WO2014020133A2 - Process and device - Google Patents
Process and device Download PDFInfo
- Publication number
- WO2014020133A2 WO2014020133A2 PCT/EP2013/066239 EP2013066239W WO2014020133A2 WO 2014020133 A2 WO2014020133 A2 WO 2014020133A2 EP 2013066239 W EP2013066239 W EP 2013066239W WO 2014020133 A2 WO2014020133 A2 WO 2014020133A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition according
- hydrogen
- wound
- salt
- quaternary ammonium
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims abstract description 58
- 239000000203 mixture Substances 0.000 claims abstract description 217
- 230000000845 anti-microbial effect Effects 0.000 claims abstract description 207
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims abstract description 144
- 150000003839 salts Chemical class 0.000 claims abstract description 103
- 239000007787 solid Substances 0.000 claims abstract description 47
- 239000004599 antimicrobial Substances 0.000 claims abstract description 46
- 206010052428 Wound Diseases 0.000 claims description 237
- 208000027418 Wounds and injury Diseases 0.000 claims description 237
- 239000000463 material Substances 0.000 claims description 169
- 239000002250 absorbent Substances 0.000 claims description 139
- 230000002745 absorbent Effects 0.000 claims description 130
- 125000002091 cationic group Chemical group 0.000 claims description 104
- -1 2-hydroxynapthoate Chemical compound 0.000 claims description 60
- ZRALSGWEFCBTJO-UHFFFAOYSA-N Guanidine Chemical compound NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 claims description 59
- 239000002243 precursor Substances 0.000 claims description 38
- 150000001450 anions Chemical class 0.000 claims description 37
- 238000011282 treatment Methods 0.000 claims description 31
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 claims description 30
- 125000000217 alkyl group Chemical group 0.000 claims description 30
- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 claims description 30
- 210000000416 exudates and transudate Anatomy 0.000 claims description 30
- 239000006260 foam Substances 0.000 claims description 30
- 239000012530 fluid Substances 0.000 claims description 29
- 241001465754 Metazoa Species 0.000 claims description 25
- 125000004432 carbon atom Chemical group C* 0.000 claims description 25
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 25
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 22
- 210000001124 body fluid Anatomy 0.000 claims description 20
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 19
- 239000007788 liquid Substances 0.000 claims description 19
- 229940095064 tartrate Drugs 0.000 claims description 19
- 229920002413 Polyhexanide Polymers 0.000 claims description 18
- 239000000443 aerosol Substances 0.000 claims description 18
- 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 17
- 125000003118 aryl group Chemical group 0.000 claims description 17
- 229960003260 chlorhexidine Drugs 0.000 claims description 17
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000001257 hydrogen Substances 0.000 claims description 17
- 229910052739 hydrogen Inorganic materials 0.000 claims description 17
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 claims description 16
- 239000007864 aqueous solution Substances 0.000 claims description 16
- 239000004744 fabric Substances 0.000 claims description 16
- 238000011321 prophylaxis Methods 0.000 claims description 16
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 16
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 claims description 15
- 229920001661 Chitosan Polymers 0.000 claims description 15
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 claims description 15
- 238000010521 absorption reaction Methods 0.000 claims description 15
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 15
- 229940049920 malate Drugs 0.000 claims description 15
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 15
- 210000001519 tissue Anatomy 0.000 claims description 15
- VAZJLPXFVQHDFB-UHFFFAOYSA-N 1-(diaminomethylidene)-2-hexylguanidine Polymers CCCCCCN=C(N)N=C(N)N VAZJLPXFVQHDFB-UHFFFAOYSA-N 0.000 claims description 14
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 14
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 13
- FATUQANACHZLRT-KMRXSBRUSA-L calcium glucoheptonate Chemical compound [Ca+2].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)C([O-])=O FATUQANACHZLRT-KMRXSBRUSA-L 0.000 claims description 13
- DGTVXEHQMSJRPE-UHFFFAOYSA-N difluorophosphinic acid Chemical compound OP(F)(F)=O DGTVXEHQMSJRPE-UHFFFAOYSA-N 0.000 claims description 13
- FEWJPZIEWOKRBE-JCYAYHJZSA-M L-tartrate(1-) Chemical compound OC(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-M 0.000 claims description 12
- 125000003710 aryl alkyl group Chemical group 0.000 claims description 12
- 125000001183 hydrocarbyl group Chemical group 0.000 claims description 12
- 208000015181 infectious disease Diseases 0.000 claims description 12
- 230000000813 microbial effect Effects 0.000 claims description 12
- 238000005507 spraying Methods 0.000 claims description 12
- 229940086735 succinate Drugs 0.000 claims description 12
- 235000010443 alginic acid Nutrition 0.000 claims description 11
- 229920000615 alginic acid Polymers 0.000 claims description 11
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 claims description 11
- 239000002904 solvent Substances 0.000 claims description 11
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 11
- 239000004094 surface-active agent Substances 0.000 claims description 11
- 229920002678 cellulose Polymers 0.000 claims description 10
- 235000010980 cellulose Nutrition 0.000 claims description 10
- NBIIXXVUZAFLBC-UHFFFAOYSA-M dihydrogenphosphate Chemical compound OP(O)([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-M 0.000 claims description 10
- 229920003023 plastic Polymers 0.000 claims description 10
- 239000004033 plastic Substances 0.000 claims description 10
- 229920001410 Microfiber Polymers 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 9
- 239000003658 microfiber Substances 0.000 claims description 9
- 229910021653 sulphate ion Inorganic materials 0.000 claims description 9
- FHVDTGUDJYJELY-UHFFFAOYSA-N 6-{[2-carboxy-4,5-dihydroxy-6-(phosphanyloxy)oxan-3-yl]oxy}-4,5-dihydroxy-3-phosphanyloxane-2-carboxylic acid Chemical compound O1C(C(O)=O)C(P)C(O)C(O)C1OC1C(C(O)=O)OC(OP)C(O)C1O FHVDTGUDJYJELY-UHFFFAOYSA-N 0.000 claims description 8
- 229940072056 alginate Drugs 0.000 claims description 8
- 125000001931 aliphatic group Chemical group 0.000 claims description 8
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- 230000035699 permeability Effects 0.000 claims description 8
- 229920000728 polyester Polymers 0.000 claims description 8
- QEVGZEDELICMKH-UHFFFAOYSA-L 2-(carboxylatomethoxy)acetate Chemical compound [O-]C(=O)COCC([O-])=O QEVGZEDELICMKH-UHFFFAOYSA-L 0.000 claims description 7
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 7
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 claims description 7
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 7
- AFVFQIVMOAPDHO-UHFFFAOYSA-M Methanesulfonate Chemical compound CS([O-])(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-M 0.000 claims description 7
- NBIIXXVUZAFLBC-UHFFFAOYSA-L Phosphate ion(2-) Chemical compound OP([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-L 0.000 claims description 7
- 150000005215 alkyl ethers Chemical class 0.000 claims description 7
- 229940072107 ascorbate Drugs 0.000 claims description 7
- 235000010323 ascorbic acid Nutrition 0.000 claims description 7
- 239000011668 ascorbic acid Substances 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 229940050410 gluconate Drugs 0.000 claims description 7
- 229930195712 glutamate Natural products 0.000 claims description 7
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 claims description 7
- KQNPFQTWMSNSAP-UHFFFAOYSA-N isobutyric acid Chemical compound CC(C)C(O)=O KQNPFQTWMSNSAP-UHFFFAOYSA-N 0.000 claims description 7
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 7
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 claims description 7
- 229960001860 salicylate Drugs 0.000 claims description 7
- JDVPQXZIJDEHAN-UHFFFAOYSA-M succinamate Chemical compound NC(=O)CCC([O-])=O JDVPQXZIJDEHAN-UHFFFAOYSA-M 0.000 claims description 7
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 7
- 229940070710 valerate Drugs 0.000 claims description 7
- FWWOWPGPERBCNJ-UHFFFAOYSA-N 2-hydroxy-4-(2-hydroxyethoxy)-4-oxobutanoic acid Chemical compound OCCOC(=O)CC(O)C(O)=O FWWOWPGPERBCNJ-UHFFFAOYSA-N 0.000 claims description 6
- BWLBGMIXKSTLSX-UHFFFAOYSA-N 2-hydroxyisobutyric acid Chemical compound CC(C)(O)C(O)=O BWLBGMIXKSTLSX-UHFFFAOYSA-N 0.000 claims description 6
- HKAGPQUVIAEHSO-UHFFFAOYSA-M 2-iodobutanoate Chemical compound CCC(I)C([O-])=O HKAGPQUVIAEHSO-UHFFFAOYSA-M 0.000 claims description 6
- KRKNYBCHXYNGOX-UHFFFAOYSA-M 3-carboxy-2-(carboxymethyl)-2-hydroxypropanoate Chemical compound OC(=O)CC(O)(C(O)=O)CC([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-M 0.000 claims description 6
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 6
- QEVGZEDELICMKH-UHFFFAOYSA-N Diglycolic acid Chemical compound OC(=O)COCC(O)=O QEVGZEDELICMKH-UHFFFAOYSA-N 0.000 claims description 6
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 6
- 239000004433 Thermoplastic polyurethane Substances 0.000 claims description 6
- NAFSLMFLGYXGIF-UHFFFAOYSA-N [n'-[n'-(4-chlorophenyl)carbamimidoyl]carbamimidoyl]azanium;chloride Chemical compound Cl.NC(N)=NC(N)=NC1=CC=C(Cl)C=C1 NAFSLMFLGYXGIF-UHFFFAOYSA-N 0.000 claims description 6
- 239000000853 adhesive Substances 0.000 claims description 6
- WNLRTRBMVRJNCN-UHFFFAOYSA-M adipate(1-) Chemical compound OC(=O)CCCCC([O-])=O WNLRTRBMVRJNCN-UHFFFAOYSA-M 0.000 claims description 6
- 125000003342 alkenyl group Chemical group 0.000 claims description 6
- 125000005210 alkyl ammonium group Chemical group 0.000 claims description 6
- 235000010948 carboxy methyl cellulose Nutrition 0.000 claims description 6
- WDRFFJWBUDTUCA-UHFFFAOYSA-N chlorhexidine acetate Chemical compound CC(O)=O.CC(O)=O.C=1C=C(Cl)C=CC=1NC(N)=NC(N)=NCCCCCCN=C(N)N=C(N)NC1=CC=C(Cl)C=C1 WDRFFJWBUDTUCA-UHFFFAOYSA-N 0.000 claims description 6
- 229960001884 chlorhexidine diacetate Drugs 0.000 claims description 6
- 229940114081 cinnamate Drugs 0.000 claims description 6
- SVPIHEFTAQDGFI-UHFFFAOYSA-M dimethyl-octadecyl-(2-trimethoxysilylethyl)azanium;chloride Chemical group [Cl-].CCCCCCCCCCCCCCCCCC[N+](C)(C)CC[Si](OC)(OC)OC SVPIHEFTAQDGFI-UHFFFAOYSA-M 0.000 claims description 6
- WHUUTDBJXJRKMK-UHFFFAOYSA-M glutamate Chemical compound [O-]C(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-M 0.000 claims description 6
- FUZZWVXGSFPDMH-UHFFFAOYSA-M hexanoate Chemical compound CCCCCC([O-])=O FUZZWVXGSFPDMH-UHFFFAOYSA-M 0.000 claims description 6
- QQVIHTHCMHWDBS-UHFFFAOYSA-L isophthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC(C([O-])=O)=C1 QQVIHTHCMHWDBS-UHFFFAOYSA-L 0.000 claims description 6
- 229940001447 lactate Drugs 0.000 claims description 6
- OFOBLEOULBTSOW-UHFFFAOYSA-M malonate(1-) Chemical compound OC(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-M 0.000 claims description 6
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 claims description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 6
- 239000002736 nonionic surfactant Substances 0.000 claims description 6
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical group CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002245 particle Substances 0.000 claims description 6
- 239000011148 porous material Substances 0.000 claims description 6
- KDYFGRWQOYBRFD-UHFFFAOYSA-M succinate(1-) Chemical compound OC(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-M 0.000 claims description 6
- 229920002803 thermoplastic polyurethane Polymers 0.000 claims description 6
- WBYWAXJHAXSJNI-VOTSOKGWSA-M trans-cinnamate Chemical compound [O-]C(=O)\C=C\C1=CC=CC=C1 WBYWAXJHAXSJNI-VOTSOKGWSA-M 0.000 claims description 6
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000004952 Polyamide Substances 0.000 claims description 5
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 5
- 239000008112 carboxymethyl-cellulose Substances 0.000 claims description 5
- 229920001542 oligosaccharide Polymers 0.000 claims description 5
- 150000002482 oligosaccharides Chemical class 0.000 claims description 5
- 230000007170 pathology Effects 0.000 claims description 5
- 229920002647 polyamide Polymers 0.000 claims description 5
- 238000007711 solidification Methods 0.000 claims description 5
- 230000008023 solidification Effects 0.000 claims description 5
- 244000043261 Hevea brasiliensis Species 0.000 claims description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 4
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 claims description 4
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
- 239000006261 foam material Substances 0.000 claims description 4
- 125000001072 heteroaryl group Chemical group 0.000 claims description 4
- 125000000623 heterocyclic group Chemical group 0.000 claims description 4
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- JDRSMPFHFNXQRB-CMTNHCDUSA-N Decyl beta-D-threo-hexopyranoside Chemical compound CCCCCCCCCCO[C@@H]1O[C@H](CO)C(O)[C@H](O)C1O JDRSMPFHFNXQRB-CMTNHCDUSA-N 0.000 claims description 3
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 3
- 229920001710 Polyorthoester Polymers 0.000 claims description 3
- 125000002947 alkylene group Chemical group 0.000 claims description 3
- 229940073499 decyl glucoside Drugs 0.000 claims description 3
- 229930182478 glucoside Natural products 0.000 claims description 3
- PYIDGJJWBIBVIA-UYTYNIKBSA-N lauryl glucoside Chemical compound CCCCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PYIDGJJWBIBVIA-UYTYNIKBSA-N 0.000 claims description 3
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 claims description 3
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- 150000003335 secondary amines Chemical group 0.000 claims description 3
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- HTYFFCPFVMJTKM-UHFFFAOYSA-N 2-(4-chlorophenyl)-1-(diaminomethylidene)guanidine Chemical compound NC(N)=NC(N)=NC1=CC=C(Cl)C=C1 HTYFFCPFVMJTKM-UHFFFAOYSA-N 0.000 claims description 2
- ZILVNHNSYBNLSZ-UHFFFAOYSA-N 2-(diaminomethylideneamino)guanidine Chemical group NC(N)=NNC(N)=N ZILVNHNSYBNLSZ-UHFFFAOYSA-N 0.000 claims description 2
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- ARPJZLLWCWXWJQ-UHFFFAOYSA-N dihydrogen phosphate;ethylazanium Chemical compound CCN.OP(O)(O)=O ARPJZLLWCWXWJQ-UHFFFAOYSA-N 0.000 claims 1
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- QCGQQHKOYONPIO-UHFFFAOYSA-M octadecyl-dipropyl-(2-trimethoxysilylethyl)azanium;acetate Chemical compound CC([O-])=O.CCCCCCCCCCCCCCCCCC[N+](CCC)(CCC)CC[Si](OC)(OC)OC QCGQQHKOYONPIO-UHFFFAOYSA-M 0.000 claims 1
- 230000000699 topical effect Effects 0.000 abstract description 17
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- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 17
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- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 12
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- PRIVYYLGCISZCL-UHFFFAOYSA-M hexadecyl-dimethyl-(2-trimethoxysilylpropyl)azanium;chloride Chemical compound [Cl-].CCCCCCCCCCCCCCCC[N+](C)(C)CC(C)[Si](OC)(OC)OC PRIVYYLGCISZCL-UHFFFAOYSA-M 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
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- 229960001680 ibuprofen Drugs 0.000 description 1
- WPKHBCAWHARYQZ-UHFFFAOYSA-M icosyl-dimethyl-(2-trimethoxysilylpropyl)azanium;benzoate Chemical compound [O-]C(=O)C1=CC=CC=C1.CCCCCCCCCCCCCCCCCCCC[N+](C)(C)CC(C)[Si](OC)(OC)OC WPKHBCAWHARYQZ-UHFFFAOYSA-M 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/34—Shaped forms, e.g. sheets, not provided for in any other sub-group of this main group
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N25/00—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests
- A01N25/08—Biocides, pest repellants or attractants, or plant growth regulators, characterised by their forms, or by their non-active ingredients or by their methods of application, e.g. seed treatment or sequential application; Substances for reducing the noxious effect of the active ingredients to organisms other than pests containing solids as carriers or diluents
- A01N25/10—Macromolecular compounds
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N47/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid
- A01N47/40—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides
- A01N47/42—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom not being member of a ring and having no bond to a carbon or hydrogen atom, e.g. derivatives of carbonic acid the carbon atom having a double or triple bond to nitrogen, e.g. cyanates, cyanamides containing —N=CX2 groups, e.g. isothiourea
- A01N47/44—Guanidine; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N55/00—Biocides, pest repellants or attractants, or plant growth regulators, containing organic compounds containing elements other than carbon, hydrogen, halogen, oxygen, nitrogen and sulfur
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/22—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons containing macromolecular materials
- A61L15/28—Polysaccharides or their derivatives
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/425—Porous materials, e.g. foams or sponges
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/46—Deodorants or malodour counteractants, e.g. to inhibit the formation of ammonia or bacteria
-
- 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
- A61L15/00—Chemical aspects of, or use of materials for, bandages, dressings or absorbent pads
- A61L15/16—Bandages, dressings or absorbent pads for physiological fluids such as urine or blood, e.g. sanitary towels, tampons
- A61L15/42—Use of materials characterised by their function or physical properties
- A61L15/48—Surfactants
-
- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
- A61L2300/206—Biguanides, e.g. chlorohexidine
-
- 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
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
- A61L2300/208—Quaternary ammonium 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
- 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
Definitions
- the present invention relates to an anti-microbial composition for use as a component of a topical anti-microbial device; in particular an absorbent device, such as a medical absorbent device, for example an absorbent wound dressing, and an absorbent device for the personal care sector; and a medical cushioning device; a process for the manufacture of such devices, and to a method of prophylactic and therapeutic use of the device
- the term 'absorbent component' as used herein refers to any conformable component of an antimicrobial device for the antimicrobial treatment of animate surfaces, such as the skin of a human or animal.
- the absorbent component comprises a synthetic or natural porous absorbent material that is substantially insoluble in a relevant bodily fluid, such as wound exudate, menses or urine, but absorbs the fluid.
- the absorbent component may be in a medical absorbent device, such as an absorbent wound dressing, or in a non-medical absorbent device for the personal care sector.
- the absorbent component has a proximal face, as defined herein, which in use of the device will be in direct or fluidic contact with the skin of a human or animal.
- 'absorbent device' as used herein includes medical absorbent devices and non-medical absorbent devices, as defined herein.
- an absorbent device comprising a water-insoluble antimicrobial absorbent material as defined herein, in which an absorbent component cushioning devices exudate migration and/or absorption and retention of a relevant bodily fluid, such as wound exudate when in a medical absorbent device, such as an absorbent wound dressing, or such as menses or urine when in a non-medical absorbent device, such as a disposable sanitary device.
- a relevant bodily fluid such as wound exudate when in a medical absorbent device, such as an absorbent wound dressing, or such as menses or urine when in a non-medical absorbent device, such as a disposable sanitary device.
- Absorption of a relevant bodily fluid may occur in two dimensions (for example in an absorbent dressing or a sanitary towel), or three dimensions (for example in a deep-wound dressing or a tampon).
- the term 'absorbent material' as used herein is defined herein under "absorbent component" above.
- Such an absorbent material may be in the form of fibres, such as in an, often non-woven, fabric or a more random assembly of fibres, for example of randomly spun fibres; it may be in the form of a particulate. It may have fluids (including air) in its interstices and/or synthetic or natural biological or chemical agents in its interstices and/or its structural members.
- 'antimicrobial' as used herein in relation to a therapeutically active material includes materials which have
- MRSA Methicillin-resistant Staphylococcus aureus
- Clostridium difficile Salmonella typhimurium, Leigonella, Listeria monocytogenes and Escherichia coli
- antimycotic activity including against one or more of Aspergillus niger and Candida albicans, and/or
- 'antimicrobial device' as used herein means a device for the antimicrobial treatment of animate surfaces, and includes
- a medical device which is an absorbent device, such as an absorbent wound dressing used in the treatment of acute wounds, including surgical wounds, and chronic and burn wounds; an ostomy device, or a surgical or dental sponge; a non-medical device which is an absorbent device, such as one for use in the personal care sector, in particular for disposable sanitary devices such as nappies (diapers), disposable nappies and training pants, and feminine care products, for example, tampons, sanitary towels, or napkins and pant liners, and incontinence products, and
- a medical device which is an absorbent or non-absorbent cushioning device, such as a cushioning layer or cushioning device used in the prophylaxis or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and/or ulcers.
- an absorbent or non-absorbent cushioning device such as a cushioning layer or cushioning device used in the prophylaxis or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and/or ulcers.
- biocompatible refers to any material which does not induce adverse effects such as immunological reactions and/or rejections in a human or animal.
- biodegradable refers to any material which can be degraded and bioresorbed into the physiological environment.
- biodegradable materials include carboxymethylcellulose materials, carboxymethylchitosan materials, hyaluronic acid- and alginate-based materials; and certain copoly(etheresters), and poly(alkylene oxides).
- conformable container herein in relation to the absorbent material in an absorbent component in an absorbent device refers to any container, such as an envelope, pouch or sachet.
- Such a container may be formed by the proximal cover of a synthetic or natural layer or sheet material being attached to a dressing backing layer.
- a container may be, for example a stand-alone envelope, pouch or sachet, which in use lies between the wound and the backing layer, and may be attached to a dressing backing layer, and may be an 'inner container', contained in another stand-alone conformable Outer container').
- 'cushioning component' refers to any conformable component of a cushioning device, or a cushioning device which consists essentially of such a component, which may be used in the treatment or prophylaxis of wound precursors, as defined herein and chronic wounds, on or in the skin of a human or animal, or in the tissue underlying it. It comprises a cushioning material that is substantially insoluble in a relevant bodily fluid,
- the term 'cushioning device' as used herein refers to any conformable medical device, which is used to relieve pressure on a pressure-sensitive area of a human or animal, and acts as a source of topical therapeutic agents.
- the cushioning device is thus used for the prophylaxis and/or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and ulcers on or in the skin, or in the tissue underlying it. .
- 'cushioning material' is the cushioning material in a medical cushioning device or cushioning component, and is a soft, flexible often polymeric material that is substantially insoluble in a relevant bodily fluid. Such materials may also often be hydrophobic.
- references to "derivatised” in relation to a material herein is to a substance, for example a quaternary ammonium salt or a cationic antimicrobial (which may be a guanidine-containing antimicrobial) substituted by a tris(hydrocarbyl or hydrocarbyloxy)-silylhydrocarbyl group.
- aqueous in the context of an aqueous medium is meant herein that the medium comprises at least 85%, for example at least 90%, such as at least 95% w/w water.
- the terms "medical” and “non-medical” in relation to a device herein are as defined herein under “antimicrobial device", and may relate to an absorbent medical or non-medical device or a non-absorbent medical cushioning device.
- micro in relation to a particulate or fibrous material herein means that the majority of particle or fibre diameters in the material are less than 100 micrometres.
- nano in relation to a particulate or fibrous material herein means that the majority of particle or fibre diameters in the material are less than 100 nanometres.
- non-biodegradable refers to any material which cannot be degraded and bioresorbed into the physiological environment.
- non-biodegradable materials include polyalkylenes, such as polyethylene, polypropylene and polybutylene, and combinations thereof.
- non-woven in relation to fabrics in the absorbent component means that the majority of fibres in the fabric are neither woven nor knit together. They are typically manufactured by putting small fibres together to form a sheet or web, and then binding them together mechanically, with an adhesive, or by thermal bonding, in particular by spin bonding.
- Organic or inorganic acyl' as used herein includes organic acid residues such as carboxyl and inorganic acid residues such as sulpho.
- acylhydrocarbyl substituted polysaccharide means a polysaccharide derivatised by optionally salified HORO groups, where HOR is a hydrocarbyl oxoacid residue.
- polysaccharide' as used herein means any polymeric carbohydrate structure, formed of repeat monomer units which are monosaccharides joined together by glycosidic bonds, with two free hydroxyl functions and optionally one amine function per monomer unit, typically having between 200 and 2500 monomer units in the polymer molecule.
- These structures include linear homopolysaccharides, such as celluloses, chitosans and alginates.
- the term also includes derivatised polysaccharides, such as carboxymethyl celluloses and carboxymethyl chitosans.
- substitution may take place at any hydroxyl position and/or at the amine group up to a hypothetical mean maximum degree of conversion of 2 hydroxyl groups per monomer unit of the polysaccharide.
- the average degree of substitution in the derivatised polysaccharides used in devices is often less than 0.8, such as less than 0.7, for example less than 0.6.
- the average molecular weight of such a polysaccharide is often between 3800 to 20,000 daltons. Such polysaccharides are substantially insoluble in water.
- proximal in relation to a face of a component in a device is meant herein that the face is a body-facing face in general or a wound-facing face in a wound dressing in use.
