 (en) | 2015-03-31 | 2024-03-19 | Multi-layered polymer film for sustained release of agents |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB1505527.0 | 2015-03-31 | ||
GBGB1505527.0A GB201505527D0 (en) | 2015-03-31 | 2015-03-31 | Composition |
PCT/SG2016/050158 WO2016159885A1 (en) | 2015-03-31 | 2016-03-31 | Elastic antimicrobial film and socket made therefrom |
US201715563527A | 2017-09-29 | 2017-09-29 | |
US16/366,323 US20190351108A1 (en) | 2015-03-31 | 2019-03-27 | Multi-layered polymer film for sustained release of agents |
Related Parent Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/563,527 Continuation US20180193537A1 (en) | 2015-03-31 | 2016-03-31 | Elastic antimicrobial film and socket made therefrom |
PCT/SG2016/050158 Continuation WO2016159885A1 (en) | 2015-03-31 | 2016-03-31 | Elastic antimicrobial film and socket made therefrom |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/305,851 Continuation US11964076B2 (en) | 2015-03-31 | 2021-07-15 | Multi-layered polymer film for sustained release of agents |
Publications (1)
Publication Number | Publication Date |
---|---|
US20190351108A1 true US20190351108A1 (en) | 2019-11-21 |
Family
ID=53178424
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/563,527 Abandoned US20180193537A1 (en) | 2015-03-31 | 2016-03-31 | Elastic antimicrobial film and socket made therefrom |
US16/366,323 Abandoned US20190351108A1 (en) | 2015-03-31 | 2019-03-27 | Multi-layered polymer film for sustained release of agents |
US17/305,851 Active 2036-08-23 US11964076B2 (en) | 2015-03-31 | 2021-07-15 | Multi-layered polymer film for sustained release of agents |
US18/609,954 Pending US20240226394A1 (en) | 2015-03-31 | 2024-03-19 | Multi-layered polymer film for sustained release of agents |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US15/563,527 Abandoned US20180193537A1 (en) | 2015-03-31 | 2016-03-31 | Elastic antimicrobial film and socket made therefrom |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US17/305,851 Active 2036-08-23 US11964076B2 (en) | 2015-03-31 | 2021-07-15 | Multi-layered polymer film for sustained release of agents |
US18/609,954 Pending US20240226394A1 (en) | 2015-03-31 | 2024-03-19 | Multi-layered polymer film for sustained release of agents |
Country Status (6)
Country | Link |
---|---|
US (4) | US20180193537A1 (en) |
EP (3) | EP3277330A4 (en) |
JP (3) | JP6824188B2 (en) |
CN (2) | CN107921180A (en) |
GB (1) | GB201505527D0 (en) |
WO (1) | WO2016159885A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11202754B2 (en) | 2017-10-06 | 2021-12-21 | Foundry Therapeutics, Inc. | Implantable depots for the controlled release of therapeutic agents |
US11964076B2 (en) | 2015-03-31 | 2024-04-23 | Foundry Therapeutics, Inc. | Multi-layered polymer film for sustained release of agents |
Families Citing this family (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3323435A1 (en) * | 2016-11-17 | 2018-05-23 | Heiko Sorg | Active envelope silicone implant with drug space and multiphase mode of action for breast augmentation |
CN107574581B (en) * | 2017-08-03 | 2019-09-10 | 天津大学 | A kind of antibiotic property poly- (6-caprolactone)/simulation antibacterial peptide electrospun fiber membrane and preparation method thereof |
CA3099890A1 (en) * | 2018-05-12 | 2019-11-21 | Foundry Therapeutics, Inc. | Implantable polymer depots for the controlled release of therapeutic agents |
CN111150888B (en) | 2018-11-07 | 2022-03-15 | 财团法人工业技术研究院 | Double-effect film and preparation method thereof |
US11464889B2 (en) | 2018-11-29 | 2022-10-11 | Ethicon, Inc. | Antimicrobial-containing silicone lubricious coatings |
DE102019213178A1 (en) * | 2019-08-30 | 2021-03-04 | Resorba Medical Gmbh | Polymer film and polymer pouch for holding a medical-technical product to be implanted |
KR102352952B1 (en) * | 2021-03-29 | 2022-01-19 | (주) 일론 | An electrode pad frame for selectively fixing an active ingredient sheet, an apparatus including the same, and an active ingredient sheet used therein |
WO2022216259A1 (en) * | 2021-04-09 | 2022-10-13 | Bogazici Universitesi | An envelope for implantable cardiac pacemakers |
CN113398311B (en) * | 2021-05-25 | 2022-08-02 | 周建大 | Polymeric composite protective membrane loaded with nano antibacterial peptide, preparation method and application |
WO2023233223A1 (en) * | 2022-05-31 | 2023-12-07 | Medtronic, Inc. | Cardiac monitor device |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110137243A1 (en) * | 2007-09-06 | 2011-06-09 | Abbott Cardiovascular Systems Inc. | Coating On A Balloon Device |
US20130164347A1 (en) * | 2011-12-22 | 2013-06-27 | Michel Gensini | Multilayer polymeric drug delivery system |
Family Cites Families (289)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4601893A (en) | 1984-02-08 | 1986-07-22 | Pfizer Inc. | Laminate device for controlled and prolonged release of substances to an ambient environment and method of use |
US4666704A (en) | 1985-05-24 | 1987-05-19 | International Minerals & Chemical Corp. | Controlled release delivery system for macromolecules |
US4919939A (en) | 1986-04-29 | 1990-04-24 | Pharmetrix Corporation | Periodontal disease treatment system |
DE3734223A1 (en) | 1987-10-09 | 1989-04-20 | Boehringer Ingelheim Kg | IMPLANTABLE, BIODEGRADABLE ACTIVE SUBSTANCE RELEASE SYSTEM |
US5227165A (en) | 1989-11-13 | 1993-07-13 | Nova Pharmaceutical Corporation | Liposphere delivery systems for local anesthetics |
AU1579092A (en) * | 1991-02-27 | 1992-10-06 | Nova Pharmaceutical Corporation | Anti-infective and anti-inflammatory releasing systems for medical devices |
US5540912A (en) | 1992-03-30 | 1996-07-30 | Alza Corporation | Viscous suspensions of controlled-release drug particles |
US5458582A (en) | 1992-06-15 | 1995-10-17 | Nakao; Naomi L. | Postoperative anesthetic delivery device and associated method for the postoperative treatment of pain |
US5700485A (en) | 1992-09-10 | 1997-12-23 | Children's Medical Center Corporation | Prolonged nerve blockade by the combination of local anesthetic and glucocorticoid |