- distal in relation to a face of a component in a device is meant herein that the face faces away from the body in general or away from a wound in a wound dressing.
- substantially water-insoluble in relation to a material is meant herein that the material is soluble in an aqueous medium to less than 1 % w/w.
- synthetic herein means any material that is not found in nature, and the term “semi-synthetic” means made from naturally occurring biomaterials. Examples include respectively plastics polymers and derivatised polysaccharides.
- wound in relation to the present invention means any soft tissue with compromised integrity, including acute wounds, such as surgical and infectious disease wounds; chronic wounds, such as diabetic ulcers or venous leg ulcers; and burns.
- wound contact integer as used herein includes a component in a wound dressing which comprises a porous absorbent component and optionally an elastically resilient, for example a foam, wound filler which lies distally of the absorbent component.
- wound precursor herein means any condition on or in the skin of a human or animal, or in the tissue underlying it, which in the absence of treatment is at substantial risk of developing into tissue of compromised integrity, such tissue including chronic wounds, including pressure sores, ulcers and infected wounds.
- tissue of compromised integrity such tissue including chronic wounds, including pressure sores, ulcers and infected wounds.
- Such conditions on or in the skin of a human or animal or in the tissue underlying it include discomfort, inflammation, pain and haematoma, which may be caused or exacerbated by pressure on the skin.
- Such therapeutically active materials have good activity in contact with wound exudate, for example when in a dressing component which has a proximal surface. It Is also preferred that they and the other component materials in the compositions are biodegradable and biocompatible with human and animal tissue, as well as more preferably being odourless, and when in a dressing component having wound healing capability.
- such a therapeutically active material should be in a water-insoluble form which does not dissolve into solution to be uncontrolledly released from the dressing to any significant extent.
- the therapeutically active component of the dressing is an ionic material that is soluble when exposed to a highly aqueous medium such as a bodily fluid on a body surface or wound exudate, in particular in the latter case at the pH levels found in some chronic wounds at a typical patient body temperature.
- compositions comprising a derivatised cationic antimicrobial, in particular a water-soluble derivatised quaternary ammonium salt and a water- soluble underivatised cationic antimicrobial, in particular an underivatised cationic antimicrobial, such as an underivatised quaternary ammonium salt, or an underivatised guanidine based salt or a mixture thereof, all as defined as a biocidal component of a water-soluble composition for the treatment of inanimate surfaces, such as floors. Since the composition is only used on inanimate surfaces, such as floors, the other component materials in the compositions may be non-biodegradable and not biocompatible with human and animal tissue, as well as not having specific wound healing capability and not being odourless.
- composition occurs to a significant extent when the composition is exposed to a highly aqueous medium at a typical patient body temperature, such as a bodily fluid on a body surface or wound exudate, in particular a bodily fluid on a body surface or at the pH levels found in some chronic and burn wounds.
- a highly aqueous medium at a typical patient body temperature such as a bodily fluid on a body surface or wound exudate, in particular a bodily fluid on a body surface or at the pH levels found in some chronic and burn wounds.
- Another technical problem of the prior art is that the longer-term stability of the derivatised quaternary ammonium salt in an aqueous fluid is sub-optimal.
- compositions may be non-biodegradable and not biocompatible with human and animal tissue, as well as not having specific wound healing capability and not being odourless, which makes the known derivatised quaternary ammonium salts compositions highly unsuitable for use as antimicrobial materials in antimicrobial medical devices such as wound dressings, and non- medical device, such as one for use in the personal care sector.
- composition for an antimicrobial device, such as a medical device such as a wound dressing, and a non-medical device, such as one for use in the personal care sector, which composition comprises a water-insoluble form of a quaternary ammonium salt and a cationic antimicrobial salt, which is not released or only controlledly and relatively slowly released, on contact with the bodily fluids of a patient or user.
- Such a composition should have longer-term stability on contact with an aqueous fluid. This is especially the case when it is exposed to a highly aqueous medium, such as a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic wounds.
- an a solid substantially water-insoluble antimicrobial composition for a device comprising
- each of R 1 , R 2 and R 3 is an optionally substituted hydrocarbyl group, and R 4 is an optionally substituted hydrocarbadiyl group,
- a group R 5 which is an optionally substituted hydrocarbyl group
- a solid substantially water-insoluble carrier within to and/or within which the derivatised quaternary ammonium salt is attached and/or dispersed; and c) at least one salt of an underivatised cationic antimicrobial.
- the underivatised cationic antimicrobial, c) may be an underivatised quaternary ammonium salt or an underivatised guanidine-based salt.
- a topical anti-microbial device comprising a solid substantially water-insoluble antimicrobial composition of the first aspect of the present invention.
- the device may be an absorbent device, such as a medical absorbent device, for example an absorbent wound dressing, an absorbent device for the personal care sector; and/or a medical cushioning device.
- a medical absorbent device for example an absorbent wound dressing, an absorbent device for the personal care sector; and/or a medical cushioning device.
- the antimicrobial composition of the first aspect of the present invention is often in particular comprised in an absorbent material in an absorbent component, but may be comprised another integer of the absorbent component, such as the proximal cover of a conformable container, which contains the absorbent material.
- the antimicrobial composition is often comprised in a cushioning material in a cushioning component, but may be comprised another integer of the cushioning component.
- the derivatised quaternary ammonium salt and underivatised cationic antimicrobial in the composition of this first aspect of the present invention are highly advantageous for use as antimicrobial materials in medical and nonmedical absorbent devices. This is for the following reasons:
- Each of the derivatised quaternary ammonium salt and the underivatised cationic antimicrobial used in the composition is per se water-soluble, and has longer- term instability, in an aqueous medium.
- Such media include a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds).
- Each salt is rendered stable and substantially water-insoluble, but still therapeutically active, by being attached and/or dispersed within a solid substantially water-insoluble carrier.
- composition has good antimicrobial activity in contact with a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds, for example when in a medical device such as a wound dressing, or a non-medical device, such as one for use in the personal care sector.
- compositions of the invention thus exhibit a surprising and advantageously diminished or negligible degree and rate of release by a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds of the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c), for example in an antimicrobial device, such as a dressing.
- an antimicrobial device such as a dressing.
- the rate and degree of release can be controlled in particular by the choice of a) the derivatised quaternary ammonium salt,
- the derivatised quaternary ammonium salt and solid substantially water-insoluble carrier may be linked by covalent bonding, optionally with condensation and/or cross-linking, as described further hereinafter.
- Treatment or prophylaxis of microbial infections using an antimicrobial composition according to this first aspect of the present invention does not cause microbial resistance, for example by
- bacteria such as Staphylococcus aureus (MRSA), Clostridium difficile, Salmonella typhimurium, Leigonella, Listeria monocytogenes and Escherichia coli,
- mycotic species including Aspergillus niger and Candida albicans, and/or viruses,
- wound dressing for wounds, including acute wounds, including surgical wounds, and chronic and burn wounds, but also when in topically applied personal care devices, and medical cushioning devices.
- compositions of this first aspect of the present invention which comprises derivatised quaternary ammonium salts and underivatised cationic antimicrobial highly suitable for prophylactic and therapeutic use as antimicrobial materials in antimicrobial devices.
- Each of R 1 , R 2 , R 3 and R 4 may independently be oxa-substituted, preferably to produce R 1 , R 2 and R 3 optionally substituted hydrocarbyloxy groups, and, for example to produce an R 4 optionally substituted hydrocarbylene group with an internal ether linkage.
- Each of R 1 , R 2 , R 3 and R 4 may independently be oxa-substituted, preferably to produce R 1 , R 2 and R 3 optionally substituted hydrocarbyloxy groups, and, for example to produce an R 4 optionally substituted hydrocarbadiyl group with an internal ether linkage.
- Each of R 1 , R 2 and R 3 independently may be an optionally oxa-substituted alkyl group, preferably a lower alkyl group with 1 to 6 carbon atoms, such as a methyl, ethyl, propyl or butyl group, preferably a methyl group. Any propyl or butyl group is preferably attached in the 1 -position to the silicon atom.
- Each of R 1 , R 2 and R 3 is preferably a hydrocarbyloxy residue, for example a lower alkoxy group with 1 to 6 carbon atoms.
- R 1 , R 2 and R 3 may thus suitably be, for example, a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, preferably a methoxy group.
- Any component propyl or butyl group group is preferably attached in the 1 -position to the oxygen atom.
- the alkyl moiety in all the above groups may be branched or unbranched, and hence suitable butyl groups may be n-butyl, iso-butyl or tert. butyl groups. Most preferably, such R 1 , R 2 and R 3 groups are the same.
- the most preferred R 1 , R 2 and R 3 residue is a methoxy residue.
- R 1 , R 2 and R 3 independently may also suitably be an aryl group, such as phenyl or tolyl, preferably phenyl.
- aryl group such as phenyl or tolyl, preferably phenyl.
- R 1 , R 2 and R 3 is an aryl group, such as phenyl.
- Each of R 1 , R 2 and R 3 independently may be an optionally oxa-substituted aralkyl group, preferably a lower alkyl group with 1 to 6 carbon atoms, such as a methyl, ethyl, propyl or butyl group, preferably a methyl group, substituted by an aryl group, such as phenyl or tolyl, preferably phenyl. Any component propyl or butyl group is preferably attached in the 1 -position to the silicon atom.
- Each of R 1 , R 2 and R 3 independently may be an aralkoxy group.
- Each of R 1 , R 2 and R 3 may thus suitably be, for example, a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, preferably a methoxy group, substituted by an aryl group, such as phenyl or tolyl, preferably phenyl.
- R 1 , R 2 and R 3 is an aralkyl group, such as benzyloxy. Any component propyl or butyl group is preferably attached in the 1 -position to the oxygen atom.
- the alkyl moiety in all the above groups may be branched or unbranched, and hence suitable butyl groups may be n-butyl, iso-butyy or tert. butyl groups.
- R 4 is an optionally substituted hydrocarbadiyl group, which may be oxa-substituted, for example to produce an R 4 optionally substituted hydrocarbadiyl group with an internal ether linkage.
- R 4 may be an optionally oxa-substituted alkanediyl group, preferably a lower alkylene group with 1 to 6 carbon atoms, such as a methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl or butan-1 ,4-diyl group, preferably an ethan-1 ,2-diyl group.
- R 5 is an optionally substituted hydrocarbyl group, which may be oxa-substituted, for example to produce an R 5 optionally substituted hydrocarbyl group with an internal ether linkage.
- R 5 may be an optionally oxa-substituted alkyl group, preferably a higher alkyl group with 8 to 22 carbon atoms, such as an octyl, decyl, dodecyl, tetradecyl, hexadecyl (cetyl or palmityl), octadecyl or eicosyl group.
- the alkyl moiety may be branched or unbranched, and oxa-substituted, for example to produce an R 5 optionally substituted unsaturated hydrocarbyl group with an internal ether linkage.
- Examples include 3,6-dioxa- substituted higher alkyl groups with 8 to 22 carbon atoms, more preferably such an octadecyl group, in which case, if the remaining N-substituents are methyl groups, the derivatised quaternary ammonium salt is a derivatised benzethonium salt congener.
- R 5 may be an optionally oxa-substituted alkenyl group, preferably a higher alkenyl group with 8 to 22 carbon atoms, such as an octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl or eicosenyl group.
- the alkenyl moiety may be branched or unbranched, and oxa-substituted. It may be in a cis- or trans- configuration about any double bond.
- Examples include a cis-octadec-9-en-1 -yl moiety, which is an oleyl moiety; and a cis-, cis-octadeca- 9,12-dien-1 -yl moiety which is a linoleyl moiety,
- R 5 is preferably an unbranched unsubstituted higher alkyl group with 8 to 22 carbon atoms, more preferably such an octadecyl group.
- Each of the two remaining N-substituents other than the tris(hydrocarbyl or hydrocarbyloxy)-silylhydrocarbyl group of formula (I) and R 5 may independently be an alkyl group, preferably an optionally substituted lower alkyl group with 1 to 6 carbon atoms, such as a methyl, ethyl or propyl, preferably methyl.
- the alkyl moiety may be branched or unbranched, and hence suitable propyl may be n- propyl or iso-propyl.
- One of the groups may be an aralkyl group, such as benzyl, in which case, if the remaining N-substituent is a methyl group, the derivatised quaternary ammonium salts is a derivatised benzalkonium salt.
- the groups are the same and are methyl groups. Less preferably they may also independently be an aryl group, such as phenyl or tolyl, preferably phenyl. They may also independently be an optionally oxa-substituted aralkyl group, such as benzyl. Each group may thus be an aryloxyalkyl group.
- the alkyl moiety may be branched or unbranched, and hence suitable propyl may be n-propyl or iso-propyl. Any component propyl or butyl group is preferably attached in the 1 -position to the nitrogen atom.
- one of the groups is an aryl or optionally oxa-substituted aralkyl group.
- the other may be an alkyl group, preferably methyl.
- any N- substituent in the derivatised quaternary ammonium salt will depend on the type and size of, and steric hindrance around the nitrogen atom of the derivatised quaternary ammonium salt caused by, the other substituent groups present.
- the anion of the derivatised quaternary ammonium salt for prophylactic and therapeutic use as antimicrobial materials in antimicrobial compositions of the first aspect of the present invention may be any pharmacologically acceptable anion.
- Any pharmacologically acceptable anion may be selected from the anion of an inorganic acid, such as chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, or
- an organic acid such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate.
- an organic acid such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate
- the anion may be a pharmacologically acceptable dianion, when there will be two derivatised quaternary ammonium cations per dianion, which may be then selected from a dianion of
- an inorganic diacid such as sulphate, hydrogen phosphate and/or hydrogen difluorophosphate
- an organic diacid such as succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
- Examples of the salt thus include salts with an inorganic acid, such as chloride, sulphate and/or phosphate.
- Examples of the salt also include salts with an organic acid, such as a organic acid, for example acetate, benzoate, tartrate, adipate, lactate, maleate, glutamate, ascorbate, citrate, gluconate, succinate, pamoate, salicylate, isethionate, succinamate, mono-diglycollate, methanesulphonate, isobutyrate,/or glucoheptonate.
- a organic acid for example acetate, benzoate, tartrate, adipate, lactate, maleate, glutamate, ascorbate, citrate, gluconate, succinate, pamoate, salicylate, isethionate, succinamate, mono-diglycollate, methanesulphonate, isobutyrate,/or glucoheptonate.
- Favoured anions include halides, for example chloride and bromide.
- Preferred derivatised quaternary ammonium salts for use in antimicrobial medical compositions of the first aspect of the present invention include derivatised quaternary ammonium salt, wherein the quaternary ammonium salt is N- substituted by
- each of R 1 , R 2 and R 3 is a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, preferably a methoxy group, and any component propyl or butyl group group is preferably attached in the 1 -position to the oxygen atom.
- R 4 is a methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl or butan-1 ,4-diyl group, preferably an ethan-1 ,2-diyl group,
- a group R 5 which is a dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl group, which may be branched or unbranched and/or oxa-substituted to produce a higher alkyl group with an internal ether linkage.
- More preferred derivatised quaternary ammonium salts for use in antimicrobial compositions of the first aspect of the present invention include derivatised quaternary ammonium salts such as
- N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium acetate N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium tartrate, N,N-dimethyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium chloride,
- derivatised quaternary ammonium salts in antimicrobial compositions of the first aspect of the present invention include derivatised quaternary ammonium salts such as
- the composition may suitably comprise up to 10 wt% of the derivatised quaternary ammonium salt component a), favourably up to 7.5 wt%, preferably up to 5 wt%, more preferably up to 3 wt%.
- the composition comprises at least 0.001 wt% of the derivatised quaternary ammonium salt component a), favourably at least 0.1 wt%, more favourably at least 0.5 wt%, preferably at least 0.7 wt%, more preferably at least 0.9 wt%, especially at least 1 wt%.
- a mixture of two or more derivatised quaternary ammonium salts may be present in component a) of the compositions of the present invention.
- the above amounts refer to the combination of all the derivatised cationic antimicrobials present.
- the above amounts refer to the combination of all the underivatised cationic antimicrobials present.
- component a) consists of one derivatised quaternary ammonium salt.
- composition of the present invention also comprises at least one cationic antimicrobial component c).
- Preferred cationic antimicrobials for use herein include underivatised quaternary ammonium-based antimicrobials and guanidine-based cationic antimicrobials.
- component c) comprises one cationic antimicrobial.
- the composition may suitably comprise up to 10 wt% cationic antimicrobial component c), favourably up to 7.5 wt%, preferably up to 5 wt%, more preferably up to 3 wt%.
- the composition may comprise at least 0.001 wt% of cationic antimicrobial component c), favourably at least 0.1 wt%, more favourably at least 0.5 wt%, preferably at least 0.7 wt%, more preferably at least 0.9 wt%, especially at least 1 wt%.
- a mixture of two or more cationic antimicrobial components may be present in component c) of the compositions of the present invention.
- the above amounts refer to the combination of all the underivatised cationic antimicrobials present.
- Such a mixture of two or more cationic antimicrobial components present in component c) of the compositions of the present invention may be a combination of two or more underivatised quaternary ammonium-based antimicrobials, of two or more guanidine-based cationic antimicrobials, including guanidine-based compounds, diguanidine-based compounds and polymeric guanidine-based compounds, or of at least one underivatised quaternary ammonium-based antimicrobial and at least one guanidine-based cationic antimicrobial.
- component c) comprises one cationic antimicrobial.
- Suitable quaternary ammonium cationic antimicrobials have the structure shown in formula (II):
- R 8 where each of R 6 , R 7 , R 8 and R 9 is an optionally substituted alkyl, alkenyl, aralkyl or aryl group and X " is an anion.
- suitable groups R 6 , R 7 , R 8 and R 9 are as so described hereinbefore in relation to corresponding groups, other than groups of formula (I), which form the derivatised quaternary ammonium salts for use in antimicrobial medical compositions of the first aspect of the present invention include derivatised quaternary ammonium salts of component a) of the compositions of the present invention.
- each of R 6 , R 7 , R 8 and R 9 is an optionally substituted alkyl or aralkyl I group, more preferably an unsubstituted alkyl or aralkyl group.
- R 6 is an optionally oxa-substituted alkyl group, preferably a higher alkyl group with 8 to 22 carbon atoms, such as an octyl, decyl, dodecyl, tetradecyl, hexadecyl (cetyl or palmityl), octadecyl or eicosyl group.
- the alkyl moiety may be branched or unbranched. It may also be oxa-substituted, for example to produce an R 5 optionally substituted unsaturated hydrocarbyl group with an internal ether linkage.
- Examples include 3,6-dioxa-substituted higher alkyl groups with 8 to 22 carbon atoms, more preferably such an octadecenyl group, in which case, if the remaining N-substituents are methyl groups, the derivatised quaternary ammonium salt is a benzethonium salt congener.
- R 6 may be an optionally oxa-substituted alkenyl group, preferably a higher alkenyl group with 8 to 22 carbon atoms, such as an octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl or eicosenyl group.
- the alkenyl moiety may be branched or unbranched, and oxa-substituted. It may be in a cis- or trans- configuration about any double bond.
- R 7 may be an optionally substituted lower alkyl group with 1 to 6 carbon atoms, such as methyl, ethyl or propyl, preferably methyl.
- the alkyl moiety may be branched or unbranched, and hence suitable propyl may be n-propyl or iso-propyl.
- the groups are the same and are methyl groups.
- R 7 may be an optionally substituted higher alkyl groups with 8 to 22 carbon atoms, such as an octyl, decyl, dodecyl, tetradecyl, hexadecyl (cetyl or palmityl), octadecyl or eicosyl group.
- the alkyl moiety may be branched or unbranched.
- R 7 may be an aralkyl group, in which case, the alkyi moiety is favourably a lower alkyi group with 1 to 6 carbon atoms, such as methyl, ethyl or propyl, preferably methyl.
- the alkyi moiety may be branched or unbranched, and hence suitable propyl may be n-propyl or iso-propyl.
- the aryl group is phenyl to form an R 6 benzyl group.
- Each of R 8 and R 9 may independently be an alkyi group, preferably an optionally substituted lower alkyi group with 1 to 6 carbon atoms, such as a methyl, ethyl or propyl, preferably methyl.
- the alkyi moiety may be branched or unbranched. Most preferably, the groups are the same and are methyl groups.
- each of R 7 , R 8 and R 9 may independently be an alkyi group, preferably an optionally substituted lower alkyi group with 1 to 6 carbon atoms, such as a methyl, ethyl or propyl, preferably methyl.
- the alkyi moiety may be branched or unbranched. Most preferably, the groups are the same and are methyl groups.
- Favoured component c) quaternary ammonium cationic antimicrobials with the structure shown in formula (II) include those N-substituted by one or more unsubstituted higher alkyi groups, or one aralkyl group, optionally with an unsubstituted higher alkyi group, the remaining N-substituents each independently being an unsubstituted lower alkyi group.
- Any pharmacologically acceptable anion X " may be used.
- X may be selected from an the anion of
- an inorganic acid such as chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, or
- an organic acid such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate.
- an organic acid such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate
- X " may be a pharmacologically acceptable dianion, X 2" , when there will be two quaternary ammonium cations with the structure shown in formula (II) per dianion X 2" may be then selected from a dianion of
- an inorganic diacid such as sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, or
- an organic diacid such as succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
- Favoured anions include halides, example chloride and bromide.
- X is chloride or bromide.
- N,N-trimethyl-N-octadecylammonium chloride in particular N,N-trimethyl-N-octadecylammonium chloride, .
- N-benzyl-N,N-dimethyl-N-C 8 - 22 alkylammonium chloride or bromide N-benzyl-N,N-dimethyl-N-C 8 - 22 alkylammonium chloride or bromide.
- Suitable underivatised guanidine-based cationic antimicrobials for component c) include guanidine-based compounds, diguanidine-based compounds and polymeric guanidine-based compounds.
- Component c) may comprise at least one, preferably, only one, such cationic antimicrobial, and in that case no quaternary ammonium-based antimicrobial.
- Suitable guanidine-based compounds include biguanidine and polymeric guanidine compounds of formula (III): Y 1 - [ X 1 - NH - C - NH - C - NH -X 2 - ] m - Y 2 [ H+ X ] n (III)
- NZ 1 NZ 2 wherein X 1 and X 2 are either a bond or an aliphatic, cycloaliphatic, aromatic, substituted aliphatic, substituted aromatic, heteroaliphatic, heterocyclic, and/or heteroaromatic divalent residue, and X 1 and X 2 may be the same or different; Y 1 and Y 2 are an aliphatic, cycloaliphatic, aromatic, substituted aliphatic, substituted aromatic, heteroaliphatic, heterocyclic, and/or heteroaromatic divalent residue, and Y 1 and Y 2 may be the same or different:
- m is a number equal to or greater than 1 ;
- Z 1 and Z 2 are either a hydrogen atom or a salt.
- Z 1 and Z 2 may be the same or different;
- n 1 or 2
- a proton H + is N-bonded to one or two of the secondary amine groups to form a secondary ammonium group
- X " is an anion or X " 2 is two anions or a dianion.
- the biguanide residue includes two protons H + each N- bonded to a different one of the three secondary amine groups to form a secondary ammonium group, and there are two X " anions or one X 2 " anion per biguanide residue.
- the former salts include chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidine di-valerate and chlorhexidine dicaproate.
- Examples of the latter include chlorhexidine succinate, chlorhexidine malate, chlorthexidine tartrate and chlorhexidine malonate.
- m has an average value such that the molecular weight of the biguanide residues is about 1000-1400. However, the molecular weight may be higher or lower. Generally m is about 2-20.
- n is 1 and X ⁇ is a pharmacologically acceptable anion, or n is 2 and X ⁇ 2 is two anions, any pharmacologically acceptable anion X " may be used.
- X " may be selected from an anion from
- an inorganic acid such as chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate
- an organic acid such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate.
- n is 2 and X " 2 is a pharmacologically acceptable dianion, any pharmacologically acceptable dianion X “ 2 may be used.
- X " 2 may be selected from a dianion from
- an inorganic diacid such as sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, or
- an organic diacid such as succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate, pamoate and tartrate.
- Examples of these compounds include those salts listed above of polyhexamethylene biguanide (PHMB), p-chlorophenyl biguanide and 4- chlorobenzhydryl biguanide.
- PHMB polyhexamethylene biguanide
- p-chlorophenyl biguanide 4- chlorobenzhydryl biguanide.
- the salts include, but are not limited to, polyhexamethylene biguanide hydrochloride (PHMB), p-chlorophenyl biguanide hydrochloride, and 4-chlorobenzhydryl biguanide hydrochloride.
- the biguanide residue includes, but is not limited to, halogenated hexidine compounds including those salts listed above of chlorhexidine (1 ,1 -hexamethylene-bis-5-(4-chlorophenyl biguanide).
- salts include, but are not limited to, chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dichloride and chlorhexidine dihydroiodide,
- composition of the present invention may further comprise one or more surfactants.
- a surfactant will often be residues of a surfactant used in the process for producing the solid substantially water-insoluble antimicrobial composition according to this first aspect of the present invention to promote wetting of the carrier.
- any such surfactant should promote wetting of the carrier without competing with the derivatised quaternary ammonium salt for typical sites of attachment to the solid carrier by pairing of ions of opposite charges, typically the anions of salts, such as of salified carboxylic acids.
- Favoured surfactants thus include nonionic surfactants, such as polymeric material of which the largest part (by weight) consists of homo- or copolymers of oxyolefins such as oxyethylene, oxypropylene, oxybutylene or oxy-4-methyl-l- pentene.
- polyoxyethylene alkyl ethers (Brij), for example of the formula: CH 3 -(CH 2 )io-i6-(O-C 2 H 4 ) _25-OH, such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether; and polyoxypropylene glycol alkyl ethers, for example of the formula: CH 3 -(CH 2 )io-i6-(O-C 3 H6)i-25-O; and
- Such non-Ionic surfactants preferably comprise residues of an oligosaccharide with alkylated hydroxyl functions, typically oligoglucoside alkyl ethers, for example decyl glucoside, dodecyl glucoside, octyl glucoside and decyl octyl glucoside (APG). These are often formed by an alkylation reaction between a function such as the anion of an alkali metal oxide, such as a sodium oxide group, in the oligosaccharide.
- oligoglucoside alkyl ethers for example decyl glucoside, dodecyl glucoside, octyl glucoside and decyl octyl glucoside (APG).
- APG decyl octyl glucoside
- compositions of the invention exhibit a surprising and advantageously diminished or negligible degree and rate of release by water of the derivatised quaternary ammonium salt a), and of any cationic antimicrobial c). This is in particular the case when they are exposed to a highly aqueous medium, such as a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds).
- the rate and degree of release can be controlled in particular by the choice of a) the derivatised quaternary ammonium salt,
- the derivatised quaternary amnnoniunn salts comprise a tris(hydrocarbyl) or tris(hydrocarbyloxy) -silylhydrocarbyl group of formula (I): R 1 (R 2 ) (R 3 ) Si R 4 (I) in which each of R 1 , R 2 , R 3 and R 4 is as hereinbefore defined, by which the ionic therapeutically active derivatised quaternary ammonium salt may be attached to a solid substantially water-insoluble carrier.
- the primary purpose of the solid substantially water-insoluble carrier component b) is to render the derivatised quaternary ammonium salt a), and it is also believed the cationic antimicrobial salt c), substantially water- insoluble, but still therapeutically active, by being attached to and/or dispersed in a solid substantially water-insoluble carrier.
- compositions of the invention thus exhibit a surprising and advantageously diminished or negligible degree and rate of release by water of the derivatised quaternary ammonium salt, in particular when it is exposed to a highly aqueous medium, such as a bodily fluid on a body surface or wound exudate, in the latter case in particular at the pH levels found in some chronic and burn wounds.
- the rate and degree of release can be controlled in particular by the choice of the derivatised quaternary ammonium salt and the material(s) of the solid substantially water-insoluble carrier, in particular when the two components may be linked by covalent bonding optionally with condensation and/or cross-linking.
- the therapeutically active derivatised quaternary ammonium salt may be attached to a solid substantially water-insoluble carrier by hydrogen bonding and/or pairing of ions of opposite charges, and/or by covalent bonding, optionally with condensation and/or cross-linking.
- the solid carrier should be non-toxic and biocompatible with human or animal tissue, and must be substantially water-insoluble and have the capability of having the derivatised quaternary ammonium salt attached to and/or dispersed within it.
- the therapeutically active derivatised quaternary ammonium salt a) and the cationic antimicrobial c) may be attached to a solid substantially water-insoluble carrier by hydrogen bonding and/or pairing of ions of opposite charges, and/or in the case of the therapeutically active derivatised quaternary ammonium salt a) by covalent bonding, optionally with condensation and/or cross-linking.
- the solid carrier should be non-toxic and biocompatible with human and animal tissue, and must be substantially water-insoluble and have the activity of having the derivatised quaternary ammonium salt a) and the cationic antimicrobial c) attached and/or dispersed within it.
- the carrier may have any composition, form, structure or physical property, such as wet strength, that is compatible with its use in a device, in particular a wound dressing, and with the properties of the carrier.
- Suitable materials for the carrier in medical and non-medical absorbent devices include the following polymeric materials:
- polyesters including aliphatic polyesters, polyurethanes, copoly(etheresters), polyamides, polycarbonates, poly(iminocarbonates) and polyorthoesters
- semi-synthetic polymeric materials such as those with reactive functions, by which the derivatised quaternary ammonium salt may be attached to the solid carrier, such as cellulose-based materials, such as carboxymethylcellulose materials, chitosans; and chitosan-based materials, such as carboxymethylchitosan materials, and alginate-based materials; and
- the carrier is preferably of a polyester, an alginate, a cellulose material or a chitosan material, or a derivative of such materials such as a carboxymethylcellulose material or a carboxymethylchitosan material, and in particular a polyester, especially when comprised in a wound dressing.
- Suitable carrier materials include materials with polar groups, such as ester, urethane, ether, amide, imine and hydroxyl functions, for example respectively on a polyester, copoly(etherester), polycarbonate, poly(iminocarbonate) or a polyorthoester; a polyurethane, a copoly(etherester), a polyamide, a poly(iminocarbonate), or a polysaccharide, by which the derivatised quaternary ammonium salt may be attached to the solid carrier by hydrogen bonding,
- ionic functions typically the anion of salts, such as of salified carboxylic acids, for example on a polysaccharide, by which the cation of the derivatised quaternary ammonium salt may be attached to the solid carrier by pairing of ions of opposite charges and/or
- reactive functions typically hydroxyl functions or oxide anionic functions, typically the anion of an alkali metal oxide, such as a sodium alkoxide group, for example on a polysaccharide, by which the derivatised quaternary ammonium salt may be attached to the solid carrier by covalent bonding optionally with condensation and/or cross-linking.
- reactive functions typically hydroxyl functions or oxide anionic functions, typically the anion of an alkali metal oxide, such as a sodium alkoxide group, for example on a polysaccharide, by which the derivatised quaternary ammonium salt may be attached to the solid carrier by covalent bonding optionally with condensation and/or cross-linking.
- reaction may occur between such a function in the polysaccharide and the silylhydrocarbyl group of formula (I): R 1 (R 2 ) (R 3 ) Si R 4 (I) in which each of R 1 , R 2 , R 3 and R 4 is as hereinbefore defined, in the therapeutically active derivatised quaternary ammonium salt to attach it to the solid substantially water-insoluble carrier.
- reaction between such function in the polysaccharide and the silylhydrocarbyl group of formula (I) may be facilitated by the presence of an alkali metal, in particular a sodium, cation. It is further believed that once reaction between such a function in the polysaccharide and the silylhydrocarbyl group of formula (I):
- R 1 (R 2 ) (R 3 ) Si R 4 (I) where the R 1 , R 2 and R 3 groups are the same and each is a methoxy group, has taken place, cross-linking via a reaction which comprises a condensation reaction between adjacent groups of formula (I): R 1 (R 2 ) (R 3 ) Si R 4 (I) may occur with elimination of methanol to form silyl ether cross-links between adjacent groups of formula (I).
- siloxy groups present in the compound comprised in component a) enable it to bind to the surface, but that the surfactive combination of the hydrophobic group R 5 and quaternary ammonium function help direct the other antimicrobial compound c) to the solid substantially water- insoluble carrier, such as a structural polysaccharide, to which it has been attached by covalent bonding with condensation and/or cross-linking.
- Such direction of the other antimicrobial compound c) to the solid substantially water-insoluble carrier may occur by way of boundary mixed micelle formation at the surface of the solid substantially water-insoluble carrier.
- the hydrophobic group R 5 in the derivatised quaternary ammonium salt component a), which may help direct the other antimicrobial compound c) may for example be a dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl group, which may be branched or unbranched and/or oxa-substituted.
- Examples of such a group R 5 in the derivatised quaternary ammonium salt component a) include octadecyl, which may be branched or unbranched, in a preferred derivatised quaternary ammonium salt a) such as N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium chloride.
- the cationic antimicrobial salt component c) may include an underivatised quaternary ammonium-based antimicrobial and/or an underivatised or derivatised guanidine-containing antimicrobial salt.
- Any cationic antimicrobial salt c) is rendered substantially water-insoluble, but still therapeutically active, and/or its rate and degree of release can be controlled by being attached to the solid substantially water-insoluble carrier by hydrogen bonding, by pairing of ions of opposite charges and/or by way of boundary mixed micelle formation at the surface of the solid substantially water-insoluble carrier.
- hydrophobic group R 5 is for example a dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl group, which may be branched or unbranched). It may also be attached by, it is believed, being held by and/or under the derivatised quaternary ammonium salt a) which is attached to the solid carrier,
- the substantially water-insoluble materials of the carrier in any form or structure are provided.
- i) may be readily produced by conventional processes which are well-known to the skilled person, or
- compositions of the first aspect of the present invention include those comprising
- N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium acetate N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen tartrate, and/or
- N,N-trimethyl-N-octadecylammonium chloride in particular N,N-trimethyl-N-octadecylammonium chloride, and/or
- chlorhexidine dichloride The skilled person will appreciate that such compounds may often be present as a mixture of homologues.
- the carrier may have any form, structure and physical property that is compatible with its use in a device, in particular a wound dressing.
- an absorbent composition for an absorbent device comprising a particulate form of the substantially water-insoluble carrier b) to which the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) are attached. It may typically be a microparticulate as defined herein, having an average pre-absorption diameter in the micrometre scale, for example from about 0.1 to 10 microns and more particularly of from about 1 .2 to 4.0 microns.
- the particulate may have a mean pre-absorption size of the interstices between its particles of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and (pre-absorption if the particles are of a water-absorbent material and the composition is used in a wound dressing).
- composition when such a composition is used in an absorbent device, unless it is all irremovably attached to a dressing backing layer, it cannot be used in direct contact with a wound, but must be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
- a second embodiment of this first aspect of the present invention provides an absorbent composition for an absorbent device comprising the substantially water-insoluble carrier to which the derivatised quaternary ammonium salt and the cationic antimicrobial salt c) are attached, as a random assembly of flexible fibres.
- a composition when used in a device, it may be in the form of at least one piece of wadding, such as a cushion or pad.
- the fibres are optionally bonded to each other, to a backing layer and/or to a wound filler, and may be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
- Such fibres are typically microfibres or nanofibres as defined herein, frequently having an average preabsorption diameter in the micrometre or nanometre scale, for example from about 50 nanometres to 50 microns, particularly of from about 0.1 to 10 microns and more particularly of from about 1 .2 to 4.0 microns.
- the assembly of flexible fibres may have a mean pre- absorption pore size of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and 25 microns, and more preferably between 5 and 20 microns.
- an absorbent composition that comprises a substantially water- insoluble carrier as a, for example non-woven, fabric. As described further hereinafter, when such a composition is used in an absorbent device, it may be in the form of at least one piece of woven or, typically non-woven, fabric.
- the or each piece is optionally bonded to another, to a backing layer and/or to a wound filler and may be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
- the fibres in such a composition that comprises a substantially water-insoluble carrier as a, for example non-woven, fabric are preferably microfibres or nanofibres as defined herein. They generally having a monofilament linear density of 0.1 to 30, preferably about 0.5 to 20, and more preferably 0.9 to 8, for example 1 3 to 5 decitex, and a strength of 0.8 to 2.2, such as 1 to 2, for example 1 .2 to 1 .8 cN/dtex.
- The, typically non-woven, fabric may suitably have a thickness of 30 to 200g/m 2 or more.
- fibres are of a water-absorbent material and the composition is used in a wound dressing. Whilst they may swell in contact with water and may become an elastic gel material, they exhibit good maintained integrity and wet strength.
- the carrier material is often the only carrier material present.
- other materials for example strengthening polymeric materials, are present, often in the form of reinforcing fibres, in general microfibres or nanofibres as defined herein, which are intermingled and blended with the carrier fibres according to the invention.
- thermoplastic bicomponent fibres preferably comprising a polyolefin-containing polymeric material of which the largest part (by weight) consists of homo- or copolymers of monoolefins such as ethylene, propylene, 1 -butene or 4-methyl-l-pentene. .
- These may be added, in a weight ratio of 1 :9 to 9:1 , for example of 1 :6 to 6:1 or 1 :3 to 3:1 .
- the addition of such materials may have a significant improving effect on the strength of the material in a non-woven fabric.
- an absorbent composition that comprises a substantially water-insoluble carrier as a foam, such as an open-cell foam.
- a substantially water-insoluble carrier as a foam
- foam such as an open-cell foam.
- the or each piece is optionally bonded to another, to a backing layer and/or to a wound filler and may be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
- the foam absorbent material in the composition of the first aspect of the present invention may have a mean pre-absorption pore size of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and 25 microns, and more preferably between 5 and 20 microns.
- the second aspect of the present invention provides a topical anti-microbial device comprising a solid substantially water-insoluble antimicrobial composition of the present invention, which may be an antimicrobial medical or non-medical absorbent device or a medical cushioning device.
- a medical device which is a wound dressing has an absorbent component for absorbing wound exudate from a wound during use, and will typically comprise the following non-limiting components:
- the wound dressing frequently comprises a wound contact integer attached to the proximal face of a backing layer of the dressing.
- the wound contact integer may consist essentially of an absorbent component for absorbing wound exudate from the wound during use, or may comprise an absorbent component lying in contact with the proximal face of a wound filler, in turn in contact with the backing layer of the dressing.
- the absorbent component may consist essentially of an absorbent material for absorbing wound exudate from the wound during use, or may comprise an absorbent material lying in contact with, and contained in, a conformable container. In such case, such an absorbent material must be irremovably attached directly or indirectly to a dressing backing layer and in use must not adhere to a wound on removal of the wound dressing from the wound.
- the absorbent component will comprise the absorbent material, usually in a conformable container, which comprises a layer or sheet proximal cover which is permeable to wound exudate and of a biocompatible material, lying between the wound and the dressing backing layer.
- the container may be formed by the proximal cover being attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
- such a conformable container may be in the form of a stand-alone envelope, pouch or sachet, which may be attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
- the conformable container must itself (as an 'inner container') be contained in another conformable container (as an Outer container') which also comprises a proximal cover.
- the proximal cover of the outer container must be permeable to wound exudate and not adhere to a wound in use on removal of the wound dressing from the wound.
- the outer container may be formed by the proximal cover being attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
- a conformable container may be in the form of a stand-alone envelope, pouch or sachet, which may be attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
- the inner container would not adhere in use to a wound on removal of the wound dressing from the wound, but may itself still be contained in a conformable outer container.
- the substantially water-insoluble antimicrobial composition of the first aspect of the present invention may be or form part of one or more components of a device, such as a wound dressing.
- the antimicrobial composition of the first aspect of the present invention may essentially be or form part of one or more of the following components of an absorbent wound dressing:
- any conformable container which comprises the absorbent material which cover may be, for example in an outer container and/or an inner container contained in the outer container, each of which may more favourably be a stand-alone envelope, pouch or sachet, and/or
- the absorbent material in the wound dressing may consist essentially of the substantially water-insoluble antimicrobial composition of the first aspect of the present invention.
- the carrier in the composition of the first aspect of the present invention will be the absorbent material of the wound dressing, and suitable and preferred materials, sizes, forms and structures of the absorbent material will be as so described hereinbefore in relation to corresponding absorbent materials, forms and structures of the carrier of the antimicrobial composition.
- the absorbent material in the wound dressing may comprise the substantially water-insoluble antimicrobial composition of the first aspect of the present invention.
- suitable or preferred derivatised quaternary ammonium salts will be as so described hereinbefore in relation to corresponding components of the antimicrobial composition
- suitable and preferred materials, sizes, forms and structures of the absorbent material may be as so described hereinbefore in relation to corresponding absorbent materials, forms and structures of the carrier of the antimicrobial composition.
- the composition of the first aspect of the present invention and/or the absorbent material in the wound dressing may be in the form of, for example, a particulate; fibres, frequently microfibres or nanofibres as defined herein, as a random assembly of flexible fibres, which may be in the form of at least one piece of wadding, such as a cushion or pad, or as an, often non- woven, fabric; and/or a foam, such as an open-cell foam.
- composition of the first aspect of the present invention and/or the absorbent material must be irremovably attached directly or indirectly to a dressing backing layer and in use must not adhere to a wound on removal of the wound dressing from the wound. Otherwise, the absorbent component in the wound dressing will usually comprise the composition of the first aspect of the present invention and/or absorbent material, in a conformable container. As noted above, such a container will comprise a layer or sheet proximal cover which is permeable to wound exudate and of a biocompatible material, lying between the wound and the dressing backing layer.
- the container may be formed by the proximal cover being attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
- a conformable container may be in the form of a stand-alone envelope, pouch or sachet, which may be attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
- any conformable container may optionally comprise an antimicrobial composition of the first aspect of the present invention.
- the cover that is permeable to wound exudate and forms the proximal face of the above conformable container may consist essentially of, or comprise the substantially water-insoluble composition of the first aspect of the present invention.
- the composition of the first aspect of the present invention in this embodiment of the second aspect of the invention may be in the form of, for example, an, often non-woven, in particular spun-bonded, fabric and/or a layer or sheet of an open- cell foam, which is permeable to wound exudate.
- the conformable container of which the relevant proximal layer or sheet cover which consists essentially of or comprises the substantially water-insoluble antimicrobial composition of the first aspect of the present invention must be contained in an outer container.
- such an outer container will also comprise a layer or sheet proximal cover which is permeable to wound exudate and of a biocompatible material, lying between the wound and the dressing backing layer.
- This proximal layer or sheet cover may alternatively or additionally, usually alternatively, consist essentially of or comprise the substantially water-insoluble antimicrobial composition of the first aspect of the present invention.
- composition of the first aspect of the present invention in this embodiment of the second aspect of the invention may be in the form of, for example, an, often non-woven, in particular spun-bonded, fabric and/or a layer or sheet of an open-cell foam, which is permeable to wound exudate.
- the antimicrobial composition of the present invention with a derivatised quaternary ammonium salt and an underivatised cationic antimicrobial (which may be an underivatised quaternary ammonium salt or an underivatised guanidine-based salt) comprised therein has been mainly in relation to absorbent carrier materials for use in medical and non-medical absorbent devices, and in particular to medical absorbent devices such as wound dressings.
- the antimicrobial compositions of the present invention with a derivatised quaternary ammonium salt and an underivatised cationic antimicrobial comprised therein include a cushioning composition.
- a cushioning composition for a cushioning device comprising a substantially water-insoluble carrier to which the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached in the form of a body of a soft, flexible material.
- the cushioning composition may be comprised in a cushioning material in a cushioning component, or may essentially be the cushioning material.
- the cushioning component may be comprised in a cushioning device, or may essentially be the cushioning device.
- the cushioning composition will often essentially be the cushioning material.
- the cushioning component will often essentially be the cushioning device.
- the cushioning composition of the present invention with a derivatised quaternary ammonium salt and the cationic antimicrobial salt comprised therein will be illustrated by the following non-limiting description mainly in relation to the cushioning device.
- the skilled person will appreciate that other integers may be present in the cushioning material, cushioning component or cushioning device, which are compatible with the use of the device as a medical cushioning device.
- the conformable cushioning device of the present invention may suitably be in any form or shape that is compatible with its functions of relieving pressure on a pressure-sensitive area of a human or animal, and acting as a source of topical therapeutic agents.
- the cushioning device is thus used for the prophylaxis and/or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and ulcers on or in the skin, or in the tissue underlying it.
- MVP moisture vapour permeability
- ⁇ cushioning device It should preferably take up as little space as possible so that ⁇ cushioning device can be worn under ordinary human clothing or footwear (shoes etc.), or bedclothes without causing much inconvenience It may be a device which is not shaped to conform in use to a pressure-sensitive part of the body, an 'unshaped device', such as a layer or sheet or it may be shaped to conform in use to a pressure-sensitive part of the body, such as the feet or the sacrum, a 'shaped device'.
- parts of the body for example on each side of the torso and the back tend to be pressure-sensitive parts of the body, at risk of developing wound precursors and/or chronic wounds, including pressure sores, ulcers and infected wounds.
- Cushioning devices of the present invention may suitably be used on pressure- sensitive parts of the body, for example on each side of the torso and the back of such a patient who is known to be at risk of developing pressure sores and/or ulcers.
- the conformable cushioning device for application to a human or animal body is not shaped to conform to affected areas to which it is applied.
- Such cushioning devices are usually in the form which comprises a conformable component, or consists essentially of such a component in the form of at least one layer or sheet of a absorbent material.
- Such structures often have a shape such as an elongate strip, band or ribbon, a quadrilateral, such as a rectangle or oblong, or an equilateral, such as a square, or a round, but not necessarily regularly round, disc such as circular, elliptical or oval disc such as circular, elliptical or oval cushioning device.
- This embodiment of the first aspect of the present invention will typically have a thickness that tends to be constant and towards the lower figures in the ranges given hereinbefore for the thickness of the general cushioning device of the present invention; that is in the ranges of from 0.1 to 1 .5 cm, for example from 0.2 to 1 cm, such as from 0.3 to 0.5 cm.
- such cushioning devices may comprise a material which characteristically has a good permeability to water vapour, and at least part of the proximal face of which is inherently self-adhesive to skin, thus avoiding any need for a layer of pressure-sensitive adhesive around the periphery of its proximal face, or retaining strapping or other means of attachment.
- Such self-adhesion is usually relatively unaggressive, which is among the especially advantageous properties of a cushioning device with a proximal face comprising such a material.
- the present cushioning device may suitably be provided with conventional (generally pressure-sensitive) adhesive around the periphery of its proximal face, or retaining strapping or other appropriate means for it to be secured, which are well-known to the skilled person, or are described further in the patent or literature prior art.
- the present cushioning device may suitably be made of at least one piece, typically one piece, of foam. Two or more pieces are optionally bonded to each other.
- the foam may be a foamed plastics material, foam natural rubber or another foam material, preferably with a good permeability to water vapour. Suitable such materials include thermoplastic polyurethane foams. These are characteristically extremely soft and pliable.
- This form of the material may be an open-cell foam, that is one in which at least some of the pores in the material form the plurality of channels running between opposite faces, or it may be a closed-cell foam.
- the lower parts of the body for example the soles and heels of the feet and the sacrum, tend to be particularly pressure-sensitive parts of the body, where the risk of developing wound precursors and/or wounds referred to above tends to occur. This is especially the case in those patients with arthritis, diabetes or cardiovascular conditions who are not bedridden or chairbound.
- Such cushioning devices are usually shaped to conform in use to, and to be in direct or indirect contact with, a relevant body part when used in
- a second from of the fifth aspect of the present invention is a shaped cushioning device, that is one that is shaped to conform in use to the body over an affected area to which it is applied.
- Such a conformable, flexible cushioning devices of the present invention is in general shaped to conform to, for example, the foot or the sacrum.
- the thickness of such a cushioning device of the present invention tends to range between the lowest and highest figures in these ranges, that is in the ranges of from 0.3 to 5 cm, for example from 0.5 to 3 cm, such as from 1 to 1 .5 cm.
- the cushioning device has an increased thickness at the point where it is required to cushion the arch, or where the proximal face conforms in use to, for example the soft tissue over the sacrum, the cushioning device has an increased thickness at that point where it is required to cushion the sacrum.
- a cushioning device of this embodiment of the first aspect of the present invention will generally not need to be provided with means for it to be secured to the body of a patient who is potentially at risk, over the affected areas to which it is applied.
- Such cushioning devices are in general held in position over the affected parts, in the foot by conforming footwear, or in other parts of the body, for example over the sacrum, by clothing.
- Any conforming footwear or clothing should not of course block the surfaces of this embodiment to such an extent that the moisture vapour permeability (MVP) of the cushioning device on the relevant part of the body is impaired, and in particular falls below 250 g/m 2 /24hr, and thus put a patient at risk of developing wound precursors and/or chronic wounds, including pressure sores, ulcers and infected wounds.
- MVP moisture vapour permeability
- the present cushioning device may suitably be made of at least one piece, typically one piece, of foam. Two or more pieces are optionally bonded to each other.
- the foam may be a foamed plastics material, foam natural rubber or another foam material, preferably with a good permeability to water vapour. Suitable such materials include thermoplastic polyurethane foams. These are characteristically extremely soft and pliable.
- This form of the material may be an open-cell foam, that is one in which at least some of the pores in the material form the plurality of channels running between opposite faces, or it may be a closed-cell foam.
- the conformable cushioning devices may suitably be made of a soft, pliable plastics material.
- Suitable materials for use in the cushioning devices the first aspect of the present invention include synthetic polymeric materials, with a good permeability to water vapour, such as gels,
- elastomers for example one based on one or more alkylenes, such as ethylene, propylene and butylene, and styrene and combinations thereof,
- thermoplastic polyurethanes also preferred materials
- closed-cell foamed plastics materials for example a thermoplastic polyurethane closed-cell foam, closed-cell foamed natural rubber or any other closed-cell foam material All of the plastics materials listed above are characteristically extremely soft and pliable.
- the cushioning device In the cushioning devices of the present invention that are shaped to conform to affected areas to which they are applied, for example the foot or the sacrum, it is preferred that the cushioning device be made of a soft, pliable, almost viscous fluid-like plastics material. Preferably the cushioning device is made of a conformable gel of this type.
- the cushioning device of the present invention that are not shaped to conform to affected areas to which they are applied, for example each side of the torso and the back, it is preferred that the cushioning device be made of a soft, pliable plastics material, but one that is not almost viscous fluid-like.