ES2170074T3 (en) | 1992-09-10 | 2002-08-01 | Childrens Medical Center | BIODEGRADABLE POLYMER MATRICES FOR THE PROLONGED RELEASE OF LOCAL ANESTHETIC AGENTS. |
US5807306A (en) | 1992-11-09 | 1998-09-15 | Cortrak Medical, Inc. | Polymer matrix drug delivery apparatus |
AU5895994A (en) | 1993-10-04 | 1995-05-01 | Mark Chasin | Controlled release microspheres |
US5451408A (en) | 1994-03-23 | 1995-09-19 | Liposome Pain Management, Ltd. | Pain management with liposome-encapsulated analgesic drugs |
CA2195119C (en) | 1995-06-09 | 2001-09-11 | Mark Chasin | Formulations and methods for providing prolonged local anesthesia |
US5931809A (en) | 1995-07-14 | 1999-08-03 | Depotech Corporation | Epidural administration of therapeutic compounds with sustained rate of release |
GB9605915D0 (en) | 1996-03-21 | 1996-05-22 | Univ Bruxelles | Liposome encapsulated amphiphilic drug compositions |
US5747060A (en) | 1996-03-26 | 1998-05-05 | Euro-Celtique, S.A. | Prolonged local anesthesia with colchicine |
US5891506A (en) * | 1996-08-09 | 1999-04-06 | Medtronic, Inc. | Oxidative method for attachment of glycoproteins or glycopeptides to surfaces of medical devices |
EP0954301A4 (en) | 1996-06-24 | 2006-03-08 | Euro Celtique Sa | Methods for providing safe local anesthesia |
US6046187A (en) | 1996-09-16 | 2000-04-04 | Children's Medical Center Corporation | Formulations and methods for providing prolonged local anesthesia |
US5919473A (en) | 1997-05-12 | 1999-07-06 | Elkhoury; George F. | Methods and devices for delivering opioid analgesics to wounds via a subdermal implant |
US6326020B1 (en) | 1997-05-16 | 2001-12-04 | Children's Medical Center Corporation | Local anesthetic formulations |
US6110902A (en) | 1997-06-23 | 2000-08-29 | Moehler; Hanns | Method for the inhibition of neuronal activity leading to a focal epileptic seizure by local delivery of adenosine |
KR100367144B1 (en) | 1997-07-02 | 2003-01-14 | 유로-셀티크 소시에떼 아노뉨 | prolonged anesthesia in joints and body spaces |
US6432986B2 (en) | 1997-07-21 | 2002-08-13 | Bruce H. Levin | Compositions, kits, and methods for inhibiting cerebral neurovascular disorders and muscular headaches |
US6306166B1 (en) | 1997-08-13 | 2001-10-23 | Scimed Life Systems, Inc. | Loading and release of water-insoluble drugs |
JP4467789B2 (en) | 1997-09-18 | 2010-05-26 | パシラ ファーマシューティカルズ インコーポレーテッド | Sustained release liposome anesthetic composition |
US6342250B1 (en) | 1997-09-25 | 2002-01-29 | Gel-Del Technologies, Inc. | Drug delivery devices comprising biodegradable protein for the controlled release of pharmacologically active agents and method of making the drug delivery devices |
KR100289471B1 (en) | 1998-01-19 | 2001-09-17 | 김충섭 | A controlled/sustained implant delivery containing fentanyls |
US6623521B2 (en) | 1998-02-17 | 2003-09-23 | Md3, Inc. | Expandable stent with sliding and locking radial elements |
US6503231B1 (en) | 1998-06-10 | 2003-01-07 | Georgia Tech Research Corporation | Microneedle device for transport of molecules across tissue |
US6451335B1 (en) | 1998-07-02 | 2002-09-17 | Euro-Celtique S.A. | Formulations and methods for providing prolonged local anesthesia |
US20020022055A1 (en) | 1999-02-23 | 2002-02-21 | Signore Pierre E | Composition and methods for immproving integrity of compromised body passageways and cavities |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
US9302903B2 (en) | 2000-12-14 | 2016-04-05 | Georgia Tech Research Corporation | Microneedle devices and production thereof |
WO2002058670A1 (en) | 2001-01-25 | 2002-08-01 | Euroceltique S.A. | Local anesthetic, and method of use |
WO2002089849A1 (en) | 2001-05-07 | 2002-11-14 | Corium International | Compositions and delivery systems for administration of a local anesthetic agent |
CN1514729B (en) | 2001-06-05 | 2012-09-05 | 控制释放系统公司 | Sustained-release analgesic compounds |
US6913760B2 (en) | 2001-08-06 | 2005-07-05 | New England Medical Hospitals, Inc. | Drug delivery composition |
US6913626B2 (en) | 2001-08-14 | 2005-07-05 | Mcghan Jim J. | Medical implant having bioabsorbable textured surface |
WO2003028660A2 (en) | 2001-10-04 | 2003-04-10 | Case Western Reserve University | Drug delivery devices and methods |
CA2473719A1 (en) | 2002-01-22 | 2003-07-31 | Wisconsin Alumni Research Foundation | Liposome-encapsulated opioid analgesics prepared by rehydration/dehydration method |
US7993390B2 (en) * | 2002-02-08 | 2011-08-09 | Boston Scientific Scimed, Inc. | Implantable or insertable medical device resistant to microbial growth and biofilm formation |
US7074426B2 (en) | 2002-03-27 | 2006-07-11 | Frank Kochinke | Methods and drug delivery systems for the treatment of orofacial diseases |
US7264822B2 (en) | 2002-04-03 | 2007-09-04 | Poly-Med, Inc. | Conjugated drug-polymer coated stent |
JP2005525911A (en) * | 2002-05-20 | 2005-09-02 | オーバス メディカル テクノロジーズ インク. | Implantable drug eluting medical device |
US20040109893A1 (en) | 2002-06-25 | 2004-06-10 | Guohua Chen | Sustained release dosage forms of anesthetics for pain management |
CN1267084C (en) * | 2002-08-01 | 2006-08-02 | 复旦大学 | Medicine releasing control method for implanting type medical equipment |
US20050019404A1 (en) | 2003-06-30 | 2005-01-27 | Hsing-Wen Sung | Drug-eluting biodegradable stent |
US20120097194A1 (en) * | 2002-09-09 | 2012-04-26 | Reactive Surfaces, Ltd. | Polymeric Coatings Incorporating Bioactive Enzymes for Catalytic Function |
FR2846557B1 (en) | 2002-10-30 | 2007-06-08 | Statice Sante | IMPLANTABLE STRUCTURE FOR PROLONGED AND CONTROLLED RELEASE OF AN ACTIVE INGREDIENT |
US20050058734A1 (en) | 2002-12-18 | 2005-03-17 | Algorx | Administration of capsaicinoids |
US7220433B2 (en) | 2003-06-27 | 2007-05-22 | Ethicon, Inc. | Compositions for parenteral administration and sustained-release of therapeutic agents |
WO2005007209A1 (en) | 2003-07-17 | 2005-01-27 | Bioretec Oy | Synthetic, bioabsorbable polymer materials and implants |
US20050048115A1 (en) | 2003-08-27 | 2005-03-03 | Murty Mangena | Buprenorphine microspheres |