- Suitable and preferred derivatised quaternary ammonium salts in cushioning antimicrobial compositions of the invention are in general as so described hereinbefore in relation to corresponding components of absorbent antimicrobial compositions.
- a cushioning device comprises an absorbent conformable component, which comprises a substantially water-insoluble antimicrobial composition of the first aspect of the present invention, on or in a proximal face of a cushioning component, as defined herein, but optionally without an antimicrobial composition of the first aspect of the present invention.
- the two components are optionally bonded to each other.
- the cushioning device thus provides topical anti-microbial activity in contact with bodily fluid on a body surface or wound exudate, and cushioning of pressure- sensitive parts of the body, from two different components.
- the cushioning component may be unshaped, such as a layer or sheet, or one shaped to conform in use to a pressure-sensitive part of the body.
- the absorbent component which comprises a substantially water-insoluble antimicrobial composition of the first aspect of the present invention, will usually conform to, and be roughly coterminous with the cushioning component, and thus have the same or similar configurations, dimensions and shapes as the cushioning component.
- Suitable and preferred derivatised quaternary ammonium salts and cationic antimicrobial salts, and solid substantially water-insoluble carriers to and/or within which the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached and/or dispersed, for the cushioning component are as so described hereinbefore for respectively the absorbent component.
- the device comprising the antimicrobial composition of the first aspect of the invention is in the form of an antimicrobial spraying device containing the antimicrobial composition for spraying a surface with an aerosol comprising an aqueous liquid medium comprising the antimicrobial composition.
- Such a device comprising the antimicrobial composition of the first aspect of the invention may be
- a wound care antimicrobial device for spraying the composition (which is optionally absorbent for absorbing wound exudate from a wound) onto a wound;
- a personal care antimicrobial device for spraying the composition (which is optionally absorbent for absorbing a bodily fluid from a body surface) onto a body surface.
- Either antimicrobial device for spraying the composition may be in the form of a pressurised vessel such as a can or canister with the capability of spraying the composition in the form of an aerosol comprising an aqueous liquid medium comprising the water-insoluble antimicrobial composition, typically as a suspension of a fine particulate of a substantially water-insoluble carrier to which the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached.
- the carrier of the antimicrobial composition of the first aspect of the invention may not only to comprise an absorbent material but such a material which may swell in contact with water to become an elastic gel material. This may coalesce to form an integral conformable absorbent material, in the manner of a so-called plastic skin, which may be removed from the wound site in one piece, without irrigation, and with minimum pain and shedding.
- All the antimicrobial cushioning or absorbent devices, corresponding components, compositions and materials of the present invention may also comprise therapeutically active materials other than the derivatised quaternary ammonium salt and the cationic antimicrobial salt.
- biocompatible materials which are compatible with the other device components, compositions and materials, and in particular when in a wound dressing and in direct or fluidic contact with wound exudate, preferably attached to the solid substantially water-insoluble carrier.
- any such therapeutic agent should be pharmaceutically acceptable, and may suitably be any of the following pharmaceutically acceptable ingredients: emollients, such as skin lipids and sterols, oils, for example lightweight oils, such as cetyl alcohol, or silicone-derived oils, such as cyclomethicone, and heavier oils, such as grape seed oil or dimethicone, and petrolatum;
- emollients such as skin lipids and sterols
- oils for example lightweight oils, such as cetyl alcohol, or silicone-derived oils, such as cyclomethicone, and heavier oils, such as grape seed oil or dimethicone, and petrolatum
- emollients such as skin lipids and sterols
- oils for example lightweight oils, such as cetyl alcohol, or silicone-derived oils, such as cyclomethicone, and heavier oils, such as grape seed oil or dimethicone, and petrolatum
- silicone-derived oils such as cyclomethicone
- heavier oils such as grape seed oil
- topical analgesics such as ibuprofen, diclofenac and capsaicin; to treat pain in combination with the soothing effect of the present cushioning device (optionally in relation to cushioning devices for relieving pressure on painful arthritic joints, such as fallen arches of the foot, for longer-term pain relief);
- topical anaesthetics such as lidocaine to numb affected parts of the human or animal body
- topical antiinflammatories such as steroids, such as Cortisol.
- the present invention provides a process for producing a solid substantially water-insoluble antimicrobial composition according to the first aspect of the present invention for an antimicrobial device, which process comprises
- a first embodiment of this third aspect of the present invention provides a process for producing an absorbent antimicrobial composition according to the first aspect of the present invention for an antimicrobial device.
- This process comprises adding to a carrier, and/or impregnating the carrier with, the water- soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a fluid medium.
- the fluid is often a highly aqueous fluid, especially when the material for the carrier is a water-absorbent polymeric material that is substantially water-insoluble, as described hereinbefore in greater detail.
- a second embodiment of this third aspect of the present invention provides a process for producing a cushioning antimicrobial composition according to the first aspect of the present invention which process comprises dispersing the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a, typically fluid, precursor of the carrier, followed by solidification of the precursor of the carrier to form the carrier.
- the fluid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt is usually
- aqueous solution in which the quaternary ammonium salt is dissolved to at least 0.1 %, and up to 0.5%, for example up to 1 % w/w, usually in a highly aqueous medium as defined; or
- the aqueous solution comprising the derivatised quaternary ammonium salt and the cationic antimicrobial salt is usually in a highly aqueous medium as defined. It will generally comprise at least 0.1 %, and up to 0.5%, for example up to 1 % w/w, of a surfactant to promote wetting of the carrier.
- the surfactant should promote wetting of the carrier without competing with the derivatised quaternary ammonium salt for typical sites of attachment to the solid carrier by pairing of ions of opposite charges, typically the anions of salts, such as of salified carboxylic acids.
- Favoured surfactants thus include nonionic surfactants, such as polymeric material of which the largest part (by weight) consists of homo- or copolymers of oxyolefins such as oxyethylene, oxypropylene, oxybutylene or oxy-4-methyl-l- pentene.
- polyoxyethylene alkyl ethers (Brij), for example of the formula: CH 3 -(CH 2 )io-i6-(O-C 2 H 4 ) _25-OH, such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether; and polyoxypropylene glycol alkyl ethers, for example of the formula: CH 3 -(CH 2 )io-i6-(O-C 3 H6)i-25-O.
- Brij polyoxyethylene alkyl ethers
- Such non-Ionic surfactants preferably comprise residues of an oligosaccharide with alkylated hydroxyl functions, typically oligoglucoside alkyl ethers, for example decyl glucoside, dodecyl glucoside, octyl glucoside and decyl octyl glucoside (APG), often formed by an alkylation reaction between a function such as the anion of an alkali metal oxide, such as a sodium oxide group, in the oligosaccharide.
- APG decyl octyl glucoside
- compositions for example for absorbent fibre, typically microfibre or nanofibre pads or layers as defined herein, it may be desirable to incorporate a relatively volatile non-aqueous liquid in the frequently highly aqueous medium in particular in an aerosol comprising the aqueous solution.
- a solvent for the derivatised quaternary ammonium salt and/or the cationic antimicrobial salt c typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such as 3 to 8 %, for example 5 to 6 % w/w, in the aqueous solution per se or in the aerosol.
- anion of such derivatised quaternary ammonium salt and the cationic antimicrobial salts may alternatively or additionally, usually alternatively, be chosen to help to solubilise therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salts.
- anions of these anions include anions of an organic acid, such as hydrogen pamoate and/or pamoate.
- the carrier is of a water-absorbent material, for example if the composition is used in a wound dressing, absorption of the fluid comprising the therapeutically is active ionic material virtually instantaneous, but depending on the particular therapeutically active material the time for the treatment process overall may suitably be 1 to 60 min, such as 2 to 45 min. 2 to 45 min. is found to be most suitable to give a more useful substrate in an economic time.
- the treatment process may often be carried out by immersing the carrier, which is or comprises a water-absorbent material, in the liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt for the a suitable length of time, as above.
- This forms a first variant of the first embodiment of this third aspect of the present invention (a process for producing an absorbent antimicrobial composition).
- the treatment may suitably be carried out at a temperature of up to 30°C, which may suitably be 5 to 25° C, for example 10 to 20° C.
- This first variant of the first embodiment may in some cases be operated as a semi-continuous process for producing an absorbent antimicrobial composition.
- This may be carried out by threading a length of the carrier, which is or comprises a water-absorbent material, through rollers into and through a bath containing a solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt. Excess solution is then removed, and the carrier is impregnated with the water-soluble therapeutically derivatised quaternary ammonium salt and the cationic antimicrobial salt under pressure by feeding the carrier through nip rollers. The carrier, loaded with the derivatised quaternary ammonium salt and the cationic antimicrobial salt, is then dried, for example in an oven, and cooled, for example with a chill roller.
- the carrier is already mounted in a precursor of a wound dressing comprising the therapeutically active ionic material;
- the solid substantially water-insoluble carrier is of a particularly water- absorbent and -retaining material and/or structure
- composition is to be used in a wound dressing
- ii) may swell in contact with water and/or
- ii) may become an irreversible elastic gel material
- an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, optionally also comprising a non-aqueous liquid which is a water-miscible non-solvent for the carrier.
- the carrier is already mounted in a precursor of a wound dressing comprising the therapeutically active ionic material, it will usually not be possible for the carrier to be immersed in the liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in the treatment process without compromising the other components of the dressing.
- the substantially water-insoluble but hydrophilic absorbent material used in the carrier, and/or its form and/or structure may also have the physical property of retaining an excess of the liquid medium of this process of the first embodiment.
- the undesired excess of the aqueous medium cannot be readily be removed after direct contact with the liquid medium, for example by the carrier loaded with the therapeutic derivatised quaternary ammonium salt and the cationic antimicrobial salt being left to drain.
- the composition in a wound dressing it also functions as an absorbent component of the dressing. The presence of an excess of an aqueous medium in which it has been immersed is likely to impair the absorbent performance of the dressing.
- the material of the carrier with the above properties may also be a substantially water-insoluble superabsorbent gelling, water insoluble derivatised alginate, cellulose or chitosan and/or its form and/or structure may be a foam. If it is an open-cell foam which exhibits good absorption and retention of fluid, undesired excess of the aqueous medium cannot be readily be removed after direct contact with the liquid medium, for example by the carrier loaded with the therapeutic derivatised quaternary ammonium salt and the cationic antimicrobial salt being left to drain. More importantly, it can no longer function as an absorbent in the dressing.
- the second variant of the treatment process of this first embodiment of this third aspect of the present invention third aspect of the invention should be used.
- an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt will typically take less than 10 min, although multiple spraying may be desirable, for example for absorbent fibre, often microfibre or nanofibre pads or layers as defined herein.
- the time for the treatment process overall may still suitably be 1 to 60 min, such as 2 to
- compositions for example for absorbent fibre, typically microfibre or nanofibre pads or layers as defined herein, it may be desirable to incorporate a relatively volatile non-aqueous liquid which is a water- miscible non-solvent for the carrier, but a solvent for the derivatised quaternary ammonium salt and the cationic antimicrobial salt, typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such as 3 to 8 %, for example 5 to 6 % w/w, to the aqueous solution in the aerosol to aid evaporation.
- a relatively volatile non-aqueous liquid which is a water- miscible non-solvent for the carrier, but a solvent for the derivatised quaternary ammonium salt and the cationic antimicrobial salt, typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such as 3 to 8 %, for example 5 to 6 % w/w, to the aque
- a good to very good transfer loading of the derivatised quaternary ammonium salt and the cationic antimicrobial salt in a practical length of time may be achieved in this second process variant of the first embodiment of this third aspect of the present invention.
- the treatment may suitably be carried out at a temperature of up to 30°C, which may suitably be 5 to 25° C, for example 10 to 20° C.
- spraying the surface of the carrier with an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, optionally also comprising a volatile non-aqueous liquid.
- Such a liquid should be a water-miscible non- solvent for the carrier.
- the spraying may be carried out as appropriate by electrospraying, that is, by forcing the above solution through a capillary nozzle or needle tip, which may optionally be made to traverse over the carrier, and applying a large potential difference of the order of several kV to the tip relative to the carrier.
- the carrier may be mounted on a counterelectrode, as a collection target, so forming a so-called Taylor cone of the solution at the tip. Applying the large potential difference also causes charged droplets to break away from the Taylor cone of the solution at the tip, and the electric field accelerates the charged droplets to towards the collection target
- the solvent evaporates from each droplet of the solution, and the maximum amount of charge the diminishing droplet can carry is reached (the "Rayleigh limit").
- Each droplet then undergoes a Coulomb explosion in which the Coulombic repulsion of the components of the droplet of the solution having the same electric charge breaks the bonds that hold it together.
- This forms a fine aerosol comprising the aqueous solution, which forms a layer that comprises the derivatised quaternary ammonium salt and the cationic antimicrobial salt on the target.
- a solvent for the derivatised quaternary ammonium salt and the cationic antimicrobial salt typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such as 3 to 8 %, for example 5 to 6 % w/w, in the aqueous solution per se or in the aerosol.
- the Coulomb explosion forms a fine aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, which forms a layer that comprises the derivatised quaternary ammonium salt and the cationic antimicrobial salt on the target.
- the form and/or structure of the substantially water-insoluble carrier corresponds to the composition form and/or structure when it is a component of a dressing.
- the component fibres may be treated with an aqueous medium comprising the derivatised quaternary ammonium salt and the cationic antimicrobial salt, left to drain and/or be air-dried, and then processed according to known methods into a wide variety of forms of the composition as a component of an antimicrobial devices, and in particular in an advanced wound dressing.
- This may be, for example in the form of a non-woven fabric comprising the treated fibres.
- Such a non-woven fabric may be produced by conventional fibre opening, web formation and needling, and may suitably have a thickness of 30 to 200g/m 2 or more.
- a second embodiment of this third aspect of the present invention provides a process for producing a cushioning antimicrobial composition according to the first aspect of the present invention, which process comprises dispersing the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a, typically fluid, precursor of the carrier, followed solidification of the precursor of the carrier, to form the cushioning antimicrobial composition or device composition of the first aspect of the present invention.
- the product of this second variant of the second process embodiment may be a cushioning device which comprises a cushioning component, but is more usually in a form which consists essentially of such a component.
- the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt is dispersed in a, typically fluid, precursor of the carrier, followed solidification of the precursor of the carrier. Solidification of the precursor is often characterised by the crosslinking of a non-crosslinked, or monomeric or oligomeric precursor of the material of the cushioning device according to the present invention, often in the course of reactive injection moulding or casting.
- the cushioning device is shaped to conform in use to the body over a given pressure-sensitive area where device is needed.
- a cushioning device is often relatively thick, and may have an increased thickness at the point where it is required, for example to cushioning device the arch of the foot or where it is required to cushion the sacrum.
- the process for the preparation of the cushioning device according to the first aspect of the present invention is then characterised by reactive injection moulding, for example of a room-temperature curing fluid precursor system.
- the mould into which the fluid precursor system is injected typically has inner faces that are shaped to conform to the proximal face and the opposite outer face of the desired form of the cushioning device, and is often in two cooperating parts.
- the cushioning device is often relatively thin, and may have an essentially constant thickness.
- the process for the preparation of the cushioning device according to the first aspect of the present invention is then characterised by reactive casting, for example of a room-temperature curing fluid precursor system.
- the platen onto which the fluid precursor system is cast typically has a flat face with a raised periphery or other appropriate means for containing the fluid precursor system shaped to conform to the desired form of the cushioning device.
- the invention provides a method of treatment or prophylaxis of microbial infections using an antimicrobial composition according to the first aspect of the present invention.
- a method of treatment or prophylaxis of microbial infections and any underlying pathologies in wound precursors and wounds comprising administering a therapeutically effective amount of a composition according to the first aspect of the present invention to a wound or wound precursor.
- a method of treatment or prophylaxis of microbial infections and any underlying pathologies in wound precursors and wounds comprising applying an absorbent medical device, which is a wound dressing, comprising a therapeutically effective amount of a composition according to the first aspect of the present invention to a wound or wound precursor.
- Such a dressing can be easily applied to treat a wound on a human or animal body; including an acute wound, for example a surgical wound; a chronic wound, for example a diabetic ulcer or a venous leg ulcer; or a burn.
- an acute wound for example a surgical wound
- a chronic wound for example a diabetic ulcer or a venous leg ulcer
- a burn for example a burn.
- the dressing may be used as appropriate in a wound that extends to at least the epidermis of the animal's skin, in a wound that extends to the dermis or the subcutaneous fat region of the animal's skin, in a wound that extends into the musculature of the animal, or in a wound that extends into the viscera of the animal.
- a method of treatment or prophylaxis of a pressure-sensitive part of the body of a patient at risk of developing wound precursors and/or wounds comprising applying a medical device, which is a cushioning device to the part of the body at risk.
- a medical device which is a cushioning device to the part of the body at risk.
- Such a cushioning device of the present invention as defined can be easily applied to patients who have, or are at substantial risk of developing, wound precursors include, for example those with arthritis, diabetes, cardiovascular conditions or paralysis.
- the cushioning, medical device relieves the pressure on the skin of the patient, and makes a water-insoluble form of a quaternary ammonium salt available to the skin and/or the tissue underlying it, to combat any microbial infections and any underlying pathologies in any wound. .
- the device may also be a non-medical device, often an absorbent device which is a personal care device, such as a disposable sanitary device, such as a nappy (diaper), a disposable nappy or training pants, a feminine care product, for example, a tampon, a sanitary towel, or a napkin or a pant liner, or an incontinence product.
- a personal care device such as a disposable sanitary device, such as a nappy (diaper), a disposable nappy or training pants, a feminine care product, for example, a tampon, a sanitary towel, or a napkin or a pant liner, or an incontinence product.
- a personal care device such as a disposable sanitary device, such as a nappy (diaper), a disposable nappy or training pants, a feminine care product, for example, a tampon, a sanitary towel, or a nap
- a method of removal of bodily fluid (excluding wound exudate) from a body surface(including the skin and internal mucosa) of a human or animal comprising applying a non-medical absorbent device which is a personal care device, to the body surface.
- This example demonstrates a first variant of the process for making an absorbent water-insoluble composition with a derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) comprised in a non-woven fabric absorbent material, for use as an absorbent component of an antimicrobial medical or nonmedical device.
- a Werner Mathis AG coater was set up.
- a 20m roll of spunbond polyester material was placed on one side of the machine, and was threaded at a speed of 1 .5m/min through a bath containing a solution of the derivatised quaternary ammonium salt a), N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethyl- ammonium chloride (0.2% w/w solution), the cationic antimicrobial salt c) polyhexamethylene biguanide (PHMB) hydrochloride (0.2% w/w solution), and a decyl octyl oligoglucoside ether surfactant (APG) (0.2% w/w solution) the remainder being deionised water.
- the derivatised quaternary ammonium salt a N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethyl- ammonium chloride (0.
- the material was then fed through nip rollers exerting a pressure of 1 .25 bar to remove excess solution, then fed into a first oven at 100° C and a second oven also at 100° C to dry the material.
- the width of material entering the machine was 20.5cm and leaving the machine was 18cm.
- the shrinkage is likely to do with drying and stretching.
- the above process for an antimicrobial composition for a wound dressing is used mutatis mutandis to produce antimicrobial compositions of the first aspect of the present invention.
- N N- dipropyl-N-octadecyl- N-2-(trimethoxysilyl)propylammonium acetate
- N N- dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate
- a solid carrier b) which is an alginate, cellulose, carboxvmethvlcellulose, chitosan or carboxymethyl-chitosan; with optionally salified carboxylic acid residues.
- This example demonstrates a second variant of the process for making an absorbent water-insoluble composition with a derivatised quaternary ammonium salt a) and cationic antimicrobial salt c) comprised in a polyester open-cell foam which exhibits good absorption and retention of fluid.
- the surface of a 5cm x 5cm piece of the open-cell foam is sprayed with an aerosol comprising an aqueous solution of the derivatised quaternary ammonium salt, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium chloride (0.2% w/w solution), the cationic antimicrobial salt c) polyhexamethylene biguanide (PHMB) hydrochloride (0.2% w/w solution), and a decyl octyl oligoglucoside ether surfactant (0.2% w/w solution) the remainder being deionised water.
- the derivatised quaternary ammonium salt N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium chloride (0.2% w/w solution)
- the cationic antimicrobial salt
- the foam carrier loaded with the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) is left to allow the relatively small undesired excess of the aqueous medium to drain or evaporate from the surface of the carrier.
- a solid carrier b) which is an alginate, cellulose, carboxymethylcellulose, chitosan or carboxymethyl-chitosan; with optionally salified carboxylic acid residues.
- the antinnicrobial activity and the degree of release by water of a derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) from the composition of Example 1 were determined as follows:
- PHMB polyhexamethylene biguanide
- compositions had good antimicrobial activity in contact with the bacterial culture, and exhibit a surprising and advantageously negligible degree of release by water of the derivatised quaternary ammonium salt, and only slight leaching of polyhexamethylene biguanide (PHMB) hydrochloride. .
- PHMB polyhexamethylene biguanide
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Abstract
An anti-microbial composition comprising a) a silyl-derivatised quaternary ammonium salt, b )a solid substantially water-insoluble carrier, and c) an underivatised quaternary ammonium salt or an underivatised guanidine- based salt, for use as a component of a topical anti-microbial medical device, a topical device for the personal care sector, or a medical cushioning device; a process for the manufacture of such devices, and a method of prophylactic and therapeutic use of the devices.
Description
Process and Device
The present invention relates to an anti-microbial composition for use as a component of a topical anti-microbial device; in particular an absorbent device, such as a medical absorbent device, for example an absorbent wound dressing, and an absorbent device for the personal care sector; and a medical cushioning device; a process for the manufacture of such devices, and to a method of prophylactic and therapeutic use of the device
The term 'absorbent component' as used herein refers to any conformable component of an antimicrobial device for the antimicrobial treatment of animate surfaces, such as the skin of a human or animal. The absorbent component comprises a synthetic or natural porous absorbent material that is substantially insoluble in a relevant bodily fluid, such as wound exudate, menses or urine, but absorbs the fluid. The absorbent component may be in a medical absorbent device, such as an absorbent wound dressing, or in a non-medical absorbent device for the personal care sector. The absorbent component has a proximal face, as defined herein, which in use of the device will be in direct or fluidic contact with the skin of a human or animal.
The term 'absorbent device' as used herein includes medical absorbent devices and non-medical absorbent devices, as defined herein.
It in particular includes (but is not limited to) an absorbent device comprising a water-insoluble antimicrobial absorbent material as defined herein, in which an absorbent component cushioning devices exudate migration and/or absorption and retention of a relevant bodily fluid, such as wound exudate when in a medical absorbent device, such as an absorbent wound dressing, or such as menses or urine when in a non-medical absorbent device, such as a disposable sanitary device.
Absorption of a relevant bodily fluid may occur in two dimensions (for example in an absorbent dressing or a sanitary towel), or three dimensions (for example in a deep-wound dressing or a tampon).
The term 'absorbent material' as used herein is defined herein under "absorbent component" above. Such an absorbent material may be in the form of fibres, such as in an, often non-woven, fabric or a more random assembly of fibres, for example of randomly spun fibres; it may be in the form of a particulate. It may have fluids (including air) in its interstices and/or synthetic or natural biological or chemical agents in its interstices and/or its structural members.
The term 'antimicrobial' as used herein in relation to a therapeutically active material includes materials which have
antibacterial activity, for example against Methicillin-resistant Staphylococcus aureus (MRSA), Clostridium difficile, Salmonella typhimurium, Leigonella, Listeria monocytogenes and Escherichia coli,
antimycotic activity, including against one or more of Aspergillus niger and Candida albicans, and/or
antiviral activity.
The term 'antimicrobial device' as used herein means a device for the antimicrobial treatment of animate surfaces, and includes
a medical device which is an absorbent device, such as an absorbent wound dressing used in the treatment of acute wounds, including surgical wounds, and chronic and burn wounds; an ostomy device, or a surgical or dental sponge; a non-medical device which is an absorbent device, such as one for use in the personal care sector, in particular for disposable sanitary devices such as nappies (diapers), disposable nappies and training pants, and feminine care products, for example, tampons, sanitary towels, or napkins and pant liners, and incontinence products, and
a medical device which is an absorbent or non-absorbent cushioning device, such as a cushioning layer or cushioning device used in the prophylaxis or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and/or ulcers.
When used herein, the term "biocompatible" refers to any material which does not induce adverse effects such as immunological reactions and/or rejections in a human or animal.
The term "biodegradable" herein refers to any material which can be degraded and bioresorbed into the physiological environment.
Examples of such biodegradable materials include carboxymethylcellulose materials, carboxymethylchitosan materials, hyaluronic acid- and alginate-based materials; and certain copoly(etheresters), and poly(alkylene oxides). The term "conformable container" herein in relation to the absorbent material in an absorbent component in an absorbent device refers to any container, such as an envelope, pouch or sachet. This contains the absorbent material and lies between it and the wound in use, and comprises a cover of a synthetic or natural layer or sheet material that is substantially insoluble in but permeable to a relevant bodily fluid, and does not adhere to the body of a patient on removal of the absorbent device.
Such a container may be formed by the proximal cover of a synthetic or natural layer or sheet material being attached to a dressing backing layer. Alternatively, it may be, for example a stand-alone envelope, pouch or sachet, which in use lies between the wound and the backing layer, and may be attached to a dressing backing layer, and may be an 'inner container', contained in another stand-alone conformable Outer container'). The term 'cushioning component' as used herein refers to any conformable component of a cushioning device, or a cushioning device which consists essentially of such a component, which may be used in the treatment or prophylaxis of wound precursors, as defined herein and chronic wounds, on or in the skin of a human or animal, or in the tissue underlying it. It comprises a cushioning material that is substantially insoluble in a relevant bodily fluid,
The term 'cushioning device' as used herein refers to any conformable medical device, which is used to relieve pressure on a pressure-sensitive area of a human or animal, and acts as a source of topical therapeutic agents. The cushioning device is thus used for the prophylaxis and/or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and ulcers on or in the skin, or in the tissue underlying it. .
It may be a device which is not shaped to conform in use to a pressure-sensitive part of the body, an 'unshaped device', such as a layer or sheet or it may be shaped to conform in use to a pressure-sensitive part of the body, such as the feet or the sacrum, a 'shaped device'.
The term 'cushioning material' as used herein is the cushioning material in a medical cushioning device or cushioning component, and is a soft, flexible often polymeric material that is substantially insoluble in a relevant bodily fluid. Such materials may also often be hydrophobic.
Reference to "derivatised" in relation to a material herein is to a substance, for example a quaternary ammonium salt or a cationic antimicrobial (which may be a guanidine-containing antimicrobial) substituted by a tris(hydrocarbyl or hydrocarbyloxy)-silylhydrocarbyl group.
By the term 'highly aqueous' in the context of an aqueous medium is meant herein that the medium comprises at least 85%, for example at least 90%, such as at least 95% w/w water. The terms "medical" and "non-medical" in relation to a device herein are as defined herein under "antimicrobial device", and may relate to an absorbent medical or non-medical device or a non-absorbent medical cushioning device.
The term "micro" in relation to a particulate or fibrous material herein means that the majority of particle or fibre diameters in the material are less than 100 micrometres.
The term "nano" herein in relation to a particulate or fibrous material herein means that the majority of particle or fibre diameters in the material are less than 100 nanometres.
The term "natural" herein refers to any material that is naturally occurring.
The term "non-biodegradable" herein refers to any material which cannot be degraded and bioresorbed into the physiological environment. Examples of such non-biodegradable materials include polyalkylenes, such as polyethylene, polypropylene and polybutylene, and combinations thereof.
The term "non-woven" herein in relation to fabrics in the absorbent component means that the majority of fibres in the fabric are neither woven nor knit together.
They are typically manufactured by putting small fibres together to form a sheet or web, and then binding them together mechanically, with an adhesive, or by thermal bonding, in particular by spin bonding. The term Organic or inorganic acyl' as used herein includes organic acid residues such as carboxyl and inorganic acid residues such as sulpho.
The term 'partially organic or inorganic acylhydrocarbyl substituted polysaccharide' means a polysaccharide derivatised by optionally salified HORO groups, where HOR is a hydrocarbyl oxoacid residue.
The term 'polysaccharide' as used herein means any polymeric carbohydrate structure, formed of repeat monomer units which are monosaccharides joined together by glycosidic bonds, with two free hydroxyl functions and optionally one amine function per monomer unit, typically having between 200 and 2500 monomer units in the polymer molecule.
These structures include linear homopolysaccharides, such as celluloses, chitosans and alginates. The term also includes derivatised polysaccharides, such as carboxymethyl celluloses and carboxymethyl chitosans.
In derivatised polysaccharides substitution may take place at any hydroxyl position and/or at the amine group up to a hypothetical mean maximum degree of conversion of 2 hydroxyl groups per monomer unit of the polysaccharide. The average degree of substitution in the derivatised polysaccharides used in devices is often less than 0.8, such as less than 0.7, for example less than 0.6.
The average molecular weight of such a polysaccharide is often between 3800 to 20,000 daltons. Such polysaccharides are substantially insoluble in water.
By "proximal" in relation to a face of a component in a device is meant herein that the face is a body-facing face in general or a wound-facing face in a wound dressing in use. By "distal" in relation to a face of a component in a device is meant herein that the face faces away from the body in general or away from a wound in a wound dressing.
By "substantially water-insoluble" in relation to a material is meant herein that the material is soluble in an aqueous medium to less than 1 % w/w.
Reference herein to "swelling" herein in relation to fibres in an absorbent component means the fibre structure swelling and/or forming gel.
The term "synthetic" herein means any material that is not found in nature, and the term "semi-synthetic" means made from naturally occurring biomaterials. Examples include respectively plastics polymers and derivatised polysaccharides.
By the term 'water-soluble' in the context of a material is meant herein that the material is soluble in an aqueous medium to more than 5% w/w. The term "wound" in relation to the present invention means any soft tissue with compromised integrity, including acute wounds, such as surgical and infectious disease wounds; chronic wounds, such as diabetic ulcers or venous leg ulcers; and burns. The term "wound contact integer" as used herein includes a component in a wound dressing which comprises a porous absorbent component and optionally an elastically resilient, for example a foam, wound filler which lies distally of the absorbent component. The term "wound precursor" herein means any condition on or in the skin of a human or animal, or in the tissue underlying it, which in the absence of treatment is at substantial risk of developing into tissue of compromised integrity, such tissue including chronic wounds, including pressure sores, ulcers and infected wounds. Such conditions on or in the skin of a human or animal or in the tissue underlying it include discomfort, inflammation, pain and haematoma, which may be caused or exacerbated by pressure on the skin.
No statements made on belief herein, in particular as to the nature, physical form and physical properties of any product, and of any fabric or device, in particular any wound dressing comprising such a product, or of any process for the manufacture thereof, shall be construed as in any way as limiting the scope of the present invention. .
There is a need for, and it is known to produce and process, therapeutically active materials (which are typically antimicrobials) for example for therapeutically active devices, such as topical medical devices, for example wound dressings, and topical non-medical absorbent devices, for example for the personal care sector.
It is preferred that such therapeutically active materials have good activity in contact with wound exudate, for example when in a dressing component which has a proximal surface. It Is also preferred that they and the other component materials in the compositions are biodegradable and biocompatible with human and animal tissue, as well as more preferably being odourless, and when in a dressing component having wound healing capability.
However, it is also preferred that such a therapeutically active material should be in a water-insoluble form which does not dissolve into solution to be uncontrolledly released from the dressing to any significant extent.
This is particularly desirable for a wound dressing comprising an antimicrobial composition in view of the regulatory burden faced by antimicrobial dressings in which release of a therapeutically active component of the dressing into a wound occurs.
This is especially desirable when the therapeutically active component of the dressing is an ionic material that is soluble when exposed to a highly aqueous medium such as a bodily fluid on a body surface or wound exudate, in particular in the latter case at the pH levels found in some chronic wounds at a typical patient body temperature.
It is known to use a composition comprising a derivatised cationic antimicrobial, in particular a water-soluble derivatised quaternary ammonium salt and a water- soluble underivatised cationic antimicrobial, in particular an underivatised cationic antimicrobial, such as an underivatised quaternary ammonium salt, or an underivatised guanidine based salt or a mixture thereof, all as defined as a biocidal component of a water-soluble composition for the treatment of inanimate surfaces, such as floors.
Since the composition is only used on inanimate surfaces, such as floors, the other component materials in the compositions may be non-biodegradable and not biocompatible with human and animal tissue, as well as not having specific wound healing capability and not being odourless.
It is also known to use a water-soluble underivatised quaternary ammonium salt or an underivatised guanidine based salt as a topical antimicrobial, for example in therapeutically active compositions. A very significant technical problem and disadvantage of such prior art compositions is the water-solubility and uncontrolled release from such a product of these topical antimicrobials. .
This is potentially a problem and disadvantage not only for any such materials in any topical medical absorbent devices, for example wound dressings, but also in topical non-medical absorbent devices, for example for the personal care sector, for the treatment of animate surfaces,
The latter occurs to a significant extent when the composition is exposed to a highly aqueous medium at a typical patient body temperature, such as a bodily fluid on a body surface or wound exudate, in particular a bodily fluid on a body surface or at the pH levels found in some chronic and burn wounds. This can present a risk of only short-term efficacy of the device and, in the case of wound dressings, a risk of resultant overdosing and the considerably higher regulatory burden faced by dressings in which release of a therapeutically active component into a wound occurs.
Another technical problem of the prior art is that the longer-term stability of the derivatised quaternary ammonium salt in an aqueous fluid is sub-optimal.
A further technical problem of the prior art is that the other component materials in the compositions may be non-biodegradable and not biocompatible with human and animal tissue, as well as not having specific wound healing capability and not being odourless, which makes the known derivatised quaternary ammonium salts compositions highly unsuitable for use as antimicrobial materials in antimicrobial medical devices such as wound dressings, and non- medical device, such as one for use in the personal care sector.
It is therefore an object of the present invention to provide a therapeutically active composition for an antimicrobial device, such as a medical device such as a wound dressing, and a non-medical device, such as one for use in the personal care sector, which composition comprises a water-insoluble form of a quaternary ammonium salt and a cationic antimicrobial salt, which is not released or only controlledly and relatively slowly released, on contact with the bodily fluids of a patient or user.
Such a composition should have longer-term stability on contact with an aqueous fluid. This is especially the case when it is exposed to a highly aqueous medium, such as a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic wounds.
It is also an object of the present invention to provide such a composition for an antimicrobial device which is non-toxic, odourless, and biocompatible with human and animal tissue, and preferably is biodegradable, and when in a dressing component has wound healing activity.
Surprisingly, we have now found that the above technical problems of the prior art can be solved, and the above disadvantages of the prior art can be avoided, by incorporating a mixture which comprises a derivatised quaternary ammonium salt antimicrobial and/or an underivatised cationic antimicrobial in a solid significantly water-insoluble composition for an antimicrobial device.
Thus, in order to solve the above technical problems, according to a first aspect of the present invention, there is provided an a solid substantially water-insoluble antimicrobial composition for a device comprising
a) a derivatised quaternary ammonium salt, wherein the quaternary ammonium salt is N-substituted by
i) a group of formula (I)
R1 (R2) (R3) Si - (R4) - (I) wherein
each of R1, R2 and R3 is an optionally substituted hydrocarbyl group, and
R4 is an optionally substituted hydrocarbadiyl group,
and
ii) A group R5 , which is an optionally substituted hydrocarbyl group;
and
b) a solid substantially water-insoluble carrier within to and/or within which the derivatised quaternary ammonium salt is attached and/or dispersed; and c) at least one salt of an underivatised cationic antimicrobial.
The underivatised cationic antimicrobial, c) may be an underivatised quaternary ammonium salt or an underivatised guanidine-based salt.
According to a second aspect of the present invention, there is provided a topical anti-microbial device comprising a solid substantially water-insoluble antimicrobial composition of the first aspect of the present invention.
The device may be an absorbent device, such as a medical absorbent device, for example an absorbent wound dressing, an absorbent device for the personal care sector; and/or a medical cushioning device.
The antimicrobial composition of the first aspect of the present invention is often in particular comprised in an absorbent material in an absorbent component, but may be comprised another integer of the absorbent component, such as the proximal cover of a conformable container, which contains the absorbent material. The antimicrobial composition is often comprised in a cushioning material in a cushioning component, but may be comprised another integer of the cushioning component.
The derivatised quaternary ammonium salt and underivatised cationic antimicrobial in the composition of this first aspect of the present invention are highly advantageous for use as antimicrobial materials in medical and nonmedical absorbent devices. This is for the following reasons: Each of the derivatised quaternary ammonium salt and the underivatised cationic antimicrobial used in the composition is per se water-soluble, and has longer- term instability, in an aqueous medium.
Such media include a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds). Each salt is rendered stable and substantially water-insoluble, but still therapeutically active, by being attached and/or dispersed within a solid substantially water-insoluble carrier.
In particular the composition has good antimicrobial activity in contact with a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds, for example when in a medical device such as a wound dressing, or a non-medical device, such as one for use in the personal care sector.
The compositions of the invention thus exhibit a surprising and advantageously diminished or negligible degree and rate of release by a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds of the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c), for example in an antimicrobial device, such as a dressing. This is in particular the case fro the proximal surface of a wound dressing, when in contact with wound exudate at a typical patient body temperature and/or at the pH levels found in chronic and burn wounds.
The rate and degree of release can be controlled in particular by the choice of a) the derivatised quaternary ammonium salt,
b) the material(s) of the solid substantially water-insoluble carrier, and
c) the cationic antimicrobial salt c)
in particular when the derivatised quaternary ammonium salt and solid substantially water-insoluble carrier may be linked by covalent bonding, optionally with condensation and/or cross-linking, as described further hereinafter.
Treatment or prophylaxis of microbial infections using an antimicrobial composition according to this first aspect of the present invention does not cause microbial resistance, for example by
bacteria, such as Staphylococcus aureus (MRSA), Clostridium difficile, Salmonella typhimurium, Leigonella, Listeria monocytogenes and Escherichia coli,
mycotic species, including Aspergillus niger and Candida albicans, and/or
viruses,
in particular not only when comprised in a wound dressing for wounds, including acute wounds, including surgical wounds, and chronic and burn wounds, but also when in topically applied personal care devices, and medical cushioning devices.
These advantageous properties make the compositions of this first aspect of the present invention, which comprises derivatised quaternary ammonium salts and underivatised cationic antimicrobial highly suitable for prophylactic and therapeutic use as antimicrobial materials in antimicrobial devices.
In formula (I):
Each of R1, R2, R3 and R4 may independently be oxa-substituted, preferably to produce R1, R2 and R3 optionally substituted hydrocarbyloxy groups, and, for example to produce an R4 optionally substituted hydrocarbylene group with an internal ether linkage.
In formula (I):
Each of R1, R2, R3 and R4 may independently be oxa-substituted, preferably to produce R1, R2 and R3 optionally substituted hydrocarbyloxy groups, and, for example to produce an R4 optionally substituted hydrocarbadiyl group with an internal ether linkage.
Each of R1, R2 and R3 independently may be an optionally oxa-substituted alkyl group, preferably a lower alkyl group with 1 to 6 carbon atoms, such as a methyl, ethyl, propyl or butyl group, preferably a methyl group. Any propyl or butyl group is preferably attached in the 1 -position to the silicon atom.
Each of R1, R2 and R3 is preferably a hydrocarbyloxy residue, for example a lower alkoxy group with 1 to 6 carbon atoms.
Each of R1, R2 and R3 may thus suitably be, for example, a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, preferably a methoxy group. Any component propyl or butyl group group is preferably attached in the 1 -position to the oxygen atom.
The alkyl moiety in all the above groups may be branched or unbranched, and hence suitable butyl groups may be n-butyl, iso-butyl or tert. butyl groups. Most preferably, such R1, R2 and R3 groups are the same. The most preferred R1, R2 and R3 residue is a methoxy residue.
Each of R1, R2 and R3 independently may also suitably be an aryl group, such as phenyl or tolyl, preferably phenyl. Preferably only one of R1, R2 and R3 is an aryl group, such as phenyl.
Each of R1, R2 and R3 independently may be an optionally oxa-substituted aralkyl group, preferably a lower alkyl group with 1 to 6 carbon atoms, such as a methyl, ethyl, propyl or butyl group, preferably a methyl group, substituted by an aryl group, such as phenyl or tolyl, preferably phenyl. Any component propyl or butyl group is preferably attached in the 1 -position to the silicon atom.
Each of R1, R2 and R3 independently may be an aralkoxy group. Each of R1, R2 and R3 may thus suitably be, for example, a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, preferably a methoxy group, substituted by an aryl group, such as phenyl or tolyl, preferably phenyl.
Preferably only one of R1, R2 and R3 is an aralkyl group, such as benzyloxy. Any component propyl or butyl group is preferably attached in the 1 -position to the oxygen atom. The alkyl moiety in all the above groups may be branched or unbranched, and hence suitable butyl groups may be n-butyl, iso-butyy or tert. butyl groups.
In formula (I), R4 is an optionally substituted hydrocarbadiyl group, which may be oxa-substituted, for example to produce an R4 optionally substituted hydrocarbadiyl group with an internal ether linkage.
R4 may be an optionally oxa-substituted alkanediyl group, preferably a lower alkylene group with 1 to 6 carbon atoms, such as a methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl or butan-1 ,4-diyl group, preferably an ethan-1 ,2-diyl group.
R5 is an optionally substituted hydrocarbyl group, which may be oxa-substituted, for example to produce an R5 optionally substituted hydrocarbyl group with an internal ether linkage. R5 may be an optionally oxa-substituted alkyl group, preferably a higher alkyl group with 8 to 22 carbon atoms, such as an octyl, decyl, dodecyl, tetradecyl, hexadecyl (cetyl or palmityl), octadecyl or eicosyl group. The alkyl moiety may be branched or unbranched, and oxa-substituted, for example to produce an R5 optionally substituted unsaturated hydrocarbyl group with an internal ether linkage. Examples include 3,6-dioxa- substituted higher alkyl groups with 8 to 22 carbon atoms, more preferably such an octadecyl group, in which case, if the remaining N-substituents are methyl groups, the derivatised quaternary ammonium salt is a derivatised benzethonium salt congener. R5 may be an optionally oxa-substituted alkenyl group, preferably a higher alkenyl group with 8 to 22 carbon atoms, such as an octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl or eicosenyl group. The alkenyl moiety may be branched or unbranched, and oxa-substituted. It may be in a cis- or trans- configuration about any double bond. Examples include a cis-octadec-9-en-1 -yl moiety, which is an oleyl moiety; and a cis-, cis-octadeca- 9,12-dien-1 -yl moiety which is a linoleyl moiety,
R5 is preferably an unbranched unsubstituted higher alkyl group with 8 to 22 carbon atoms, more preferably such an octadecyl group.
Each of the two remaining N-substituents other than the tris(hydrocarbyl or hydrocarbyloxy)-silylhydrocarbyl group of formula (I) and R5 may independently be an alkyl group, preferably an optionally substituted lower alkyl group with 1 to 6 carbon atoms, such as a methyl, ethyl or propyl, preferably methyl. The alkyl moiety may be branched or unbranched, and hence suitable propyl may be n- propyl or iso-propyl.
One of the groups may be an aralkyl group, such as benzyl, in which case, if the remaining N-substituent is a methyl group, the derivatised quaternary ammonium salts is a derivatised benzalkonium salt. Most preferably, the groups are the same and are methyl groups. Less preferably they may also independently be an aryl group, such as phenyl or tolyl, preferably phenyl.
They may also independently be an optionally oxa-substituted aralkyl group, such as benzyl. Each group may thus be an aryloxyalkyl group.
The alkyl moiety may be branched or unbranched, and hence suitable propyl may be n-propyl or iso-propyl. Any component propyl or butyl group is preferably attached in the 1 -position to the nitrogen atom.
Preferably only one of the groups is an aryl or optionally oxa-substituted aralkyl group. The other may be an alkyl group, preferably methyl.
It will be appreciated that the feasible type and maximum size of any N- substituent in the derivatised quaternary ammonium salt will depend on the type and size of, and steric hindrance around the nitrogen atom of the derivatised quaternary ammonium salt caused by, the other substituent groups present.
The anion of the derivatised quaternary ammonium salt for prophylactic and therapeutic use as antimicrobial materials in antimicrobial compositions of the first aspect of the present invention may be any pharmacologically acceptable anion.
Any pharmacologically acceptable anion may be selected from the anion of an inorganic acid, such as chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, or
an organic acid, such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate.
The anion may be a pharmacologically acceptable dianion, when there will be two derivatised quaternary ammonium cations per dianion, which may be then selected from a dianion of
an inorganic diacid, such as sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, or
an organic diacid, such as succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
Examples of the salt thus include salts with an inorganic acid, such as chloride, sulphate and/or phosphate. Examples of the salt also include salts with an organic acid, such as a organic acid, for example acetate, benzoate, tartrate, adipate, lactate, maleate, glutamate, ascorbate, citrate, gluconate, succinate, pamoate, salicylate, isethionate, succinamate, mono-diglycollate, methanesulphonate, isobutyrate,/or glucoheptonate.
Monovalent anions are preferred. Favoured anions include halides, for example chloride and bromide.
Preferred derivatised quaternary ammonium salts for use in antimicrobial medical compositions of the first aspect of the present invention include derivatised quaternary ammonium salt, wherein the quaternary ammonium salt is N- substituted by
i) a group of formula (I) R1 (R2) (R3) Si - (R4) - (I) wherein
each of R1, R2 and R3 is a methoxy, ethoxy, propoxy, isopropoxy or butoxy group, preferably a methoxy group, and any component propyl or butyl group group is preferably attached in the 1 -position to the oxygen atom.
R4 is a methylene, ethan-1 ,2-diyl, propan-1 ,3-diyl or butan-1 ,4-diyl group, preferably an ethan-1 ,2-diyl group,
and
ii) a group R5 , which is a dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl group, which may be branched or unbranched and/or oxa-substituted to produce a higher alkyl group with an internal ether linkage.
More preferred derivatised quaternary ammonium salts for use in antimicrobial compositions of the first aspect of the present invention include derivatised quaternary ammonium salts such as
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium acetate, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium tartrate, N,N-dimethyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium chloride,
N,N-dipropyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate
N,N-dimethyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N,N-dipropyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium acetate,
N,N-dimethyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N - dipropyl - N - eicosyl - N - 2 -(trimethoxysilyl)propylammoniunn hydrogen tartrate,
N,N-dimethyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium chloride, N,N-dipropyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate
N,N-dimethyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N,N -dipropyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium acetate, N,N-dimethyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, and
N,N-dipropyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen tartrate,
Most preferred derivatised quaternary ammonium salts in antimicrobial compositions of the first aspect of the present invention include derivatised quaternary ammonium salts such as
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium chloride, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate,
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium acetate, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen tartrate, and
in particular N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium chloride.
The skilled person will appreciate that such compounds may often be present as a mixture of homologues.
The composition may suitably comprise up to 10 wt% of the derivatised quaternary ammonium salt component a), favourably up to 7.5 wt%, preferably up to 5 wt%, more preferably up to 3 wt%. Suitably the composition comprises at least 0.001 wt% of the derivatised quaternary ammonium salt component a), favourably at least 0.1 wt%, more favourably at least 0.5 wt%, preferably at least 0.7 wt%, more preferably at least 0.9 wt%, especially at least 1 wt%.
A mixture of two or more derivatised quaternary ammonium salts may be present in component a) of the compositions of the present invention. In such embodiments the above amounts refer to the combination of all the derivatised cationic antimicrobials present. In such embodiments the above amounts refer to the combination of all the underivatised cationic antimicrobials present. In preferred embodiments, component a) consists of one derivatised quaternary ammonium salt.
The composition of the present invention also comprises at least one cationic antimicrobial component c). Preferred cationic antimicrobials for use herein include underivatised quaternary ammonium-based antimicrobials and guanidine-based cationic antimicrobials.
For the avoidance of doubt, the one or more cationic antimicrobials c) which are underivatised quaternary ammonium salts are present in addition to the derivatised quaternary ammonium salt of component a) used in the composition of this first aspect of the present invention In especially preferred embodiments component c) comprises one cationic antimicrobial.
The composition may suitably comprise up to 10 wt% cationic antimicrobial component c), favourably up to 7.5 wt%, preferably up to 5 wt%, more preferably up to 3 wt%.
For example, the composition may comprise at least 0.001 wt% of cationic antimicrobial component c), favourably at least 0.1 wt%, more favourably at least 0.5 wt%, preferably at least 0.7 wt%, more preferably at least 0.9 wt%, especially at least 1 wt%.
A mixture of two or more cationic antimicrobial components may be present in component c) of the compositions of the present invention. In such embodiments the above amounts refer to the combination of all the underivatised cationic antimicrobials present.
Such a mixture of two or more cationic antimicrobial components present in component c) of the compositions of the present invention may be a combination of two or more underivatised quaternary ammonium-based antimicrobials, of two or more guanidine-based cationic antimicrobials, including guanidine-based compounds, diguanidine-based compounds and polymeric guanidine-based compounds, or of at least one underivatised quaternary ammonium-based antimicrobial and at least one guanidine-based cationic antimicrobial. In especially preferred embodiments, component c) comprises one cationic antimicrobial.
Suitable quaternary ammonium cationic antimicrobials have the structure shown in formula (II):
R 6
I
R 7 - N + - R 9 X " (II)
I
R 8 where each of R 6, R 7, R 8 and R 9 is an optionally substituted alkyl, alkenyl, aralkyl or aryl group and X " is an anion.
In such embodiments, suitable groups R 6, R 7 , R 8 and R 9 are as so described hereinbefore in relation to corresponding groups, other than groups of formula (I), which form the derivatised quaternary ammonium salts for use in antimicrobial medical compositions of the first aspect of the present invention include derivatised quaternary ammonium salts of component a) of the compositions of the present invention.
Favourably, each of R 6, R 7, R 8 and R 9 is an optionally substituted alkyl or aralkyl I group, more preferably an unsubstituted alkyl or aralkyl group.