AU2004275816A1 (en) | 2003-09-26 | 2005-04-07 | Alza Corporation | Controlled release formulations of opioid and nonopioid analgesics |
US8257393B2 (en) | 2003-12-04 | 2012-09-04 | Ethicon, Inc. | Active suture for the delivery of therapeutic fluids |
US7557051B2 (en) | 2004-03-17 | 2009-07-07 | The Board Of Trustees Of The Leland Stanford Junior University | 3-D interconnected multi-layer microstructure of thermoplastic materials |
US20070258939A1 (en) | 2004-08-03 | 2007-11-08 | Biocamparibles Uk Limited | Drug Delivery from Embolic Agents |
US20080311191A1 (en) | 2004-08-27 | 2008-12-18 | Avinash Nangia | Multi-Layer Tablets and Bioadhesive Dosage Forms |
US8603528B2 (en) | 2004-09-16 | 2013-12-10 | Abyrx, Inc. | Compositions and method for the reduction of post-operative pain |
SI2767292T1 (en) | 2004-09-17 | 2017-01-31 | Durect Corporation | Sustained Local Anesthetic Composition Containing SAIB |
AU2012201226B2 (en) | 2004-09-17 | 2014-08-14 | Durect Corporation | Sustained local anesthetic composition containing preferably a sugar ester such as SAIB |
US8750983B2 (en) | 2004-09-20 | 2014-06-10 | P Tech, Llc | Therapeutic system |
US20060079558A1 (en) | 2004-09-27 | 2006-04-13 | Bridge Pharma. Inc. | R-isomer of 2-{2[N-(2-indanyl)-N-phenylamino]ethyl}piperidine and other dermal anesthetics |
WO2006036936A2 (en) | 2004-09-27 | 2006-04-06 | Bridge Pharma, Inc. | The s-isomer of 2-{2-[n-(2-indanyl)-n-phenylamino]ethyl}piperidine and other dermal anesthetic agents |
US20060253100A1 (en) | 2004-10-22 | 2006-11-09 | Medtronic, Inc. | Systems and Methods to Treat Pain Locally |
US8067026B2 (en) | 2005-03-14 | 2011-11-29 | Boston Scientific Scimed, Inc. | Drug release regions for medical devices, which include polycyclic-structure-containing polymers |
JP2008538754A (en) | 2005-04-11 | 2008-11-06 | ザ・ボード・オブ・トラスティーズ・オブ・ザ・レランド・スタンフォード・ジュニア・ユニバーシティ | Multilayer structure having a predetermined layer pattern containing a drug |
US20090087380A1 (en) | 2005-04-11 | 2009-04-02 | Fasching Rainer J | Polymer devices for therapeutic applications |
WO2006116565A2 (en) | 2005-04-25 | 2006-11-02 | Amgen Inc. | Biodegradable peptide sustained release compositions containing porogens |
EP3056200B1 (en) | 2005-05-23 | 2023-09-06 | President and Fellows of Harvard College | Huperzine for use in treating seizure |
US8865205B2 (en) | 2005-06-15 | 2014-10-21 | Poly-Med, Inc. | Bioswellable sutures |
US8728493B2 (en) | 2005-06-17 | 2014-05-20 | Nektar Therapeutics | Polymer based compositions and conjugates of non-steroidal anti-inflammatory drugs |
US9763788B2 (en) * | 2005-09-09 | 2017-09-19 | Board Of Trustees Of The University Of Arkansas | Bone regeneration using biodegradable polymeric nanocomposite materials and applications of the same |
CA2623239C (en) | 2005-09-22 | 2016-07-12 | Medivas, Llc | Solid polymer delivery compositions and methods for use thereof |
AU2006341116C1 (en) | 2005-09-27 | 2013-05-23 | Efrat Biopolymers Ltd. | Gelling hydrophobic injectable polymer compositions |
US20070071790A1 (en) | 2005-09-28 | 2007-03-29 | Northwestern University | Biodegradable nanocomposites with enhance mechanical properties for soft tissue |
CN1762331A (en) | 2005-10-13 | 2006-04-26 | 上海交通大学 | Skeleton pattern medicine film encapsulated alimentary tract stent |
CA2625264C (en) | 2005-10-13 | 2015-12-15 | Synthes (U.S.A.) | Drug-impregnated sleeve for a medical implant |
US20070141106A1 (en) | 2005-10-19 | 2007-06-21 | Bonutti Peter M | Drug eluting implant |
US20070173787A1 (en) | 2005-11-01 | 2007-07-26 | Huang Mark C T | Thin-film nitinol based drug eluting stent |
EP1971293B1 (en) | 2006-01-13 | 2011-02-23 | Barry M. Fell | Surgically implantable prosthesis with active component |
US20070178138A1 (en) | 2006-02-01 | 2007-08-02 | Allergan, Inc. | Biodegradable non-opthalmic implants and related methods |
US7824703B2 (en) | 2006-02-01 | 2010-11-02 | Warsaw Orthopedics, Inc. | Medical implants with reservoir(s), and materials preparable from same |
US8591531B2 (en) * | 2006-02-08 | 2013-11-26 | Tyrx, Inc. | Mesh pouches for implantable medical devices |
MX2008010126A (en) | 2006-02-08 | 2010-02-22 | Tyrx Pharma Inc | Temporarily stiffened mesh prostheses. |
US8315700B2 (en) * | 2006-02-08 | 2012-11-20 | Tyrx, Inc. | Preventing biofilm formation on implantable medical devices |
JP5208916B2 (en) | 2006-03-31 | 2013-06-12 | キュー エル ティー インク. | Drug delivery methods, structures and compositions for the nasolacrimal system |
US7741273B2 (en) | 2006-04-13 | 2010-06-22 | Warsaw Orthopedic, Inc. | Drug depot implant designs |
US9173732B2 (en) | 2006-04-25 | 2015-11-03 | The Children's Medical Center Corporation | Medical devices for use in the surgical treatment of hyperproliferative diseases affecting the spinal cord |
US7833270B2 (en) | 2006-05-05 | 2010-11-16 | Warsaw Orthopedic, Inc | Implant depots to deliver growth factors to treat osteoporotic bone |
US20080124372A1 (en) | 2006-06-06 | 2008-05-29 | Hossainy Syed F A | Morphology profiles for control of agent release rates from polymer matrices |
US7723291B2 (en) | 2006-07-27 | 2010-05-25 | Warsaw Orthopedic, Inc. | Release of BMP, bioactive agents and/or cells via a pump into a carrier matrix |
US20080089923A1 (en) | 2006-09-29 | 2008-04-17 | Burkstrand Michael J | Biodegradable ocular implants and methods for treating ocular conditions |
CN101161299B (en) * | 2006-10-09 | 2011-07-06 | 乐普(北京)医疗器械股份有限公司 | Medicament release structure carrying apertured and polyalcohol as well as its preparing method |
US8039010B2 (en) | 2006-11-03 | 2011-10-18 | Allergan, Inc. | Sustained release intraocular drug delivery systems comprising a water soluble therapeutic agent and a release modifier |
JP5398535B2 (en) | 2006-11-06 | 2014-01-29 | タイレックス・インコーポレイテッド | Absorbable pouch for implantable medical devices |
EP2079387B1 (en) | 2006-11-06 | 2017-04-12 | Tyrx, Inc. | Mesh pouches for implantable medical devices |
AU2013200515C1 (en) | 2006-11-06 | 2016-09-22 | Medtronic, Inc. | Mesh pouches for implantable medical devices |