More favourably. R 6 is an optionally oxa-substituted alkyl group, preferably a higher alkyl group with 8 to 22 carbon atoms, such as an octyl, decyl, dodecyl, tetradecyl, hexadecyl (cetyl or palmityl), octadecyl or eicosyl group. The alkyl moiety may be branched or unbranched. It may also be oxa-substituted, for example to produce an R5 optionally substituted unsaturated hydrocarbyl group with an internal ether linkage. Examples include 3,6-dioxa-substituted higher alkyl groups with 8 to 22 carbon atoms, more preferably such an octadecenyl group, in which case, if the remaining N-substituents are methyl groups, the derivatised quaternary ammonium salt is a benzethonium salt congener.
R6 may be an optionally oxa-substituted alkenyl group, preferably a higher alkenyl group with 8 to 22 carbon atoms, such as an octenyl, decenyl, dodecenyl, tetradecenyl, hexadecenyl, octadecenyl or eicosenyl group. The alkenyl moiety may be branched or unbranched, and oxa-substituted. It may be in a cis- or trans- configuration about any double bond.
R7 may be an optionally substituted lower alkyl group with 1 to 6 carbon atoms, such as methyl, ethyl or propyl, preferably methyl. The alkyl moiety may be branched or unbranched, and hence suitable propyl may be n-propyl or iso-propyl. Most preferably, the groups are the same and are methyl groups.
R7 may be an optionally substituted higher alkyl groups with 8 to 22 carbon atoms, such as an octyl, decyl, dodecyl, tetradecyl, hexadecyl (cetyl or palmityl), octadecyl or eicosyl group. The alkyl moiety may be branched or unbranched.
R7 may be an aralkyl group, in which case, the alkyi moiety is favourably a lower alkyi group with 1 to 6 carbon atoms, such as methyl, ethyl or propyl, preferably methyl. The alkyi moiety may be branched or unbranched, and hence suitable propyl may be n-propyl or iso-propyl. Preferably, the aryl group is phenyl to form an R 6 benzyl group.
Each of R 8 and R 9 may independently be an alkyi group, preferably an optionally substituted lower alkyi group with 1 to 6 carbon atoms, such as a methyl, ethyl or propyl, preferably methyl. The alkyi moiety may be branched or unbranched. Most preferably, the groups are the same and are methyl groups.
Favourably, each of R 7, R 8 and R 9 may independently be an alkyi group, preferably an optionally substituted lower alkyi group with 1 to 6 carbon atoms, such as a methyl, ethyl or propyl, preferably methyl. The alkyi moiety may be branched or unbranched. Most preferably, the groups are the same and are methyl groups.
Favoured component c) quaternary ammonium cationic antimicrobials with the structure shown in formula (II) include those N-substituted by one or more unsubstituted higher alkyi groups, or one aralkyl group, optionally with an unsubstituted higher alkyi group, the remaining N-substituents each independently being an unsubstituted lower alkyi group.
Any pharmacologically acceptable anion X " may be used. X may be selected from an the anion of
an inorganic acid, such as chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, or
an organic acid, such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate.
X " may be a pharmacologically acceptable dianion, X 2", when there will be two quaternary ammonium cations with the structure shown in formula (II) per dianion X 2" may be then selected from a dianion of
an inorganic diacid, such as sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, or
an organic diacid, such as succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
Monovalent anions are preferred. Favoured anions include halides, example chloride and bromide. Preferably X is chloride or bromide.
Examples of favoured component c) quaternary ammonium cationic antimicrobials thus include
N,N-tripropyl-N-octadecylammonium hydrogen sulphate,
N,N-trimethyl-N-octadecylammonium dihydrogen phosphate
N,N-tripropyl-N-octadecylammonium acetate,
N,N-trimethyl-N-octadecylammonium benzoate,
N,N-tripropyl-N-octadecylammonium hydrogen tartrate, and
in particular N,N-trimethyl-N-octadecylammonium chloride, .
N,N-didecyl-N-dimethylammonium chloride
N,N-didecyl-N-dimethylammonium bromide, and
N-benzyl-N,N-dimethyl-N-C8-22 alkylammonium chloride or bromide.
The skilled person will appreciate that such compounds may often be present as a mixture of homologues.
Suitable underivatised guanidine-based cationic antimicrobials for component c) include guanidine-based compounds, diguanidine-based compounds and polymeric guanidine-based compounds.
Component c) may comprise at least one, preferably, only one, such cationic antimicrobial, and in that case no quaternary ammonium-based antimicrobial.
Suitable guanidine-based compounds include biguanidine and polymeric guanidine compounds of formula (III):
Y 1 - [ X 1 - NH - C - NH - C - NH -X 2 - ] m - Y 2 [ H+ X ]n (III)
NZ 1 NZ 2 wherein X 1 and X 2 are either a bond or an aliphatic, cycloaliphatic, aromatic, substituted aliphatic, substituted aromatic, heteroaliphatic, heterocyclic, and/or heteroaromatic divalent residue, and X 1 and X 2 may be the same or different; Y 1 and Y 2 are an aliphatic, cycloaliphatic, aromatic, substituted aliphatic, substituted aromatic, heteroaliphatic, heterocyclic, and/or heteroaromatic divalent residue, and Y 1 and Y 2 may be the same or different:
m is a number equal to or greater than 1 ;
Z 1 and Z 2 are either a hydrogen atom or a salt. Z 1 and Z 2 may be the same or different;
n is 1 or 2,
a proton H + is N-bonded to one or two of the secondary amine groups to form a secondary ammonium group, and
X " is an anion or X " 2 is two anions or a dianion. In one embodiment, the biguanide residue includes two protons H + each N- bonded to a different one of the three secondary amine groups to form a secondary ammonium group, and there are two X " anions or one X 2 " anion per biguanide residue. Examples of the former salts include chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidine di-valerate and chlorhexidine dicaproate. Examples of the latter include chlorhexidine succinate, chlorhexidine malate, chlorthexidine tartrate and chlorhexidine malonate.
Typically, m has an average value such that the molecular weight of the biguanide residues is about 1000-1400. However, the molecular weight may be higher or lower. Generally m is about 2-20.
When in formula (III), n is 1 and X ~ is a pharmacologically acceptable anion, or n is 2 and X ~ 2 is two anions, any pharmacologically acceptable anion X " may be used. X " may be selected from an anion from
an inorganic acid, such as chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, or
an organic acid, such as acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate.
When in formula (III), n is 2 and X " 2 is a pharmacologically acceptable dianion, any pharmacologically acceptable dianion X " 2 may be used. X " 2 may be selected from a dianion from
an inorganic diacid, such as sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, or
an organic diacid, such as succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate, pamoate and tartrate.
Examples of these compounds include those salts listed above of polyhexamethylene biguanide (PHMB), p-chlorophenyl biguanide and 4- chlorobenzhydryl biguanide.
Specific examples of these salts include, but are not limited to, polyhexamethylene biguanide hydrochloride (PHMB), p-chlorophenyl biguanide hydrochloride, and 4-chlorobenzhydryl biguanide hydrochloride. In another embodiment, the biguanide residue includes, but is not limited to, halogenated hexidine compounds including those salts listed above of chlorhexidine (1 ,1 -hexamethylene-bis-5-(4-chlorophenyl biguanide).
Specific examples of these salts include, but are not limited to, chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride, chlorhexidine dichloride and chlorhexidine dihydroiodide,
The composition of the present invention may further comprise one or more surfactants. Such a surfactant will often be residues of a surfactant used in the process for producing the solid substantially water-insoluble antimicrobial composition according to this first aspect of the present invention to promote wetting of the carrier.
As described further hereinafter, any such surfactant should promote wetting of the carrier without competing with the derivatised quaternary ammonium salt for typical sites of attachment to the solid carrier by pairing of ions of opposite charges, typically the anions of salts, such as of salified carboxylic acids.
Favoured surfactants thus include nonionic surfactants, such as polymeric material of which the largest part (by weight) consists of homo- or copolymers of oxyolefins such as oxyethylene, oxypropylene, oxybutylene or oxy-4-methyl-l- pentene.
These may be polyoxyethylene alkyl ethers (Brij), for example of the formula: CH3-(CH2)io-i6-(O-C2H4) _25-OH, such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether; and polyoxypropylene glycol alkyl ethers, for example of the formula: CH3-(CH2)io-i6-(O-C3H6)i-25-O; and
Such non-Ionic surfactants preferably comprise residues of an oligosaccharide with alkylated hydroxyl functions, typically oligoglucoside alkyl ethers, for example decyl glucoside, dodecyl glucoside, octyl glucoside and decyl octyl glucoside (APG). These are often formed by an alkylation reaction between a function such as the anion of an alkali metal oxide, such as a sodium oxide group, in the oligosaccharide.
The compositions of the invention exhibit a surprising and advantageously diminished or negligible degree and rate of release by water of the derivatised quaternary ammonium salt a), and of any cationic antimicrobial c). This is in particular the case when they are exposed to a highly aqueous medium, such as a bodily fluid on a body surface or wound exudate, in particular at the pH levels found in some chronic and burn wounds). The rate and degree of release can be controlled in particular by the choice of a) the derivatised quaternary ammonium salt,
b) the material(s) of the solid substantially water-insoluble carrier, and
c) the cationic antimicrobial salt c)
in particular when the derivatised quaternary ammonium salt and solid substantially water-insoluble carrier may be linked by covalent bonding, optionally with condensation and/or cross-linking, as described further hereinafter.
The derivatised quaternary amnnoniunn salts comprise a tris(hydrocarbyl) or tris(hydrocarbyloxy) -silylhydrocarbyl group of formula (I): R1 (R2) (R3) Si R4 (I) in which each of R1, R2, R3 and R4 is as hereinbefore defined, by which the ionic therapeutically active derivatised quaternary ammonium salt may be attached to a solid substantially water-insoluble carrier.
As noted above, the primary purpose of the solid substantially water-insoluble carrier component b) is to render the derivatised quaternary ammonium salt a), and it is also believed the cationic antimicrobial salt c), substantially water- insoluble, but still therapeutically active, by being attached to and/or dispersed in a solid substantially water-insoluble carrier.
The compositions of the invention thus exhibit a surprising and advantageously diminished or negligible degree and rate of release by water of the derivatised quaternary ammonium salt, in particular when it is exposed to a highly aqueous medium, such as a bodily fluid on a body surface or wound exudate, in the latter case in particular at the pH levels found in some chronic and burn wounds.
The rate and degree of release can be controlled in particular by the choice of the derivatised quaternary ammonium salt and the material(s) of the solid substantially water-insoluble carrier, in particular when the two components may be linked by covalent bonding optionally with condensation and/or cross-linking.
The therapeutically active derivatised quaternary ammonium salt may be attached to a solid substantially water-insoluble carrier by hydrogen bonding and/or pairing of ions of opposite charges, and/or by covalent bonding, optionally with condensation and/or cross-linking.
The solid carrier should be non-toxic and biocompatible with human or animal tissue, and must be substantially water-insoluble and have the capability of having the derivatised quaternary ammonium salt attached to and/or dispersed within it.
The therapeutically active derivatised quaternary ammonium salt a) and the cationic antimicrobial c) may be attached to a solid substantially water-insoluble carrier by hydrogen bonding and/or pairing of ions of opposite charges, and/or in the case of the therapeutically active derivatised quaternary ammonium salt a) by covalent bonding, optionally with condensation and/or cross-linking.
The solid carrier should be non-toxic and biocompatible with human and animal tissue, and must be substantially water-insoluble and have the activity of having the derivatised quaternary ammonium salt a) and the cationic antimicrobial c) attached and/or dispersed within it.
The carrier may have any composition, form, structure or physical property, such as wet strength, that is compatible with its use in a device, in particular a wound dressing, and with the properties of the carrier.
Suitable materials for the carrier in medical and non-medical absorbent devices include the following polymeric materials:
synthetic materials, such as polyesters, including aliphatic polyesters, polyurethanes, copoly(etheresters), polyamides, polycarbonates, poly(iminocarbonates) and polyorthoesters
semi-synthetic polymeric materials, such as those with reactive functions, by which the derivatised quaternary ammonium salt may be attached to the solid carrier, such as cellulose-based materials, such as carboxymethylcellulose materials, chitosans; and chitosan-based materials, such as carboxymethylchitosan materials, and alginate-based materials; and
natural materials, such as celluloses, chitosans and alginates,
The carrier is preferably of a polyester, an alginate, a cellulose material or a chitosan material, or a derivative of such materials such as a carboxymethylcellulose material or a carboxymethylchitosan material, and in particular a polyester, especially when comprised in a wound dressing.
Suitable carrier materials include materials
with polar groups, such as ester, urethane, ether, amide, imine and hydroxyl functions, for example respectively on a polyester, copoly(etherester), polycarbonate, poly(iminocarbonate) or a polyorthoester; a polyurethane, a copoly(etherester), a polyamide, a poly(iminocarbonate), or a polysaccharide, by which the derivatised quaternary ammonium salt may be attached to the solid carrier by hydrogen bonding,
with ionic functions, typically the anion of salts, such as of salified carboxylic acids, for example on a polysaccharide, by which the cation of the derivatised quaternary ammonium salt may be attached to the solid carrier by pairing of ions of opposite charges and/or
with reactive functions, typically hydroxyl functions or oxide anionic functions, typically the anion of an alkali metal oxide, such as a sodium alkoxide group, for example on a polysaccharide, by which the derivatised quaternary ammonium salt may be attached to the solid carrier by covalent bonding optionally with condensation and/or cross-linking.
It is believed that reaction may occur between such a function in the polysaccharide and the silylhydrocarbyl group of formula (I): R1 (R2) (R3) Si R4 (I) in which each of R1, R2, R3 and R4 is as hereinbefore defined, in the therapeutically active derivatised quaternary ammonium salt to attach it to the solid substantially water-insoluble carrier.
It is also believed that reaction between such function in the polysaccharide and the silylhydrocarbyl group of formula (I) may be facilitated by the presence of an alkali metal, in particular a sodium, cation. It is further believed that once reaction between such a function in the polysaccharide and the silylhydrocarbyl group of formula (I):
R1 (R2) (R3) Si R4 (I) where the R1, R2 and R3 groups are the same and each is a methoxy group, has taken place, cross-linking via a reaction which comprises a condensation reaction between adjacent groups of formula (I):
R1 (R2) (R3) Si R4 (I) may occur with elimination of methanol to form silyl ether cross-links between adjacent groups of formula (I).
It is also believed not only that the siloxy groups present in the compound comprised in component a) enable it to bind to the surface, but that the surfactive combination of the hydrophobic group R5 and quaternary ammonium function help direct the other antimicrobial compound c) to the solid substantially water- insoluble carrier, such as a structural polysaccharide, to which it has been attached by covalent bonding with condensation and/or cross-linking.
Such direction of the other antimicrobial compound c) to the solid substantially water-insoluble carrier may occur by way of boundary mixed micelle formation at the surface of the solid substantially water-insoluble carrier.
The hydrophobic group R5 in the derivatised quaternary ammonium salt component a), which may help direct the other antimicrobial compound c) may for example be a dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl group, which may be branched or unbranched and/or oxa-substituted.
Examples of such a group R5 in the derivatised quaternary ammonium salt component a) include octadecyl, which may be branched or unbranched, in a preferred derivatised quaternary ammonium salt a) such as N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium chloride.
As noted above, the cationic antimicrobial salt component c) may include an underivatised quaternary ammonium-based antimicrobial and/or an underivatised or derivatised guanidine-containing antimicrobial salt.
These per se are water-soluble, in particular when exposed to a highly aqueous medium, such as wound exudate, at a typical patient body temperature and/or at the pH levels found in chronic and burn wounds), and has longer-term stability.
Any cationic antimicrobial salt c) is rendered substantially water-insoluble, but still therapeutically active, and/or its rate and degree of release can be controlled by being attached to the solid substantially water-insoluble carrier by hydrogen bonding, by pairing of ions of opposite charges and/or by way of boundary mixed micelle formation at the surface of the solid substantially water-insoluble carrier. (This is especially the case where the hydrophobic group R5 is for example a dodecyl, tetradecyl, hexadecyl, octadecyl or eicosyl group, which may be branched or unbranched). It may also be attached by, it is believed, being held by and/or under the derivatised quaternary ammonium salt a) which is attached to the solid carrier,
The substantially water-insoluble materials of the carrier in any form or structure are
a) well-known to the skilled person and commercially available, or
b) they or their precursors, for example based on cellulose materials, chitosan materials, and alginate materials,
i) may be readily produced by conventional processes which are well-known to the skilled person, or
ii) are described further in the patent prior art, including in the case of carboxymethylchitosans, application GB 180426.4.
Most preferred compositions of the first aspect of the present invention include those comprising
a derivatised quaternary ammonium salt a) which is
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium chloride, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate,
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium acetate, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen tartrate, and/or
in particular N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium chloride,
and
a component c) quaternary ammonium cationic antimicrobial, which is
N,N-tripropyl-N-octadecylammonium hydrogen sulphate,
N,N-trimethyl-N-octadecylammonium dihydrogen phosphate
N,N-tripropyl-N-octadecylammonium acetate,
N,N-trimethyl-N-octadecylammonium benzoate,
N,N-tripropyl-N-octadecylammonium hydrogen tartrate, and/or
in particular N,N-trimethyl-N-octadecylammonium chloride, and/or
N,N-didecyl-N-dimethylammonium chloride
N,N-didecyl-N-dimethylammonium bromide, and
N-benzyl-N,N-dimethyl-N-C8-22 alkylammonium chloride or bromide,
or
a component c) guanidine-based cationic antimicrobial, which is
polyhexamethylene biguanide hydrochloride,
p-chlorophenyl biguanide hydrochloride,
p-chlorobenzhydryl biguanide hydrochloride,
chlorhexidine digluconate,
chlorhexidine diacetate, and
chlorhexidine dichloride. The skilled person will appreciate that such compounds may often be present as a mixture of homologues.
The carrier may have any form, structure and physical property that is compatible with its use in a device, in particular a wound dressing.
In a first embodiment of the composition of the first aspect of the present invention there is provided an absorbent composition for an absorbent device comprising a particulate form of the substantially water-insoluble carrier b) to which the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) are attached. It may typically be a microparticulate as defined herein, having an average pre-absorption diameter in the micrometre scale, for example from about 0.1 to 10 microns and more particularly of from about 1 .2 to 4.0 microns.
In such an embodiment, the particulate may have a mean pre-absorption size of the interstices between its particles of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and (pre-absorption if the particles are of a water-absorbent material and the composition is used in a wound dressing).
As described further hereinafter, when such a composition is used in an absorbent device, unless it is all irremovably attached to a dressing backing layer, it cannot be used in direct contact with a wound, but must be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
A second embodiment of this first aspect of the present invention provides an absorbent composition for an absorbent device comprising the substantially water-insoluble carrier to which the derivatised quaternary ammonium salt and the cationic antimicrobial salt c) are attached, as a random assembly of flexible fibres. As described further hereinafter, when such a composition is used in a device, it may be in the form of at least one piece of wadding, such as a cushion or pad. The fibres are optionally bonded to each other, to a backing layer and/or to a wound filler, and may be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
Such fibres are typically microfibres or nanofibres as defined herein, frequently having an average preabsorption diameter in the micrometre or nanometre scale, for example from about 50 nanometres to 50 microns, particularly of from about 0.1 to 10 microns and more particularly of from about 1 .2 to 4.0 microns.
In such an embodiment, the assembly of flexible fibres may have a mean pre- absorption pore size of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and 25 microns, and more preferably between 5 and 20 microns.
In a third embodiment of the first aspect of the present invention there is provided an absorbent composition that comprises a substantially water- insoluble carrier as a, for example non-woven, fabric. As described further hereinafter, when such a composition is used in an absorbent device, it may be in the form of at least one piece of woven or, typically non-woven, fabric. Where the device is a wound dressing, the or each piece is optionally bonded to another, to a backing layer and/or to a wound filler and may be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
The fibres in such a composition that comprises a substantially water-insoluble carrier as a, for example non-woven, fabric are preferably microfibres or nanofibres as defined herein. They generally having a monofilament linear density of 0.1 to 30, preferably about 0.5 to 20, and more preferably 0.9 to 8, for example 1 3 to 5 decitex, and a strength of 0.8 to 2.2, such as 1 to 2, for example 1 .2 to 1 .8 cN/dtex. The, typically non-woven, fabric may suitably have a thickness of 30 to 200g/m2 or more.
(These values are pre-absorption if the fibres are of a water-absorbent material and the composition is used in a wound dressing.) Whilst they may swell in contact with water and may become an elastic gel material, they exhibit good maintained integrity and wet strength.
In such a composition in the form of an absorbent non-woven fabric, the carrier material is often the only carrier material present. In other forms of this embodiments of the composition however, other materials, for example strengthening polymeric materials, are present, often in the form of reinforcing fibres, in general microfibres or nanofibres as defined herein, which are intermingled and blended with the carrier fibres according to the invention.
Examples of such other materials that may be present include thermoplastic bicomponent fibres, preferably comprising a polyolefin-containing polymeric material of which the largest part (by weight) consists of homo- or copolymers of monoolefins such as ethylene, propylene, 1 -butene or 4-methyl-l-pentene. .
These may be added, in a weight ratio of 1 :9 to 9:1 , for example of 1 :6 to 6:1 or 1 :3 to 3:1 . The addition of such materials may have a significant improving effect on the strength of the material in a non-woven fabric.
In a fourth embodiment of the compositions of the first aspect of the present invention there is provided an absorbent composition that comprises a substantially water-insoluble carrier as a foam, such as an open-cell foam. As described further hereinafter, when such a composition is used in an absorbent device, it may be in the form of at least one piece of a, typically open- cell, foam. Where the device is a wound dressing, the or each piece is optionally bonded to another, to a backing layer and/or to a wound filler and may be contained in a conformable container, optionally as an inner container for the absorbent material within an outer container, in turn optionally bonded to each other, to a backing layer and/or to a wound filler.
The foam absorbent material in the composition of the first aspect of the present invention may have a mean pre-absorption pore size of 1 to 50 microns, preferably between 3 and 35 microns, more preferably between 4 and 25 microns, and more preferably between 5 and 20 microns.
As noted above, the second aspect of the present invention provides a topical anti-microbial device comprising a solid substantially water-insoluble antimicrobial composition of the present invention, which may be an antimicrobial medical or non-medical absorbent device or a medical cushioning device.
A medical device which is a wound dressing has an absorbent component for absorbing wound exudate from a wound during use, and will typically comprise the following non-limiting components:
The wound dressing frequently comprises a wound contact integer attached to the proximal face of a backing layer of the dressing. The wound contact integer may consist essentially of an absorbent component for absorbing wound exudate from the wound during use, or may comprise an absorbent component lying in contact with the proximal face of a wound filler, in turn in contact with the backing layer of the dressing.
The absorbent component may consist essentially of an absorbent material for absorbing wound exudate from the wound during use, or may comprise an absorbent material lying in contact with, and contained in, a conformable container. In such case, such an absorbent material must be irremovably attached directly or indirectly to a dressing backing layer and in use must not adhere to a wound on removal of the wound dressing from the wound.
Otherwise, the absorbent component will comprise the absorbent material, usually in a conformable container, which comprises a layer or sheet proximal cover which is permeable to wound exudate and of a biocompatible material, lying between the wound and the dressing backing layer.
The container may be formed by the proximal cover being attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
Alternatively, such a conformable container may be in the form of a stand-alone envelope, pouch or sachet, which may be attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
If the proximal cover of such a conformable container in use would adhere to a wound on removal of the wound dressing from the wound, then the conformable container must itself (as an 'inner container') be contained in another conformable container (as an Outer container') which also comprises a proximal cover.
The proximal cover of the outer container must be permeable to wound exudate and not adhere to a wound in use on removal of the wound dressing from the wound.
The outer container may be formed by the proximal cover being attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer. Alternatively, such a conformable container may be in the form of a stand-alone envelope, pouch or sachet, which may be attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
In some cases, the inner container would not adhere in use to a wound on removal of the wound dressing from the wound, but may itself still be contained in a conformable outer container. As noted above, the substantially water-insoluble antimicrobial composition of the first aspect of the present invention may be or form part of one or more components of a device, such as a wound dressing. Thus, the antimicrobial composition of the first aspect of the present invention may essentially be or form part of one or more of the following components of an absorbent wound dressing:
the absorbent material:
the layer or sheet proximal cover of any conformable container which comprises the absorbent material, which cover may be, for example in an outer container and/or an inner container contained in the outer container, each of which may more favourably be a stand-alone envelope, pouch or sachet, and/or
less commonly, part of a wound filler where the device is a wound dressing, if present, or a backing layer which in use will be in contact with wound exudate and/or the wound. The absorbent material in the wound dressing may consist essentially of the substantially water-insoluble antimicrobial composition of the first aspect of the present invention. In such case,
a) suitable or preferred derivatised quaternary ammonium salts will be as so described hereinbefore in relation to corresponding components of the antimicrobial composition, and
b) the carrier in the composition of the first aspect of the present invention will be the absorbent material of the wound dressing, and suitable and preferred materials, sizes, forms and structures of the absorbent material will be as so described hereinbefore in relation to corresponding absorbent materials, forms and structures of the carrier of the antimicrobial composition.
Alternatively, the absorbent material in the wound dressing may comprise the substantially water-insoluble antimicrobial composition of the first aspect of the present invention. In such case,
i) suitable or preferred derivatised quaternary ammonium salts will be as so described hereinbefore in relation to corresponding components of the antimicrobial composition, and
ii) suitable and preferred materials, sizes, forms and structures of the absorbent material may be as so described hereinbefore in relation to corresponding absorbent materials, forms and structures of the carrier of the antimicrobial composition.