US9023114B2 (en) | 2006-11-06 | 2015-05-05 | Tyrx, Inc. | Resorbable pouches for implantable medical devices |
WO2008061355A1 (en) | 2006-11-24 | 2008-05-29 | Matregen Corp. | Glp-1 depot systems, and methods of manufacture and uses thereof |
WO2008073295A2 (en) | 2006-12-07 | 2008-06-19 | Surmodics, Inc. | Latent stabilization of bioactive agents releasable from implantable medical articles |
EP2134409A4 (en) | 2007-03-09 | 2013-07-17 | Anthem Orthopaedics Llc | Implantable medicament delivery device and delivery tool and method for use therewith |
JP5400029B2 (en) * | 2007-03-29 | 2014-01-29 | タイレックス・インコーポレイテッド | Biodegradable polymer cover material for breast implants |
EP2144640B1 (en) | 2007-04-17 | 2012-03-28 | Medtronic, Inc. | Reduction of infection associated with medical device |
US8430852B2 (en) | 2007-04-17 | 2013-04-30 | Medtronic, Inc. | Therapeutic sleeve for implantable medical device |
US20090142400A1 (en) | 2007-05-31 | 2009-06-04 | Hiles Michael C | Analgesic coated medical product |
WO2009009367A2 (en) | 2007-07-06 | 2009-01-15 | Allievion Medical, Inc. | Constrained fluid delivery device |
US20110281882A1 (en) | 2007-08-10 | 2011-11-17 | Jinzhong Zhang | Compositions and Methods for Treating, Controlling, Reducing, or Ameliorating Inflammatory Pain |
US8470360B2 (en) | 2008-04-18 | 2013-06-25 | Warsaw Orthopedic, Inc. | Drug depots having different release profiles for reducing, preventing or treating pain and inflammation |
US9248219B2 (en) | 2007-09-14 | 2016-02-02 | Boston Scientific Scimed, Inc. | Medical devices having bioerodable layers for the release of therapeutic agents |
US20090123508A1 (en) | 2007-10-04 | 2009-05-14 | Boston Scientific Scimed, Inc. | Implantable Drug Depot for Intrathecal Drug Delivery System for Pain Management |
US8703119B2 (en) | 2007-10-05 | 2014-04-22 | Polygene Ltd. | Injectable biodegradable polymer compositions for soft tissue repair and augmentation |
US20090099651A1 (en) * | 2007-10-10 | 2009-04-16 | Miv Therapeutics, Inc. | Lipid coatings for implantable medical devices |
US8974814B2 (en) * | 2007-11-12 | 2015-03-10 | California Institute Of Technology | Layered drug delivery polymer monofilament fibers |
CA2705201C (en) | 2007-11-19 | 2020-07-21 | Capsulated Systems, Inc. | Prolonged release of local anesthetics using microparticles and surgery applications related applications |
US8221358B2 (en) | 2007-11-20 | 2012-07-17 | Warsaw Orthopedic, Inc. | Devices and methods for delivering drug depots to a site beneath the skin |
WO2009069151A2 (en) | 2007-11-30 | 2009-06-04 | Matrix Laboratories Limited | Controlled release composition |
EP2067494A1 (en) | 2007-12-04 | 2009-06-10 | Charité-Universitätsmedizin Berlin | Sheet or tubular structure consisting of elastic biocompatible material and its use |
CA2710515A1 (en) | 2007-12-28 | 2009-07-09 | Khashayar Kevin Neshat | Controlled release local anesthetic for post dental surgery and method of use |
US8795713B2 (en) | 2007-12-31 | 2014-08-05 | Acclarent, Inc. | Mucosal tissue dressing and method of use |
US20090177229A1 (en) | 2008-01-03 | 2009-07-09 | New York Society Of The Ruptured And Crippled Maintaining The Hospital For Special Surgery | Suture anchor with drug/growth factor delivery reservoir |
EP3159018B1 (en) | 2008-02-29 | 2022-04-20 | Smith & Nephew, Inc | Gradient coating for biomedical applications |
US8846068B2 (en) | 2008-04-18 | 2014-09-30 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising a local anesthetic |
US8629172B2 (en) | 2008-04-18 | 2014-01-14 | Warsaw Orthopedic, Inc. | Methods and compositions for treating post-operative pain comprising clonidine |
US20090263451A1 (en) | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Anti-Inflammatory and/or Analgesic Agents for Treatment of Myofascial Pain |
US8557273B2 (en) | 2008-04-18 | 2013-10-15 | Medtronic, Inc. | Medical devices and methods including polymers having biologically active agents therein |
US8946277B2 (en) | 2008-04-18 | 2015-02-03 | Warsaw Orthopedic, Inc. | Clonidine formulations in a biodegradable polymer carrier |
US9289409B2 (en) | 2008-04-18 | 2016-03-22 | Warsaw Orthopedic, Inc. | Sulindac formulations in a biodegradable material |
US20090263443A1 (en) | 2008-04-18 | 2009-10-22 | Warsaw Orthopedics, Inc. | Methods for treating post-operative effects such as spasticity and shivering with clondine |
US9132119B2 (en) | 2008-04-18 | 2015-09-15 | Medtronic, Inc. | Clonidine formulation in a polyorthoester carrier |
US9125917B2 (en) | 2008-04-18 | 2015-09-08 | Warsaw Orthopedic, Inc. | Fluocinolone formulations in a biodegradable polymer carrier |
US9132085B2 (en) | 2008-04-18 | 2015-09-15 | Warsaw Orthopedic, Inc. | Compositions and methods for treating post-operative pain using clonidine and bupivacaine |
US8889173B2 (en) | 2008-04-18 | 2014-11-18 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of pain and/or inflammation |
US8475823B2 (en) | 2008-04-18 | 2013-07-02 | Medtronic, Inc. | Baclofen formulation in a polyorthoester carrier |
US9610243B2 (en) | 2008-04-18 | 2017-04-04 | Warsaw Orthopedic, Inc. | Clonidine compounds in a biodegradable polymer |
US9072727B2 (en) | 2008-04-18 | 2015-07-07 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of degenerative disc disease |
US20090264489A1 (en) | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc. | Method for Treating Acute Pain with a Formulated Drug Depot in Combination with a Liquid Formulation |
US20090264477A1 (en) | 2008-04-18 | 2009-10-22 | Warsaw Orthopedic, Inc., An Indiana Corporation | Beta adrenergic receptor agonists for treatment of pain and/or inflammation |
US8956642B2 (en) | 2008-04-18 | 2015-02-17 | Medtronic, Inc. | Bupivacaine formulation in a polyorthoester carrier |
US8956641B2 (en) | 2008-04-18 | 2015-02-17 | Warsaw Orthopedic, Inc. | Alpha adrenergic receptor agonists for treatment of inflammatory diseases |
US8524267B2 (en) | 2008-04-18 | 2013-09-03 | Warsaw Orthopedic, Inc. | Dexamethasone formulations in a biodegradable material |
US8420114B2 (en) | 2008-04-18 | 2013-04-16 | Warsaw Orthopedic, Inc. | Alpha and beta adrenergic receptor agonists for treatment of pain and / or inflammation |
KR20130097813A (en) | 2008-04-21 | 2013-09-03 | 오토노미, 인코포레이티드 | Auris formulations for treating otic diseases and conditions |
CA2722092C (en) | 2008-04-22 | 2016-07-12 | Angiotech Pharmaceuticals, Inc. | Biocompatible crosslinked hydrogels, drug-loaded hydrogels and methods of using the same |
CN104623741A (en) | 2008-04-30 | 2015-05-20 | 马缇医疗股份有限公司 | Composite lacrimal insert and related methods |
US8877225B2 (en) | 2008-06-03 | 2014-11-04 | Tolmar Therapeutics, Inc. | Controlled release copolymer formulation with improved release kinetics |
WO2010006046A1 (en) | 2008-07-10 | 2010-01-14 | Tyrx Pharma, Inc. | Nsaid delivery from polyarylates |
CA2730995C (en) * | 2008-07-17 | 2016-11-22 | Micell Technologies, Inc. | Drug delivery medical device |
US8202531B2 (en) | 2008-07-23 | 2012-06-19 | Warsaw Orthopedic, Inc. | Drug depots having one or more anchoring members |
ES2356883B1 (en) | 2008-07-24 | 2012-02-22 | Bcn Peptides, S.A. | COMPOSITION FOR THE TREATMENT OF PAIN AND / OR INFLAMMATION. |
AU2008360388A1 (en) | 2008-08-05 | 2010-02-11 | Children's Medical Center Corporation | Medical devices for use in the surgical treatment of hyperproliferative diseases affecting the spinal cord |
CN102177016B (en) | 2008-08-28 | 2015-11-25 | 泰科保健集团有限合伙公司 | Antimicrobial fibre and correlated product and method |
CA2736114A1 (en) | 2008-09-04 | 2010-03-11 | President And Fellows Of Harvard College | Treatment of neurological disorders using huperzine |
US9352137B2 (en) | 2008-10-29 | 2016-05-31 | Warsaw Orthopedic, Inc. | Drug cartridge for delivering a drug depot comprising a bulking agent and/or cover |
US9623222B2 (en) | 2008-10-30 | 2017-04-18 | Warsaw Orthopedic, Inc. | Drug depot with anchor |
US9161903B2 (en) | 2008-10-31 | 2015-10-20 | Warsaw Orthopedic, Inc. | Flowable composition that hardens on delivery to a target tissue site beneath the skin |
US9095506B2 (en) | 2008-11-17 | 2015-08-04 | Allergan, Inc. | Biodegradable alpha-2 agonist polymeric implants and therapeutic uses thereof |
BRPI0922224A2 (en) | 2008-12-08 | 2016-08-02 | Vm Pharma Llc | receptor protein tyrosine kinase inhibitor compositions. |
JP2012513473A (en) | 2008-12-23 | 2012-06-14 | サーモディクス ファーマシューティカルズ, インコーポレイテッド | Implantable composites and compositions comprising releasable bioactive agents |
US8980317B2 (en) | 2008-12-23 | 2015-03-17 | Warsaw Orthopedic, Inc. | Methods and compositions for treating infections comprising a local anesthetic |
WO2010088697A2 (en) * | 2009-02-02 | 2010-08-05 | Medtronic, Inc. | Antimicrobial accessory for an implantable medical device |
US20100203102A1 (en) | 2009-02-10 | 2010-08-12 | Warsaw Orthopedic, Inc. | Compositions and methods for treating post-operative pain using bupivacaine and an anti-onflammatory agent |
US20100230100A1 (en) * | 2009-03-13 | 2010-09-16 | Reservoir Management Inc. | Plug for a Perforated Liner and Method of Using Same |
US20100239632A1 (en) | 2009-03-23 | 2010-09-23 | Warsaw Orthopedic, Inc. | Drug depots for treatment of pain and inflammation in sinus and nasal cavities or cardiac tissue |
US20100249783A1 (en) | 2009-03-24 | 2010-09-30 | Warsaw Orthopedic, Inc. | Drug-eluting implant cover |
CA2777467A1 (en) | 2009-04-27 | 2010-11-04 | Intersect Ent, Inc. | Devices and methods for treating pain associated with tonsillectomies |
US8992601B2 (en) * | 2009-05-20 | 2015-03-31 | 480 Biomedical, Inc. | Medical implants |
US20120100192A1 (en) * | 2009-07-01 | 2012-04-26 | Dexcel Pharma Technologies Ltd. | Local therapeutic release device |
US8715223B2 (en) | 2009-07-22 | 2014-05-06 | Warsaw Orthopedic, Inc. | Device and method for delivery of a drug depot near the nerve |
US20110027331A1 (en) | 2009-07-29 | 2011-02-03 | Warsaw Orthopedic, Inc. | An implantable drug depot having a reversible phase transition material for treatment of pain and/or inflammation |
US8231891B2 (en) | 2009-07-31 | 2012-07-31 | Warsaw Orthopedic, Inc. | Implantable drug depot for weight control |
US9017312B2 (en) | 2009-09-10 | 2015-04-28 | Taris Biomedical Llc | Implantable device for controlled drug delivery |
US9271925B2 (en) | 2013-03-11 | 2016-03-01 | Bioinspire Technologies, Inc. | Multi-layer biodegradable device having adjustable drug release profile |
JP2013505113A (en) * | 2009-09-22 | 2013-02-14 | エボニック デグサ コーポレイション | Implant device for regulating bioactive agent release profile |
US20110082545A1 (en) | 2009-10-01 | 2011-04-07 | Lipose Corporation | Drug eluting breast implant cover or coating |
US20110097375A1 (en) | 2009-10-26 | 2011-04-28 | Warsaw Orthopedic, Inc. | Formulation for preventing or reducing bleeding at a surgical site |
US20110129801A1 (en) | 2009-11-27 | 2011-06-02 | Shikha Pramanik Barman | Compositions and methods to prevent and treat dry socket post-operatively after tooth extraction surgery |
EP2512540B1 (en) | 2009-12-15 | 2019-08-07 | Incept, LLC | Implants and biodegradable fiducial markers |
EP3884988A1 (en) | 2009-12-17 | 2021-09-29 | TARIS Biomedical LLC | Implantable device with intravesical tolerability and methods of treatment |
US20110159072A1 (en) * | 2009-12-30 | 2011-06-30 | Surmodics, Inc. | Controlled release matrix |
US9125902B2 (en) | 2010-01-28 | 2015-09-08 | Warsaw Orthopedic, Inc. | Methods for treating an intervertebral disc using local analgesics |
US8951552B2 (en) | 2010-02-02 | 2015-02-10 | Poly-Med, Inc. | In situ film-forming bioactive solutions of absorbable multiblock copolymers |
WO2011098578A2 (en) | 2010-02-12 | 2011-08-18 | Bioneer A/S | Liposome system for ocular administration |
US8758798B2 (en) | 2010-03-24 | 2014-06-24 | Covidien Lp | Therapeutic implant |
WO2011139594A2 (en) | 2010-04-27 | 2011-11-10 | Medtronic, Inc. | Artificial bursa for intra-articular drug delivery |
WO2011150175A2 (en) | 2010-05-26 | 2011-12-01 | President And Fellows Of Harvard College | Compositions and methods for pain reduction |
US20120009240A1 (en) | 2010-07-08 | 2012-01-12 | Joshua Stopek | Films for Delivery of a Therapeutic Agent |