Thus, in either case, the composition of the first aspect of the present invention and/or the absorbent material in the wound dressing may be in the form of, for example, a particulate; fibres, frequently microfibres or nanofibres as defined herein, as a random assembly of flexible fibres, which may be in the form of at least one piece of wadding, such as a cushion or pad, or as an, often non- woven, fabric; and/or a foam, such as an open-cell foam.
This composition of the first aspect of the present invention and/or the absorbent material must be irremovably attached directly or indirectly to a dressing backing layer and in use must not adhere to a wound on removal of the wound dressing from the wound. Otherwise, the absorbent component in the wound dressing will usually comprise the composition of the first aspect of the present invention and/or absorbent material, in a conformable container. As noted above, such a container will comprise a layer or sheet proximal cover which is permeable to wound exudate and of a biocompatible material, lying between the wound and the dressing backing layer.
The container may be formed by the proximal cover being attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer. Alternatively, such a conformable container may be in the form of a stand-alone envelope, pouch or sachet, which may be attached to the dressing backing layer, or attached to the wound filler where the device is a wound dressing, in turn attached to a dressing backing layer.
Any conformable container, whether as a sole, inner or outer container, may optionally comprise an antimicrobial composition of the first aspect of the present invention. Favourably, the cover that is permeable to wound exudate and forms the proximal face of the above conformable container may consist essentially of, or comprise the substantially water-insoluble composition of the first aspect of the present invention.
The composition of the first aspect of the present invention in this embodiment of the second aspect of the invention may be in the form of, for example, an, often non-woven, in particular spun-bonded, fabric and/or a layer or sheet of an open- cell foam, which is permeable to wound exudate.
It must be irremovably attached directly or indirectly to a dressing backing layer, and in use must not adhere to a wound on removal of the wound dressing from the wound. Otherwise, the conformable container, of which the relevant proximal layer or sheet cover which consists essentially of or comprises the substantially water-insoluble antimicrobial composition of the first aspect of the present invention must be contained in an outer container.
As noted above, such an outer container will also comprise a layer or sheet proximal cover which is permeable to wound exudate and of a biocompatible material, lying between the wound and the dressing backing layer.
This proximal layer or sheet cover may alternatively or additionally, usually alternatively, consist essentially of or comprise the substantially water-insoluble antimicrobial composition of the first aspect of the present invention.
Again, the composition of the first aspect of the present invention in this embodiment of the second aspect of the invention may be in the form of, for example, an, often non-woven, in particular spun-bonded, fabric and/or a layer or sheet of an open-cell foam, which is permeable to wound exudate.
The above description of the antimicrobial composition of the present invention with a derivatised quaternary ammonium salt and an underivatised cationic antimicrobial (which may be an underivatised quaternary ammonium salt or an underivatised guanidine-based salt) comprised therein has been mainly in relation to absorbent carrier materials for use in medical and non-medical absorbent devices, and in particular to medical absorbent devices such as wound dressings. However, it will be clear that the antimicrobial compositions of the present invention with a derivatised quaternary ammonium salt and an underivatised cationic antimicrobial comprised therein include a cushioning composition.
Accordingly, in a fifth embodiment of the first aspect of the invention, there is provided a cushioning composition for a cushioning device comprising a substantially water-insoluble carrier to which the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached in the form of a body of a soft, flexible material.
The cushioning composition may be comprised in a cushioning material in a cushioning component, or may essentially be the cushioning material. In turn the cushioning component may be comprised in a cushioning device, or may essentially be the cushioning device.
However, the cushioning composition will often essentially be the cushioning material. In turn the cushioning component will often essentially be the cushioning device.
For these reasons, the cushioning composition of the present invention with a derivatised quaternary ammonium salt and the cationic antimicrobial salt comprised therein will be illustrated by the following non-limiting description mainly in relation to the cushioning device. However, the skilled person will appreciate that other integers may be present in the cushioning material, cushioning component or cushioning device, which are compatible with the use of the device as a medical cushioning device.
The conformable cushioning device of the present invention may suitably be in any form or shape that is compatible with its functions of relieving pressure on a pressure-sensitive area of a human or animal, and acting as a source of topical therapeutic agents. The cushioning device is thus used for the prophylaxis and/or treatment of wound precursors, as defined herein, and chronic wounds, including pressure sores and ulcers on or in the skin, or in the tissue underlying it.
It will often comprise, or consist essentially of an imperforate integer. Accordingly, It should preferably have a moisture vapour permeability (MVP) in the range of 250 to 4 500 g/m2/24hr, more preferably with an MVP) in the range of 250 to 2 500 g/m2/24hr, facilitating moisture vapour escaping normally from under it.
It should preferably take up as little space as possible so that Ίπβ cushioning device can be worn under ordinary human clothing or footwear (shoes etc.), or bedclothes without causing much inconvenience It may be a device which is not shaped to conform in use to a pressure-sensitive part of the body, an 'unshaped device', such as a layer or sheet or it may be shaped to conform in use to a pressure-sensitive part of the body, such as the feet or the sacrum, a 'shaped device'. For those who are bedridden or chairbound, in particular bedridden, for example with paralysis, parts of the body, for example on each side of the torso and the back tend to be pressure-sensitive parts of the body, at risk of developing wound precursors and/or chronic wounds, including pressure sores, ulcers and infected wounds.
Cushioning devices of the present invention may suitably be used on pressure- sensitive parts of the body, for example on each side of the torso and the back of such a patient who is known to be at risk of developing pressure sores and/or ulcers.
Because of the variety of the points on the human or animal body where the cushioning device is used, and the relative flatness of some, for example on the back of the patient who is potentially at risk, such a cushioning device of the present invention cannot then usefully be shaped to conform in use to the body over a given area.
Accordingly, in a first form of the fifth embodiment of the present invention, the conformable cushioning device for application to a human or animal body is not shaped to conform to affected areas to which it is applied.
It is thus usually provided in a versatile lamellar form, and in a shape that is compatible with its functions referred to above. Such cushioning devices are usually in the form which comprises a conformable component, or consists essentially of such a component in the form of at least one layer or sheet of a absorbent material.
Such structures often have a shape such as an elongate strip, band or ribbon, a quadrilateral, such as a rectangle or oblong, or an equilateral, such as a square, or a round, but not necessarily regularly round, disc such as circular, elliptical or oval disc such as circular, elliptical or oval cushioning device.
This embodiment of the first aspect of the present invention will typically have a thickness that tends to be constant and towards the lower figures in the ranges given hereinbefore for the thickness of the general cushioning device of the present invention; that is in the ranges of from 0.1 to 1 .5 cm, for example from 0.2 to 1 cm, such as from 0.3 to 0.5 cm.
As described hereinafter in greater detail, such cushioning devices may comprise a material which characteristically has a good permeability to water vapour, and at least part of the proximal face of which is inherently self-adhesive to skin, thus avoiding any need for a layer of pressure-sensitive adhesive around the periphery of its proximal face, or retaining strapping or other means of attachment. Such self-adhesion is usually relatively unaggressive, which is among the especially advantageous properties of a cushioning device with a proximal face comprising such a material.
Alternatively or additionally, the present cushioning device may suitably be provided with conventional (generally pressure-sensitive) adhesive around the periphery of its proximal face, or retaining strapping or other appropriate means for it to be secured, which are well-known to the skilled person, or are described further in the patent or literature prior art.
Alternatively or additionally, the present cushioning device may suitably be made of at least one piece, typically one piece, of foam. Two or more pieces are optionally bonded to each other. The foam may be a foamed plastics material, foam natural rubber or another foam material, preferably with a good permeability to water vapour. Suitable such materials include thermoplastic polyurethane foams. These are characteristically extremely soft and pliable. This form of the material may be an open-cell foam, that is one in which at least some of the pores in the material form the plurality of channels running between opposite faces, or it may be a closed-cell foam.
The lower parts of the body, for example the soles and heels of the feet and the sacrum, tend to be particularly pressure-sensitive parts of the body, where the risk of developing wound precursors and/or wounds referred to above tends to occur. This is especially the case in those patients with arthritis, diabetes or cardiovascular conditions who are not bedridden or chairbound.
Such cushioning devices are usually shaped to conform in use to, and to be in direct or indirect contact with, a relevant body part when used in
relieving pressure on and cushioning pressure-sensitive parts of the body such as the soles and heels of the feet and the sacrum, and
protecting them against wound precursors and/or chronic wounds, including pressure sores, ulcers and infected wounds.
A second from of the fifth aspect of the present invention is a shaped cushioning device, that is one that is shaped to conform in use to the body over an affected area to which it is applied.
It may suitably be used on pressure-sensitive parts of the body, for example on parts of the body of a patient who is not bedridden, but mobile or chairbound, and is known to be at risk of developing pressure sores and/or ulcers. Such a conformable, flexible cushioning devices of the present invention is in general shaped to conform to, for example, the foot or the sacrum.
The thickness of such a cushioning device of the present invention tends to range between the lowest and highest figures in these ranges, that is in the ranges of from 0.3 to 5 cm, for example from 0.5 to 3 cm, such as from 1 to 1 .5 cm. Where the proximal face conforms in use to, for example the arch of the foot, the cushioning device has an increased thickness at the point where it is required to cushion the arch, or where the proximal face conforms in use to, for example the soft tissue over the sacrum, the cushioning device has an increased thickness at that point where it is required to cushion the sacrum.
In both cases, the opposite distal face does not conform in use to the same extent to the relevant part of the human body if at all.
A cushioning device of this embodiment of the first aspect of the present invention will generally not need to be provided with means for it to be secured to the body of a patient who is potentially at risk, over the affected areas to which it is applied. Such cushioning devices are in general held in position over the affected parts, in the foot by conforming footwear, or in other parts of the body, for example over the sacrum, by clothing. As is well-known to the skilled person, it thus does not normally need to be provided with conventional adhesive or strapping means for it to be secured However, as noted above, some materials which characteristically have a good permeability to water vapour and are coincidentally inherently self-adhesive to skin, thus further holding the cushioning device in place.
Any conforming footwear or clothing should not of course block the surfaces of this embodiment to such an extent that the moisture vapour permeability (MVP) of the cushioning device on the relevant part of the body is impaired, and in particular falls below 250 g/m2/24hr, and thus put a patient at risk of developing wound precursors and/or chronic wounds, including pressure sores, ulcers and infected wounds.
Alternatively or additionally, the present cushioning device may suitably be made of at least one piece, typically one piece, of foam. Two or more pieces are optionally bonded to each other. The foam may be a foamed plastics material, foam natural rubber or another foam material, preferably with a good permeability to water vapour. Suitable such materials include thermoplastic polyurethane foams. These are characteristically extremely soft and pliable. This form of the material may be an open-cell foam, that is one in which at least some of the pores in the material form the plurality of channels running between opposite faces, or it may be a closed-cell foam.
In all embodiments of the first aspect of the present invention, the conformable cushioning devices may suitably be made of a soft, pliable plastics material. Suitable materials for use in the cushioning devices the first aspect of the present invention include synthetic polymeric materials, with a good permeability to water vapour, such as
gels,
elastomers, for example one based on one or more alkylenes, such as ethylene, propylene and butylene, and styrene and combinations thereof,
thermoplastic polyurethanes (also preferred materials),
certain copolyesters and polyamides, and combinations thereof; and
closed-cell foamed plastics materials, for example a thermoplastic polyurethane closed-cell foam, closed-cell foamed natural rubber or any other closed-cell foam material All of the plastics materials listed above are characteristically extremely soft and pliable.
In the cushioning devices of the present invention that are shaped to conform to affected areas to which they are applied, for example the foot or the sacrum, it is preferred that the cushioning device be made of a soft, pliable, almost viscous fluid-like plastics material. Preferably the cushioning device is made of a conformable gel of this type.
In the cushioning devices of the present invention that are not shaped to conform to affected areas to which they are applied, for example each side of the torso and the back, it is preferred that the cushioning device be made of a soft, pliable plastics material, but one that is not almost viscous fluid-like.
Suitable and preferred derivatised quaternary ammonium salts in cushioning antimicrobial compositions of the invention are in general as so described hereinbefore in relation to corresponding components of absorbent antimicrobial compositions.
One form of a cushioning device comprises an absorbent conformable component, which comprises a substantially water-insoluble antimicrobial composition of the first aspect of the present invention, on or in a proximal face of a cushioning component, as defined herein, but optionally without an antimicrobial composition of the first aspect of the present invention. The two components are optionally bonded to each other.
The cushioning device thus provides topical anti-microbial activity in contact with bodily fluid on a body surface or wound exudate, and cushioning of pressure- sensitive parts of the body, from two different components. The cushioning component may be unshaped, such as a layer or sheet, or one shaped to conform in use to a pressure-sensitive part of the body.
Suitable and preferred configurations, dimensions and shapes of the cushioning component in the device are as so described hereinbefore. The absorbent component, which comprises a substantially water-insoluble antimicrobial composition of the first aspect of the present invention, will usually conform to, and be roughly coterminous with the cushioning component, and thus have the same or similar configurations, dimensions and shapes as the cushioning component.
Suitable and preferred derivatised quaternary ammonium salts and cationic antimicrobial salts, and solid substantially water-insoluble carriers to and/or within which the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached and/or dispersed, for the cushioning component are as so described hereinbefore for respectively the absorbent component.
In one embodiment of the second aspect of the invention, the device comprising the antimicrobial composition of the first aspect of the invention is in the form of an antimicrobial spraying device containing the antimicrobial composition for spraying a surface with an aerosol comprising an aqueous liquid medium comprising the antimicrobial composition.
Such a device comprising the antimicrobial composition of the first aspect of the invention may be
a) a wound care antimicrobial device for spraying the composition (which is optionally absorbent for absorbing wound exudate from a wound) onto a wound; or
b) a personal care antimicrobial device for spraying the composition (which is optionally absorbent for absorbing a bodily fluid from a body surface) onto a body surface.
Either antimicrobial device for spraying the composition may be in the form of a pressurised vessel such as a can or canister with the capability of spraying the composition in the form of an aerosol comprising an aqueous liquid medium comprising the water-insoluble antimicrobial composition, typically as a suspension of a fine particulate of a substantially water-insoluble carrier to which the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached.
Where the substrate for spraying is a wound, it may be particularly desirable for the carrier of the antimicrobial composition of the first aspect of the invention not only to comprise an absorbent material but such a material which may swell in contact with water to become an elastic gel material. This may coalesce to form an integral conformable absorbent material, in the manner of a so-called plastic skin, which may be removed from the wound site in one piece, without irrigation, and with minimum pain and shedding.
Absorption of fluid is virtually instantaneous since ionic exchange is not required for the materials to become gellable. Suitable and preferred materials, sizes, forms and structures of the absorbent carrier with these physical properties will be well-known to the skilled person, or are described further in the patent prior art.
All the antimicrobial cushioning or absorbent devices, corresponding components, compositions and materials of the present invention may also comprise therapeutically active materials other than the derivatised quaternary ammonium salt and the cationic antimicrobial salt.
These should be biocompatible materials which are compatible with the other device components, compositions and materials, and in particular when in a wound dressing and in direct or fluidic contact with wound exudate, preferably attached to the solid substantially water-insoluble carrier.
Any such therapeutic agent should be pharmaceutically acceptable, and may suitably be any of the following pharmaceutically acceptable ingredients:
emollients, such as skin lipids and sterols, oils, for example lightweight oils, such as cetyl alcohol, or silicone-derived oils, such as cyclomethicone, and heavier oils, such as grape seed oil or dimethicone, and petrolatum;
antioxidants;
lubricants;
soothing ingredients, such as chamomile and aloe vera;
topical analgesics, such as ibuprofen, diclofenac and capsaicin; to treat pain in combination with the soothing effect of the present cushioning device (optionally in relation to cushioning devices for relieving pressure on painful arthritic joints, such as fallen arches of the foot, for longer-term pain relief);
topical anaesthetics, such as lidocaine to numb affected parts of the human or animal body; and/or
topical antiinflammatories, such as steroids, such as Cortisol.
In a third aspect, the present invention provides a process for producing a solid substantially water-insoluble antimicrobial composition according to the first aspect of the present invention for an antimicrobial device, which process comprises
a) adding to a carrier a water-soluble therapeutically active derivatised quaternary ammonium salt and a cationic antimicrobial salt, wherein the quaternary ammonium salt is N-substituted by a group of formula (I) and a group R5 , which is as hereinbefore defined, optionally in a fluid medium, or b) adding the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt to, and dispersing the salt in a fluid precursor of the carrier.
A first embodiment of this third aspect of the present invention provides a process for producing an absorbent antimicrobial composition according to the first aspect of the present invention for an antimicrobial device. This process comprises adding to a carrier, and/or impregnating the carrier with, the water- soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a fluid medium.
As described hereinafter in greater detail, the fluid is often a highly aqueous fluid, especially when the material for the carrier is a water-absorbent polymeric material that is substantially water-insoluble, as described hereinbefore in greater detail.
A second embodiment of this third aspect of the present invention provides a process for producing a cushioning antimicrobial composition according to the first aspect of the present invention which process comprises dispersing the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a, typically fluid, precursor of the carrier, followed by solidification of the precursor of the carrier to form the carrier.
In the first embodiment of this third aspect of the present invention, the fluid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt is usually
a) an aqueous solution in which the quaternary ammonium salt is dissolved to at least 0.1 %, and up to 0.5%, for example up to 1 % w/w, usually in a highly aqueous medium as defined; or
b) an aerosol comprising such a solution.
The aqueous solution comprising the derivatised quaternary ammonium salt and the cationic antimicrobial salt is usually in a highly aqueous medium as defined. It will generally comprise at least 0.1 %, and up to 0.5%, for example up to 1 % w/w, of a surfactant to promote wetting of the carrier.
The surfactant should promote wetting of the carrier without competing with the derivatised quaternary ammonium salt for typical sites of attachment to the solid carrier by pairing of ions of opposite charges, typically the anions of salts, such as of salified carboxylic acids.
Favoured surfactants thus include nonionic surfactants, such as polymeric material of which the largest part (by weight) consists of homo- or copolymers of oxyolefins such as oxyethylene, oxypropylene, oxybutylene or oxy-4-methyl-l- pentene.
These may be polyoxyethylene alkyl ethers (Brij), for example of the formula: CH3-(CH2)io-i6-(O-C2H4) _25-OH, such as octaethylene glycol monododecyl ether and pentaethylene glycol monododecyl ether; and polyoxypropylene glycol alkyl ethers, for example of the formula: CH3-(CH2)io-i6-(O-C3H6)i-25-O.
Such non-Ionic surfactants preferably comprise residues of an oligosaccharide with alkylated hydroxyl functions, typically oligoglucoside alkyl ethers, for example decyl glucoside, dodecyl glucoside, octyl glucoside and decyl octyl glucoside (APG), often formed by an alkylation reaction between a function such as the anion of an alkali metal oxide, such as a sodium oxide group, in the oligosaccharide.
In some embodiments of the composition, for example for absorbent fibre, typically microfibre or nanofibre pads or layers as defined herein, it may be desirable to incorporate a relatively volatile non-aqueous liquid in the frequently highly aqueous medium in particular in an aerosol comprising the aqueous solution.
This should be a water-miscible non-solvent for the carrier, but a solvent for the derivatised quaternary ammonium salt and/or the cationic antimicrobial salt c), typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such as 3 to 8 %, for example 5 to 6 % w/w, in the aqueous solution per se or in the aerosol. This may aid evaporation and/or help to solubilise therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salts with more hydrophobic groups and/or steric hindrance around the nitrogen atom of the ammonium cation caused by the other substituent groups present. It is believed that the anion of such derivatised quaternary ammonium salt and the cationic antimicrobial salts may alternatively or additionally, usually alternatively, be chosen to help to solubilise therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salts.
Examples of these anions include anions of an organic acid, such as hydrogen pamoate and/or pamoate.
If the carrier is of a water-absorbent material, for example if the composition is used in a wound dressing, absorption of the fluid comprising the therapeutically is active ionic material virtually instantaneous, but depending on the particular therapeutically active material the time for the treatment process overall may suitably be 1 to 60 min, such as 2 to 45 min. 2 to 45 min. is found to be most suitable to give a more useful substrate in an economic time.
The treatment process may often be carried out by immersing the carrier, which is or comprises a water-absorbent material, in the liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt for the a suitable length of time, as above.
This forms a first variant of the first embodiment of this third aspect of the present invention (a process for producing an absorbent antimicrobial composition).
Depending on the given therapeutically active ionic material, a good to very good transfer loading of the derivatised quaternary ammonium salt and the cationic antimicrobial salt in a practical length of time may be achieved in this first process variant. The treatment may suitably be carried out at a temperature of up to 30°C, which may suitably be 5 to 25° C, for example 10 to 20° C.
This first variant of the first embodiment may in some cases be operated as a semi-continuous process for producing an absorbent antimicrobial composition.
This may be carried out by threading a length of the carrier, which is or comprises a water-absorbent material, through rollers into and through a bath containing a solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt. Excess solution is then removed, and the carrier is impregnated with the water-soluble therapeutically derivatised quaternary ammonium salt and the cationic antimicrobial salt under pressure by feeding the carrier through nip rollers. The carrier, loaded with the derivatised quaternary ammonium salt and the cationic antimicrobial salt, is then dried, for example in an oven, and cooled, for example with a chill roller.
However, if
a) the carrier is already mounted in a precursor of a wound dressing comprising the therapeutically active ionic material;
b) the solid substantially water-insoluble carrier is of a particularly water- absorbent and -retaining material and/or structure and
i) the composition is to be used in a wound dressing,
ii) may swell in contact with water and/or
ii) may become an irreversible elastic gel material; and/or
iii) exhibits poor maintained integrity and/or wet strength,
it is preferable to spray the surface of the carrier with an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, optionally also comprising a non-aqueous liquid which is a water-miscible non-solvent for the carrier.
Where the carrier is already mounted in a precursor of a wound dressing comprising the therapeutically active ionic material, it will usually not be possible for the carrier to be immersed in the liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in the treatment process without compromising the other components of the dressing.
The substantially water-insoluble but hydrophilic absorbent material used in the carrier, and/or its form and/or structure may also have the physical property of retaining an excess of the liquid medium of this process of the first embodiment. The undesired excess of the aqueous medium cannot be readily be removed after direct contact with the liquid medium, for example by the carrier loaded with the therapeutic derivatised quaternary ammonium salt and the cationic antimicrobial salt being left to drain. In some embodiments of the composition in a wound dressing, it also functions as an absorbent component of the dressing. The presence of an excess of an aqueous medium in which it has been immersed is likely to impair the absorbent performance of the dressing.
For example, the material of the carrier with the above properties may also be a substantially water-insoluble superabsorbent gelling, water insoluble derivatised alginate, cellulose or chitosan and/or its form and/or structure may be a foam. If it is an open-cell foam which exhibits good absorption and retention of fluid, undesired excess of the aqueous medium cannot be readily be removed after direct contact with the liquid medium, for example by the carrier loaded with the therapeutic derivatised quaternary ammonium salt and the cationic antimicrobial salt being left to drain. More importantly, it can no longer function as an absorbent in the dressing.
In all such embodiments of the composition for a wound dressing, the second variant of the treatment process of this first embodiment of this third aspect of the present invention third aspect of the invention should be used. To spray the surface of the carrier with an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt will typically take less than 10 min, although multiple spraying may be desirable, for example for absorbent fibre, often microfibre or nanofibre pads or layers as defined herein. The time for the treatment process overall may still suitably be 1 to 60 min, such as 2 to
45 min, to allow the relatively smaller undesired excess of the aqueous medium to drain or evaporate from the surface of the carrier.
In some embodiments of the composition, for example for absorbent fibre, typically microfibre or nanofibre pads or layers as defined herein, it may be desirable to incorporate a relatively volatile non-aqueous liquid which is a water- miscible non-solvent for the carrier, but a solvent for the derivatised quaternary ammonium salt and the cationic antimicrobial salt, typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such as 3 to 8 %, for example 5 to 6 % w/w, to the aqueous solution in the aerosol to aid evaporation.
Depending on the given therapeutically active ionic material, a good to very good transfer loading of the derivatised quaternary ammonium salt and the cationic antimicrobial salt in a practical length of time may be achieved in this second process variant of the first embodiment of this third aspect of the present invention. The treatment may suitably be carried out at a temperature of up to 30°C, which may suitably be 5 to 25° C, for example 10 to 20° C.
In the second variant of the treatment process of this first embodiment of this third aspect of the present invention, spraying the surface of the carrier with an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, optionally also comprising a volatile non-aqueous liquid. Such a liquid should be a water-miscible non- solvent for the carrier. The spraying may be carried out as appropriate by electrospraying, that is, by forcing the above solution through a capillary nozzle or needle tip, which may optionally be made to traverse over the carrier, and applying a large potential difference of the order of several kV to the tip relative to the carrier. The carrier may be mounted on a counterelectrode, as a collection target, so forming a so-called Taylor cone of the solution at the tip. Applying the large potential difference also causes charged droplets to break away from the Taylor cone of the solution at the tip, and the electric field accelerates the charged droplets to towards the collection target
As it travels through the air, the solvent evaporates from each droplet of the solution, and the maximum amount of charge the diminishing droplet can carry is reached (the "Rayleigh limit"). Each droplet then undergoes a Coulomb explosion in which the Coulombic repulsion of the components of the droplet of the solution having the same electric charge breaks the bonds that hold it together. This forms a fine aerosol comprising the aqueous solution, which forms a layer that comprises the derivatised quaternary ammonium salt and the cationic antimicrobial salt on the target. As noted above, it may be desirable to incorporate a relatively volatile nonaqueous liquid in the frequently highly aqueous medium in particular in an aerosol comprising the aqueous solution.