IT1401498B1 (en) | 2010-07-30 | 2013-07-26 | Mero Srl | HYDROGEL BASED ON HYALURONIC ACID AND ITS USE IN ORTHOPEDICS |
US8697117B2 (en) | 2010-08-02 | 2014-04-15 | Ramot At Tel-Aviv University Ltd. | Drug-eluting films |
US8246571B2 (en) | 2010-08-24 | 2012-08-21 | Warsaw Orthopedic, Inc. | Drug storage and delivery device having a retaining member |
US9457176B2 (en) | 2010-10-06 | 2016-10-04 | Taris Biomedical Llc | Implantable drug delivery device with bladder retention feature |
US8632839B2 (en) | 2010-10-19 | 2014-01-21 | Covidien Lp | Methods of forming self-supporting films for delivery of therapeutic agents |
US9861590B2 (en) | 2010-10-19 | 2018-01-09 | Covidien Lp | Self-supporting films for delivery of therapeutic agents |
US8920867B2 (en) | 2010-10-19 | 2014-12-30 | Covidien Lp | Methods of forming self-supporting films for delivery of therapeutic agents |
CN103260702B (en) | 2010-10-28 | 2018-07-27 | 帕西拉制药有限公司 | The sustained release preparation of non-steroid anti-inflammatory drug |
CN102389616A (en) * | 2010-11-02 | 2012-03-28 | 东南大学 | Antibacterial medical catheter coated with nano silver polymer cellular structure film |
WO2012064963A1 (en) | 2010-11-12 | 2012-05-18 | Tyrx, Inc. | Anchorage devices comprising an active pharmaceutical ingredient |
WO2012075447A2 (en) | 2010-12-03 | 2012-06-07 | Warsaw Orthopedic, Inc. | Compositions and methods for delivering clonidine and bupivacaine to a target tissue site |
CN102000366A (en) | 2010-12-08 | 2011-04-06 | 苏州同科生物材料有限公司 | Degradable self-expandable esophageal stent and preparation method thereof |
EP2654757A1 (en) | 2010-12-22 | 2013-10-30 | Entarco SA | The use of spinosyns and spinosyn compositions as local anesthetics and as antiarrhythmic agents |
US8911427B2 (en) * | 2010-12-28 | 2014-12-16 | Medtronic, Inc. | Therapeutic agent reservoir delivery system |
AU2012220537A1 (en) | 2011-02-23 | 2013-08-29 | Ams Research Corporation | Pelvic implant and therapeutic agent system and method |
US9351924B2 (en) | 2011-03-11 | 2016-05-31 | Snu R&Db Foundation | Drug delivery system including laminated structure |
US9005634B2 (en) | 2011-04-13 | 2015-04-14 | Medtronic, Inc. | Shelf stable pharmaceutical depot |
SG10201602829PA (en) | 2011-04-14 | 2016-05-30 | Univ California | Multilayer Thin Film Drug Delivery Device And Methods Of Making And Using The Same |
JP5727292B2 (en) | 2011-05-11 | 2015-06-03 | 富士フイルム株式会社 | Composite film |
KR101248368B1 (en) | 2011-05-24 | 2013-04-01 | 서울대학교산학협력단 | A suture comprising drug-loaded polymer film and a preparation method thereof |
WO2012166819A1 (en) | 2011-05-31 | 2012-12-06 | Micell Technologies, Inc. | System and process for formation of a time-released, drug-eluting transferable coating |
WO2012170655A1 (en) | 2011-06-07 | 2012-12-13 | Cornell University | Silk compositions and methods of using same |
US20120316199A1 (en) | 2011-06-07 | 2012-12-13 | Ward Keith W | Compositions and methods for treating, controlling, reducing, or ameliorating inflammatory pain |
WO2012169972A1 (en) | 2011-06-09 | 2012-12-13 | Agency For Science, Technology And Research | Core-shell microspheres |
US9132194B2 (en) | 2011-07-12 | 2015-09-15 | Warsaw Orthopedic, Inc. | Medical devices and methods comprising an adhesive sheet containing a drug depot |
CA2842107C (en) * | 2011-07-20 | 2018-01-16 | Tyrx, Inc. | Drug eluting mesh to prevent infection of indwelling transdermal devices |
WO2013040325A1 (en) | 2011-09-15 | 2013-03-21 | Arsenal Medical, Inc. | Implants for post-operative pain |
WO2013087903A1 (en) | 2011-12-16 | 2013-06-20 | Dsm Ip Assets B.V. | Process for the manufacturing of a drug delivery system based on a polymer comprising a dispersed bioactive agent |
US9198758B2 (en) | 2012-01-26 | 2015-12-01 | Warsaw Orthopedic, Inc. | Delivery systems |
WO2013124867A1 (en) | 2012-02-21 | 2013-08-29 | Amrita Vishwa Vidyapeetham University | Polymer - polymer or polymer - protein core - shell nano medicine loaded with multiple drug molecules |
WO2013126552A1 (en) | 2012-02-21 | 2013-08-29 | Auburn University | Buprenorphine nanoparticle composition and methods thereof |
US20130261594A1 (en) | 2012-03-30 | 2013-10-03 | Covidien Lp | Implantable Devices Including A Mesh And An Extendable Film |
US9668974B2 (en) | 2012-05-10 | 2017-06-06 | Painreform Ltd. | Depot formulations of a local anesthetic and methods for preparation thereof |
US9655994B2 (en) | 2012-07-25 | 2017-05-23 | William F. McKay | Delivery systems |
DK2877155T3 (en) | 2012-07-26 | 2021-01-18 | Camurus Ab | OPIOID FORMULATIONS |
US20140052183A1 (en) | 2012-08-10 | 2014-02-20 | FreeseTEC Corporation | Posterior Spine Attachment Device for Hardware and Paraspinal Musculature |
GR20120100450A (en) | 2012-08-30 | 2014-03-17 | Αριστοτελειο Πανεπιστημιο Θεσσαλονικης-Ειδικος Λογαριασμος Κονδυλιων Ερευνας, | Method for production of multi-layer nanoporous biodegradable polymeric coatings and it's products. |
US9198999B2 (en) | 2012-09-21 | 2015-12-01 | Merit Medical Systems, Inc. | Drug-eluting rotational spun coatings and methods of use |
JPWO2014046191A1 (en) | 2012-09-21 | 2016-08-18 | テルモ株式会社 | Local anesthetic sustained-release liposome preparation |
US20140105956A1 (en) | 2012-10-11 | 2014-04-17 | Rupak BANERJEE | Biodegradable polymer based microimplant for ocular drug delivery |
US20140107159A1 (en) | 2012-10-12 | 2014-04-17 | Covidien Lp | Compositions and methods of forming films for improved drug delivery |
KR20150067260A (en) | 2012-10-19 | 2015-06-17 | 올리버 야오푸 후 | Durable analgetic sebacoyl dinalbuphine ester-plga controlled release formulation |
EP2911647B1 (en) | 2012-10-23 | 2018-03-07 | DSM IP Assets B.V. | Process for the manufacturing of a multilayer drug delivery construct |
US20150290170A1 (en) | 2012-10-26 | 2015-10-15 | Allergan, Inc. | Ketorolac-containing sustained release drug delivery systems |
US20150272877A1 (en) | 2012-10-26 | 2015-10-01 | Allergan, Inc. | Ketorolac-containing sustained release drug delivery systems |
WO2014066653A1 (en) | 2012-10-26 | 2014-05-01 | Allergan, Inc. | Ketorolac-containing sustained release intraocular drug delivery systems |
KR20150075408A (en) | 2012-11-01 | 2015-07-03 | 토렌트 파마슈티칼스 리미티드 | Pharmaceutical composition of tapentadol for parenteral administration |
US9545447B2 (en) | 2013-01-04 | 2017-01-17 | The Texas A&M University System | Polymer-drug systems |
US9597132B2 (en) | 2013-01-12 | 2017-03-21 | Louis Houff | Sternum fixation device and method |
US9445884B2 (en) | 2013-01-30 | 2016-09-20 | Boston Scientific Scimed, Inc. | Ureteral stent with drug-releasing structure |
WO2014137454A1 (en) * | 2013-03-07 | 2014-09-12 | Tyrx, Inc. | Methods and compositions to inhibit the assemblage of microbial cells irreversibly associated with surfaces of medical devices |
WO2014143635A1 (en) | 2013-03-15 | 2014-09-18 | Heron Therapeutics, Inc. | Compositions of a polyorthoester and an aprotic solvent |
US20140271770A1 (en) | 2013-03-15 | 2014-09-18 | Warsaw Orthopedic, Inc. | Methods And Compositions For Treating Post-Operative Pain Comprising Clonidine |
SG11201507751YA (en) | 2013-03-21 | 2015-10-29 | Eupraxia Pharmaceuticals USA LLC | Injectable sustained release composition and method of using the same for treating inflammation in joints and pain associated therewith |
WO2014172572A1 (en) * | 2013-04-18 | 2014-10-23 | Board Of Regents, The University Of Texas System | Antimicrobial wraps for medical implants |
CN103405748B (en) | 2013-05-24 | 2015-09-30 | 浙江圣兆药物科技股份有限公司 | The polypeptide slow release release composition of brand-new ELECTRODE WITH BILAYER POLYMERIC thing parcel |
US20160144067A1 (en) * | 2013-06-21 | 2016-05-26 | DePuy Synthes Products, Inc. | Films and methods of manufacture |
US20150024031A1 (en) | 2013-07-17 | 2015-01-22 | Baxter International Inc. | Methods And Compositions For Reducing Pain, Inflammation, And/Or Immunological Reactions Associated With Parenterally Administering A Primary Therapeutic Agent |
IN2013MU02532A (en) * | 2013-07-31 | 2015-06-26 | Sahajanand Medical Technologies Pvt Ltd | |
EP3068371A1 (en) | 2013-11-15 | 2016-09-21 | Glaukos Corporation | Ocular implants configured to store and release stable drug formulations |
US20160331853A1 (en) | 2014-01-21 | 2016-11-17 | The Trustees Of Columbia University In The City Of New York | Compositions for radiotherapy and uses thereof |
ES2689073T3 (en) | 2014-03-11 | 2018-11-08 | Atro Medical B.V. | Meniscus prosthesis |
CN106535886A (en) | 2014-04-21 | 2017-03-22 | 赫伦治疗有限公司 | Long-acting polymeric delivery systems |
US20150342964A1 (en) | 2014-05-30 | 2015-12-03 | Warsaw Orthopedic, Inc. | Dexamethasone polymer implant for pain |
EP3160331A4 (en) | 2014-06-25 | 2018-09-12 | Canary Medical Inc. | Devices, systems and methods for using and monitoring orthopedic hardware |
EP3160369A4 (en) | 2014-06-25 | 2018-04-18 | Canary Medical Inc. | Devices, systems and methods for using and monitoring spinal implants |
US20160038632A1 (en) | 2014-08-07 | 2016-02-11 | Massachusetts Instutite Of Technology | Adaptive Drug Delivery from an Artificial Polymer Skin with Tunable Properties for Tissue Engineering |
SG10201902407PA (en) | 2014-09-19 | 2019-04-29 | Eupraxia Pharmaceuticals Inc | Injectable microparticles for hyper-localized release of therapeutic agents |
US10449152B2 (en) | 2014-09-26 | 2019-10-22 | Covidien Lp | Drug loaded microspheres for post-operative chronic pain |
CN104474595B (en) | 2014-11-13 | 2017-01-25 | 中国科学院化学研究所 | Production method of dilayer compounding coated esophageal stent with esophageal cancer treatment assisting function |
US20160136094A1 (en) | 2014-11-18 | 2016-05-19 | PixarBio Corporation | Compositions For Treating Acute, Post-Operative, or Chronic Pain and Methods of Using the Same |
CN104623681A (en) | 2014-11-26 | 2015-05-20 | 嘉应学院医学院 | Oleanolic acid based drug slow-release agent and preparation method thereof |
EP3250251A1 (en) | 2015-01-28 | 2017-12-06 | Allergan, Inc. | Joint fat pad formulations, and methods of use thereof |
US20160220498A1 (en) | 2015-01-29 | 2016-08-04 | Aneesh SONI | Fully or partially biodegradable device for controlled drug delivery |
US20160287367A1 (en) | 2015-03-30 | 2016-10-06 | Daniel A. Rontal | Bioresorbable septoplasty closure implant |
GB201505527D0 (en) | 2015-03-31 | 2015-05-13 | Jmedtech Pte Ltd | Composition |
CZ307444B6 (en) | 2015-04-22 | 2018-08-29 | Jakub Rak | Mucoadhesive polymer film for photosensitive therapy in the oral cavity containing photosensitizers |
JP6938462B2 (en) | 2015-07-28 | 2021-09-22 | ボード オブ リージェンツ, ザ ユニバーシティ オブ テキサス システムBoard Of Regents, The University Of Texas System | Implant composition for unidirectional delivery of therapeutic compounds to the brain |
KR20170025011A (en) | 2015-08-27 | 2017-03-08 | 고려대학교 산학협력단 | Pharmaceutical composition for sustained release of pain-relieving drugs and a device for administration thereof |
JP2018531951A (en) | 2015-10-27 | 2018-11-01 | ユープラシア ファーマシューティカルズ インク. | Sustained release formulation of local anesthetic |
US20170128632A1 (en) | 2015-11-10 | 2017-05-11 | II William Charles McJames | Device and method for controlling the release of bioactive and therapeutic agents from an implantable medical device |
US10315034B2 (en) | 2016-02-02 | 2019-06-11 | Pacesetter, Inc. | Systems and methods for reducing pain during spinal cord stimulation trial |
WO2017146819A1 (en) | 2016-02-22 | 2017-08-31 | The Methodist Hospital | Implantable drug delivery systems |
US20170239183A1 (en) | 2016-02-23 | 2017-08-24 | PixarBio Corporation | COMPOSITIONS COMPRISING NAv1.7 SELECTIVE INHIBITORS FOR TREATING ACUTE, POST-OPERATIVE, OR CHRONIC PAIN AND METHODS OF USING THE SAME |
CA3024196A1 (en) | 2016-07-06 | 2018-01-11 | Children's Medical Center Corporation | Indirect method of articular tissue repair |
EP3518999A4 (en) | 2016-09-28 | 2020-05-27 | Orchid Medical Pte Ltd | Elastic bioresorbable encasement for implants |
CN106344521B (en) | 2016-09-30 | 2019-10-25 | 沈阳药科大学 | A kind of preparation and its application of the biodegradable Bupivacaine microballoon of high drug load |