This should be a water-miscible non-solvent for the carrier, but a solvent for the derivatised quaternary ammonium salt and the cationic antimicrobial salt, typically isopropanol or ethanol, frequently at a concentration of 1 to 10 %, such
as 3 to 8 %, for example 5 to 6 % w/w, in the aqueous solution per se or in the aerosol.
This may aid evaporation and, it is believed help each droplet of the solution more quickly to reach its Rayleigh limit of the maximum amount of charge the diminishing droplet can carry before it undergoes a Coulomb explosion.
As noted above in connection with this second variant of the first embodiment of this third aspect of the present invention, the Coulomb explosion forms a fine aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, which forms a layer that comprises the derivatised quaternary ammonium salt and the cationic antimicrobial salt on the target.
In the above variants of the process of this first embodiment of this third aspect of the invention, the form and/or structure of the substantially water-insoluble carrier corresponds to the composition form and/or structure when it is a component of a dressing.
Where for example the composition of the first aspect of the invention has a structure which comprises fibres, commonly microfibres or nanofibres as defined herein, the component fibres may be treated with an aqueous medium comprising the derivatised quaternary ammonium salt and the cationic antimicrobial salt, left to drain and/or be air-dried, and then processed according to known methods into a wide variety of forms of the composition as a component of an antimicrobial devices, and in particular in an advanced wound dressing. This may be, for example in the form of a non-woven fabric comprising the treated fibres.
Such a non-woven fabric may be produced by conventional fibre opening, web formation and needling, and may suitably have a thickness of 30 to 200g/m2 or more.
This process forms a third variant of the first embodiment of this third aspect of the present invention, which is carried out as appropriate by
a) immersion of the carrier in an aqueous liquid medium comprising the water- soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt, or
b) spraying the surface of the carrier with an aerosol comprising an aqueous liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt. The simplicity of the chemistry and the availability of the reactants of all the above process variants of the first embodiment of this third aspect of the present invention, and the fact that treatment may suitably be carried out at ambient temperatures enable the cost of manufacture of a composition of the first aspect of the invention to be kept advantageously low.
As noted above, a second embodiment of this third aspect of the present invention provides a process for producing a cushioning antimicrobial composition according to the first aspect of the present invention, which process comprises dispersing the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a, typically fluid, precursor of the carrier, followed solidification of the precursor of the carrier, to form the cushioning antimicrobial composition or device composition of the first aspect of the present invention.
The product of this second variant of the second process embodiment may be a cushioning device which comprises a cushioning component, but is more usually in a form which consists essentially of such a component. The water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt is dispersed in a, typically fluid, precursor of the carrier, followed solidification of the precursor of the carrier. Solidification of the precursor is often characterised by the crosslinking of a non-crosslinked, or monomeric or oligomeric precursor of the material of the cushioning device according to the present invention, often in the course of reactive injection moulding or casting.
In one form of the second embodiment of the first aspect of the present invention, where the cushioning device is shaped to conform in use to the body over a given pressure-sensitive area where device is needed.
Such a cushioning device is often relatively thick, and may have an increased thickness at the point where it is required, for example to cushioning device the arch of the foot or where it is required to cushion the sacrum. Advantageously, the process for the preparation of the cushioning device according to the first aspect of the present invention is then characterised by reactive injection moulding, for example of a room-temperature curing fluid precursor system. The mould into which the fluid precursor system is injected typically has inner faces that are shaped to conform to the proximal face and the opposite outer face of the desired form of the cushioning device, and is often in two cooperating parts. Where the cushioning device is not shaped to conform in use to the body over a given pressure-sensitive area where cushioning is needed, the cushioning device is often relatively thin, and may have an essentially constant thickness.
Advantageously, the process for the preparation of the cushioning device according to the first aspect of the present invention is then characterised by reactive casting, for example of a room-temperature curing fluid precursor system.
The platen onto which the fluid precursor system is cast typically has a flat face with a raised periphery or other appropriate means for containing the fluid precursor system shaped to conform to the desired form of the cushioning device.
In a fourth aspect the invention provides a method of treatment or prophylaxis of microbial infections using an antimicrobial composition according to the first aspect of the present invention.
In one embodiment of the fourth aspect of the present invention, there is provided a method of treatment or prophylaxis of microbial infections and any underlying pathologies in wound precursors and wounds, comprising administering a therapeutically effective amount of a composition according to the first aspect of the present invention to a wound or wound precursor.
In another embodiment of the fourth aspect of the present invention, there is provided a method of treatment or prophylaxis of microbial infections and any underlying pathologies in wound precursors and wounds, comprising applying an absorbent medical device, which is a wound dressing, comprising a therapeutically effective amount of a composition according to the first aspect of the present invention to a wound or wound precursor.
Such a dressing can be easily applied to treat a wound on a human or animal body; including an acute wound, for example a surgical wound; a chronic wound, for example a diabetic ulcer or a venous leg ulcer; or a burn.
The dressing may be used as appropriate in a wound that extends to at least the epidermis of the animal's skin, in a wound that extends to the dermis or the subcutaneous fat region of the animal's skin, in a wound that extends into the musculature of the animal, or in a wound that extends into the viscera of the animal.
In further embodiment of the fourth aspect of the present invention, there is provided a method of treatment or prophylaxis of a pressure-sensitive part of the body of a patient at risk of developing wound precursors and/or wounds, comprising applying a medical device, which is a cushioning device to the part of the body at risk. Such a cushioning device of the present invention as defined can be easily applied to patients who have, or are at substantial risk of developing, wound precursors include, for example those with arthritis, diabetes, cardiovascular conditions or paralysis.
The cushioning, medical device relieves the pressure on the skin of the patient, and makes a water-insoluble form of a quaternary ammonium salt available to the skin and/or the tissue underlying it, to combat any microbial infections and any underlying pathologies in any wound. .
The device may also be a non-medical device, often an absorbent device which is a personal care device, such as a disposable sanitary device, such as a nappy (diaper), a disposable nappy or training pants, a feminine care product, for example, a tampon, a sanitary towel, or a napkin or a pant liner, or an incontinence product.
Accordingly, in a fifth aspect of the present invention, there is provided a method of removal of bodily fluid (excluding wound exudate) from a body surface(including the skin and internal mucosa) of a human or animal, comprising applying a non-medical absorbent device which is a personal care device, to the body surface.
The invention will now be illustrated by the following non-limiting examples. Example 1
This example demonstrates a first variant of the process for making an absorbent water-insoluble composition with a derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) comprised in a non-woven fabric absorbent material, for use as an absorbent component of an antimicrobial medical or nonmedical device. A Werner Mathis AG coater was set up. A 20m roll of spunbond polyester material was placed on one side of the machine, and was threaded at a speed of 1 .5m/min through a bath containing a solution of the derivatised quaternary ammonium salt a), N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethyl- ammonium chloride (0.2% w/w solution), the cationic antimicrobial salt c) polyhexamethylene biguanide (PHMB) hydrochloride (0.2% w/w solution), and a decyl octyl oligoglucoside ether surfactant (APG) (0.2% w/w solution) the remainder being deionised water.
The material was then fed through nip rollers exerting a pressure of 1 .25 bar to remove excess solution, then fed into a first oven at 100° C and a second oven also at 100° C to dry the material. The material loaded with the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) then left the oven, passed over a chill roller (to remove residual heat) and was batched up.
The width of material entering the machine was 20.5cm and leaving the machine was 18cm. The shrinkage is likely to do with drying and stretching. The above process for an antimicrobial composition for a wound dressing is used mutatis mutandis to produce antimicrobial compositions of the first aspect of the present invention. These include
other derivatised quaternary ammonium salts a), such as
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N, N- dipropyl-N-octadecyl- N-2-(trimethoxysilyl)propylammonium acetate, N, N- dimethyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen tartrate,
N,N-dimethyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium chloride or N,N-dipropyl-N-eicosyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate
with a component c) quaternary ammonium cationic antimicrobial, which is
N,N-tripropyl-N-octadecylammonium sulphate,
N,N-trimethyl-N-octadecylammonium phosphate
N,N-tripropyl-N-octadecylammonium acetate,
N,N-trimethyl-N-octadecylammonium benzoate,
N,N-tripropyl-N-octadecylammonium tartrate, and/or
in particular N,N-trimethyl-N-octadecylammonium chloride,
N,N-didecyl-N-dimethylammonium chloride
N,N-didecyl-N-dimethylammonium bromide, or
an N-benzyl-N,N-dimethyl-N-C8-22 alkylammonium chloride or bromide.
or
a component c) guanidine-based cationic antimicrobial, which is
p-chlorophenyl biguanide hydrochloride,
p-chlorobenzhydryl biguanide hydrochloride.
chlorhexidine digluconate,
chlorhexidine diacetate, or
chlorhexidine dichloride.
attached and/or dispersed to
a solid carrier b)which is an alginate, cellulose, carboxvmethvlcellulose, chitosan or carboxymethyl-chitosan; with optionally salified carboxylic acid residues.
Example 2:
This example demonstrates a second variant of the process for making an absorbent water-insoluble composition with a derivatised quaternary ammonium salt a) and cationic antimicrobial salt c) comprised in a polyester open-cell foam which exhibits good absorption and retention of fluid.
The surface of a 5cm x 5cm piece of the open-cell foam is sprayed with an aerosol comprising an aqueous solution of the derivatised quaternary ammonium salt, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium chloride (0.2% w/w solution), the cationic antimicrobial salt c) polyhexamethylene biguanide (PHMB) hydrochloride (0.2% w/w solution), and a decyl octyl oligoglucoside ether surfactant (0.2% w/w solution) the remainder being deionised water.
The foam carrier loaded with the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) is left to allow the relatively small undesired excess of the aqueous medium to drain or evaporate from the surface of the carrier.
It is then again sprayed with the aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c), and then placed in a first oven at 100° C and a second oven also at 100° C to dry the material.
The above process for an antimicrobial composition for a wound dressing is used mutatis mutandis to produce antimicrobial compositions of the first aspect of the present invention including
other derivatised quaternary ammonium salts a)
N, N- dimethyl-N - eicosyl - N - 2 - (trinnethoxysilyl)propylannnnoniunn benzoate, N, N- dipropyl-N - eicosyl - N - 2 - (trimethoxysilyl)propylammoniunn tartrate, N,N- dimethyl-N - hexadecyl - N - 2 - (trimethoxysilyl)propylammoniunn chloride,
N,N-dipropyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen sulphate
N,N-dimethyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium dihydrogen phosphate,
N,N-dipropyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium acetate, N,N- dimethyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium benzoate, or N,N-dipropyl-N-hexadecyl-N-2-(trimethoxysilyl)propylammonium hydrogen tartrate, with
a component c) quaternary ammonium cationic antimicrobial, which is
N,N-tripropyl-N-octadecylammonium hydrogen sulphate,
N,N-trimethyl-N-octadecylammonium dihydrogen phosphate
N,N-tripropyl-N-octadecylammonium acetate,
N,N-trimethyl-N-octadecylammonium benzoate,
N,N-tripropyl-N-octadecylammonium tartrate, and/or
in particular N,N-trimethyl-N-octadecylammonium chloride,
N,N-didecyl-N-dimethylammonium chloride
N,N-didecyl-N-dimethylammonium bromide, or
an N-benzyl-N,N-dimethyl-N-C8-22 alkylammonium chloride or bromide, or
a component c) guanidine-based cationic antimicrobial, which is
p-chlorophenyl biguanide hydrochloride,
p-chlorobenzhydryl biguanide hydrochloride.
chlorhexidine digluconate,
chlorhexidine diacetate, or
chlorhexidine dichloride.
attached and/or dispersed to
a solid carrier b)which is an alginate, cellulose, carboxymethylcellulose, chitosan or carboxymethyl-chitosan; with optionally salified carboxylic acid residues.
Example 3:
The antinnicrobial activity and the degree of release by water of a derivatised quaternary ammonium salt a) and the cationic antimicrobial salt c) from the composition of Example 1 were determined as follows:
Three fabric specimens were cut to 5cm x 5cm weighed. Primasorb wound dressings were used as an untreated control. Pre poured agar plates were inoculated with 10ΟμΙ of Staphylococcus aureus suspension and spread with sterile spreaders. One dressing is placed on each agar plate and gently pressed onto the surface using sterile spreaders. The plates were then incubated overnight at 37°C. Results
Untreated control samples - dense growth of S. aureus observed over plate including dressing. Treated samples-dense growth of S. aureus observed over plate nearly up to the dressing. No growth on surface of dressing. Slight leaching of polyhexamethylene biguanide (PHMB) hydrochloride. .
The compositions had good antimicrobial activity in contact with the bacterial culture, and exhibit a surprising and advantageously negligible degree of release by water of the derivatised quaternary ammonium salt, and only slight leaching of polyhexamethylene biguanide (PHMB) hydrochloride. .
Claims
1 . A solid substantially water-insoluble antimicrobial composition for an antimicrobial device comprising
a) a derivatised quaternary ammonium salt, wherein the quaternary ammonium salt is N-substituted by
i) a group of formula (I)
R1 (R2) (R3) Si-(R4) - (I) wherein
each of R1, R2 and R3 is an optionally substituted hydrocarbyl group, and
R4 is an optionally substituted hydrocarbylene group,
and
ii) a group R5, which is an optionally substituted hydrocarbyl group, and
b) a solid substantially water-insoluble carrier to which the derivatised quaternary ammonium salt is attached; and
c) at least one salt of a cationic antimicrobial, which is not derivatised by a group of formula (I).
2. A composition according to claim 1 , wherein the at least one salt of a cationic antimicrobial is a quaternary ammonium salt or a guanidine-based salt.
3. A composition according to claim 1 , wherein any of R1, R2 and R3 independently is an optionally oxa-substituted lower alkyl group with 1 to 6 carbon atoms.
4. A composition according to claim 2, wherein each of R1, R2 and R3 is a lower alkoxy group with 1 to 6 carbon atoms.
A composition according to claim 1 , wherein each of R1, R2 and R3 is a methoxy group.
6. A composition according to claim 1 , wherein R4 is an optionally oxa- substituted lower alkylene group with 1 to 6 carbon atoms.
7. A composition according to claim 6, wherein R4 is an ethan-1 ,2-diyl group.
8. A composition according to claim 1 , wherein R5 is an oxa-substituted hydrocarbyl group with an internal ether linkage.
9. A composition according to claim 1 , wherein R5 is a higher alkyl group with 8 to 22 carbon atoms.
10. A composition according to claim 1 , wherein R5 is an octadecyl group.
1 1 . A composition according to claim 1 , wherein each of the two remaining N- substituents other than the group of formula (I) and R5 is independently a lower alkyl group with 1 to 6 carbon atoms.
12. A composition according to claim 10, wherein the groups are the same and are methyl groups.
13. A composition according to claim 1 , wherein the anion of the derivatised quaternary ammonium salt is a pharmacologically acceptable anion selected from chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate, sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
14. A composition according to claim 1 , wherein the derivatised quaternary ammonium salt is selected from
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium chloride,
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium hydrogen sulphate,
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysNyl)ethylammonium dihydrogen phosphate,
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysNyl)ethylammonium acetate, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysNyl)ethylammonium benzoate, and
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysNyl)ethylammonium hydrogen tartrate.
15. A composition according to claim 1 , wherein the derivatised quaternary ammonium salt is N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethyl- ammonium chloride.
16. A composition according to claim 1 , wherein the component c) comprises only one cationic antimicrobial.
17. A composition according to claim 1 , wherein the at least one salt of a cationic antimicrobial which is not derivatised by a group of formula (I) is a quaternary ammonium salt.
18. A composition according to claim 17, wherein the quaternary ammonium cationic antimicrobial has the structure shown in formula (II): R 6
I
R 7-N +"R 9 X " (II)
I
R 8 where each of R 6, R 7 , R 8 and R 9 is an optionally substituted alkyl, alkenyl, aralkyl or aryl group and X-is an anion.
19. A composition according to claim 18, wherein in formula (II), each of R 6, R 7, R 8 and R 9 is an unsubstituted alkyl or aralkyl group.
20. A composition according to claim 18, wherein in formula (II), R 6 is an optionally oxa-substituted higher alkyl group with 8 to 22 carbon atoms.
21 . A composition according to claim 20, wherein in formula (II), R 6 is an octadecyl group.
22. A composition according to claim 20, wherein in formula (II), each of R 7 , R 8 and R 9 is an unsubstituted lower alkyl group with 1 to 6 carbon atoms.
23. A composition according to claim 22, wherein in formula (II), each of R 7 , R 8 and R 9 is a methyl group.
24. A composition according to claim 18, wherein in formula (II), each of R 6 and R 7 is an optionally oxa-substituted higher alkyl group with 8 to 22 carbon toms.
25. A composition according to claim 24, wherein in formula (II), each of R 6 and R 7 is a decyl group.
26. A composition according to claim 24, wherein in formula (II), each of R 8 and R 9 is an unsubstituted lower alkyl group with 1 to 6 carbon atoms.
27. A composition according to claim 26, wherein in formula (II), each of R 8 and R 9 is a methyl group.
28. A composition according to claim 18, wherein in formula (II), X is a pharmacologically acceptable anion or dianion selected from chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate, sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
29. A composition according to claim 17, wherein the quaternary ammonium salt is selected from
N,N-tripropyl-N-octadecylammonium hydrogen sulphate,
N,N-trimethyl-N-octadecylammonium dihydrogen phosphate
N,N-tripropyl-N-octadecylammonium acetate,
N,N-trimethyl-N-octadecylammonium benzoate,
N,N-tripropyl-N-octadecylammonium hydrogen tartrate, and
in particular N,N-trimethyl-N-octadecylammonium chloride, .
N,N-didecyl-N-dimethylammonium chloride
N,N-didecyl-N-dimethylammonium bromide, and
N-benzyl-N,N-dimethyl-N-C8-22 alkylammonium chloride or bromide.
30. A composition according to claim 1 , wherein the at least one salt of a cationic antimicrobial which is not derivatised by a group of formula (I) is a guanidine- based salt.
31 . A composition according to claim 30, wherein the guanidine-based salt is a guanidine-based compound, diguanidine-based compound or polymeric guanidine-based compound.
32. A composition according to claim 31 , wherein the guanidine-based salt is a biguanidine or polymeric guanidine compound of formula
[ X 1 - NH - C - NH - C - NH -X 2 ] m "Y 2 [ H+ X-]n NZ 1 NZ 2 wherein X 1 and X 2 are either a bond or an aliphatic, cycloaliphatic, aromatic, substituted aliphatic, substituted aromatic, heteroaliphatic, heterocyclic, and/or heteroaromatic divalent residue, and X 1 and X 2 may be the same or different;
Y 1 and Y 2 are an aliphatic, cycloaliphatic, aromatic, substituted aliphatic, substituted aromatic, heteroaliphatic, heterocyclic, and/or heteroaromatic divalent residue, and Y 1 and Y 2 may be the same or different:
m is a number equal to or greater than 1 ;
Z 1 and Z 2 are either a hydrogen atom or a salt. Z 1 and Z 2 may be the same or different;
n is 1 or 2,
a proton H + is N-bonded to one or two of the secondary amine groups to form a secondary ammonium group, and
X-is an anion or X " 2 is two anions or a dianion. .
33. A composition according to claim 32, wherein in formula (III), m is about 2-20.
34. A composition according to claim 32, wherein in formula (III), n is 1 and X " is a pharmacologically acceptable anion, or n is 2 and X ~ 2 is two pharmacologically acceptable anions or a dianion, selected from chloride, bromide, hydrogen sulphate, dihydrogen phosphate and/or hydrogen difluorophosphate, acetate, propionate, isobutyrate, iodobutyrate, valerate, caproate, alpha-hydroxyisobutyrate, glucoheptonate, benzoate, cinnamate, mandelate, isophthalate, 2-hydroxynapthoate, lactate, ascorbate, gluconate, salicylate, isethionate, succinamate, methanesulphonate, glucoheptonate, hydrogen tartrate, hydrogen adipate, hydrogen maleate hydrogen malate, hydrogen malonate, hydrogen glutamate, dihydrogen citrate, hydrogen succinate, hydrogen pamoate and/or hydrogen diglycolate, sulphate, hydrogen phosphate and/or hydrogen difluorophosphate, succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, maleate and tartrate.
35. A composition according to claim 32, wherein in formula (III), n is 2 and X-2 is a pharmacologically acceptable dianion, selected from sulphate, hydrogen phosphate, hydrogen difluorophosphate, succinate, malate, tartrate, malonate, diglycolate, malonate, succinate, malate and tartrate.
36. A composition according to claim 32, wherein the guanidine-based salt is a salt of polyhexamethylene biguanide (PHMB), p-chlorophenyl biguanide or 4- chlorobenzhydryl biguanide.
37. A composition according to claim 36, wherein the guanidine-based salt is polyhexamethylene biguanide hydrochloride (PHMB), p-chlorophenyl biguanide hydrochloride or 4-chlorobenzhydryl biguanide hydrochloride.
38. A composition according to claim 32, wherein the guanidine-based salt is a salt of a halogenated hexidine compound.
39. A composition according to claim 38, wherein the guanidine-based salt is a salt of chlorhexidine (1 ,1 -hexamethylene-bis-5-(4-chlorophenyl biguanide).
40. A composition according to claim 39, wherein the guanidine-based salt is chlorhexidine digluconate, chlorhexidine diacetate, chlorhexidine dichloride or chlorhexidine diodide,
41 .A composition according to claim 1 , which comprises
a derivatised quaternary ammonium salt a) which is
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium chloride, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium hydrogen sulphate,
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium dihydrogen phosphate,
N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium acetate, N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium benzoate, N,N-dipropyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium hydrogen tartrate, or
N,N-dimethyl-N-octadecyl-N-2-(trimethoxysilyl)ethylammonium chloride, and
a component c) quaternary ammonium cationic antimicrobial, which is
N,N-tripropyl-N-octadecylammonium hydrogen sulphate,
N,N-trimethyl-N-octadecylammonium phosphate
N,N-tripropyl-N-octadecylammonium acetate,
N,N-trimethyl-N-octadecylammonium benzoate,
N,N-tripropyl-N-octadecylammonium hydrogen tartrate, and/or
in particular N,N-trimethyl-N-octadecylammonium chloride,
N,N-didecyl-N-dimethylammonium chloride
N,N-didecyl-N-dimethylammonium bromide, or
an N-benzyl-N,N-dimethyl-N-C8-22 alkylammonium chloride or bromide.
or
a component c) guanidine-based cationic antimicrobial, which is
polyhexamethylene biguanide hydrochloride,
p-chlorophenyl biguanide hydrochloride,
p-chlorobenzhydryl biguanide hydrochloride,
chlorhexidine digluconate,
chlorhexidine diacetate, or
chlorhexidine dichloride.
42. A composition according to claim 1 , which comprises one or more surfactants.
43. A composition according to claim 42, which comprises one or more nonionic surfactants which are polyoxyethylene alkyl ethers.
44. A composition according to claim 42, which comprises one or more nonionic surfactants which comprise residues of an oligosaccharide with alkylated hydroxyl functions.
44. A composition according to claim 42, which comprises one or more a decyl glucoside, dodecyl glucoside, octyl glucoside and decyl octyl glucoside.
45. A composition according to claim 1 , wherein the carrier comprises a material selected from polyesters, polyurethanes, copoly(etheresters), polyalkylenes, polyamides, polycarbonates, poly(iminocarbonates) and polyorthoesters.
46. A composition according to claim 1 , wherein the carrier is a polyester.
47. A composition according to claim 1 , wherein the carrier comprises a material selected from celluloses, chitosans and alginates.
48. A composition according to claim 1 , wherein the carrier comprises a material selected from cellulose-based materials, such as carboxymethylcellulose materials, chitosans; and chitosan-based materials, such as carboxymethylchitosan materials, and alginate-based materials.
49.A composition according to claim 1 , comprising a particulate form of the substantially water-insoluble carrier.
50. A composition according to claim 49, wherein the carrier is a microparticulate, having an average diameter in the micrometre scale from about 0.1 to 10 microns (pre-absorption if the fibres are of a water-absorbent material), and a mean size of the interstices between its particles of 1 to 50 microns (pre- absorption if the particles are of a water-absorbent material).
51 .A composition according to claim 1 , wherein the carrier is a random assembly of flexible fibres in the form of at least one piece of wadding, optionally bonded to each other.
52. A composition according to claim 51 , wherein the fibres are microfibres having an average diameter from about 0.1 to 10 microns, or nanofibres having an average diameter from about 85 nanometres to 85 microns, and the assembly of flexible fibres has a mean pore size of 1 to 85 microns.
53. A composition according to claim 1 , wherein the carrier is at least one piece of woven fabric or non-woven, optionally spun-bonded, fabric, optionally bonded to another piece.
54. A composition according to claim 53, wherein the fibres in the