US11471419B2 (en) | 2016-09-30 | 2022-10-18 | The Board Of Trustees Of The University Of Illinois | Capsules with intracapsular microspheres for improved survival and function of encapsulated cells |
KR102637575B1 (en) | 2016-10-05 | 2024-02-20 | 타이탄 파머슈티컬즈 인코퍼레이티드 | Implantable devices for drug delivery with reduced burst release |
DE102017106216A1 (en) | 2017-03-22 | 2018-09-27 | Amw Gmbh | Extruded depot form for sustained release of active ingredient |
EP3638311A4 (en) | 2017-06-13 | 2020-12-16 | The University of British Columbia | Polymeric paste compositions for drug delivery |
CA3078555A1 (en) | 2017-10-06 | 2019-04-11 | Foundry Therapeutics, Inc. | Implantable depots for the controlled release of therapeutic agents |
CN111655303A (en) | 2018-01-08 | 2020-09-11 | 铸造疗法股份有限公司 | Devices, systems, and methods for treating intraluminal cancer via controlled delivery of therapeutic agents |
CA3099890A1 (en) | 2018-05-12 | 2019-11-21 | Foundry Therapeutics, Inc. | Implantable polymer depots for the controlled release of therapeutic agents |
EP3843710A1 (en) | 2018-08-28 | 2021-07-07 | Foundry Therapeutics, Inc. | Polymer implants |
US20210353532A1 (en) | 2018-08-28 | 2021-11-18 | Foundry Therapeutics 1, Inc. | Devices, systems, and methods for delivering, positioning, and securing polymer depots in situ |
WO2020210764A1 (en) | 2019-04-11 | 2020-10-15 | Foundry Therapeutics, Inc. | Implantable polymer depots for the controlled, sustained release of therapeutic agents |
CN114286668A (en) | 2019-04-11 | 2022-04-05 | 铸造疗法股份有限公司 | Local, sustained, controlled release implantable depot of therapeutic agents for treating cancer and related symptoms and conditions |
WO2021178930A1 (en) | 2020-03-05 | 2021-09-10 | Foundry Therapeutics, Inc. | Polymer implants |
EP4408403A1 (en) | 2021-09-30 | 2024-08-07 | Foundry Therapeutics, Inc. | Implantable depots with tunable release profiles |
-
2015
- 2015-03-31 GB GBGB1505527.0A patent/GB201505527D0/en not_active Ceased
-
2016
- 2016-03-31 EP EP16773584.4A patent/EP3277330A4/en not_active Withdrawn
- 2016-03-31 EP EP19174733.6A patent/EP3586886B1/en active Active
- 2016-03-31 CN CN201680030900.8A patent/CN107921180A/en active Pending
- 2016-03-31 WO PCT/SG2016/050158 patent/WO2016159885A1/en unknown
- 2016-03-31 CN CN202110288835.1A patent/CN113181439A/en active Pending
- 2016-03-31 US US15/563,527 patent/US20180193537A1/en not_active Abandoned
- 2016-03-31 JP JP2017551593A patent/JP6824188B2/en active Active
- 2016-03-31 EP EP22186638.7A patent/EP4129350A1/en active Pending
-
2019
- 2019-03-27 US US16/366,323 patent/US20190351108A1/en not_active Abandoned
-
2021
- 2021-01-12 JP JP2021002539A patent/JP7376520B2/en active Active
- 2021-07-15 US US17/305,851 patent/US11964076B2/en active Active
-
2023
- 2023-10-23 JP JP2023181875A patent/JP2024010067A/en active Pending
-
2024
- 2024-03-19 US US18/609,954 patent/US20240226394A1/en active Pending
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20110137243A1 (en) * | 2007-09-06 | 2011-06-09 | Abbott Cardiovascular Systems Inc. | Coating On A Balloon Device |
US20130164347A1 (en) * | 2011-12-22 | 2013-06-27 | Michel Gensini | Multilayer polymeric drug delivery system |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11964076B2 (en) | 2015-03-31 | 2024-04-23 | Foundry Therapeutics, Inc. | Multi-layered polymer film for sustained release of agents |
US11202754B2 (en) | 2017-10-06 | 2021-12-21 | Foundry Therapeutics, Inc. | Implantable depots for the controlled release of therapeutic agents |
US11224570B2 (en) | 2017-10-06 | 2022-01-18 | Foundry Therapeutics, Inc. | Implantable depots for the controlled release of therapeutic agents |
US11969500B2 (en) | 2017-10-06 | 2024-04-30 | Foundry Therapeutics, Inc. | Implantable depots for the controlled release of therapeutic agents |
Also Published As
Publication number | Publication date |
---|---|
JP2021072894A (en) | 2021-05-13 |
US11964076B2 (en) | 2024-04-23 |
WO2016159885A1 (en) | 2016-10-06 |
CN113181439A (en) | 2021-07-30 |
US20220072207A1 (en) | 2022-03-10 |
US20240226394A1 (en) | 2024-07-11 |
EP3586886A1 (en) | 2020-01-01 |
JP2018511410A (en) | 2018-04-26 |
GB201505527D0 (en) | 2015-05-13 |
EP3277330A4 (en) | 2018-11-14 |
EP3586886B1 (en) | 2022-07-27 |
EP4129350A1 (en) | 2023-02-08 |
JP7376520B2 (en) | 2023-11-08 |
JP6824188B2 (en) | 2021-02-03 |
US20180193537A1 (en) | 2018-07-12 |
JP2024010067A (en) | 2024-01-23 |
CN107921180A (en) | 2018-04-17 |
EP3277330A1 (en) | 2018-02-07 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US11964076B2 (en) | Multi-layered polymer film for sustained release of agents | |
US8591531B2 (en) | Mesh pouches for implantable medical devices | |
EP2079387B1 (en) | Mesh pouches for implantable medical devices | |
JP5852952B2 (en) | Absorbable pouch for implantable medical devices | |
ES2750034T3 (en) | Broad spectrum antimicrobial compositions based on combinations of taurolidine and protamine and medical devices containing such compositions | |
US20210361827A1 (en) | Elastic bioresorbable encasement for implants | |
EP2734248B1 (en) | Drug eluting mesh to prevent infection of indwelling transdermal devices | |
US20150273118A9 (en) | Mesh Pouches for Implantable Medical Devices | |
AU2013200515B2 (en) | Mesh pouches for implantable medical devices |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AS | Assignment |
Owner name: ORCHID MEDICAL PTE LTD, SINGAPORE Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:WANG, HONGLEI;LUO, JINGNAN;REEL/FRAME:048716/0862 Effective date: 20160808 Owner name: FOUNDRY THERAPEUTICS, INC., CALIFORNIA Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNOR:ORCHID MEDICAL PTE LTD;REEL/FRAME:048716/0919 Effective date: 20181015 |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: NON FINAL ACTION MAILED |
|
STPP | Information on status: patent application and granting procedure in general |
Free format text: FINAL REJECTION MAILED |
|
STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |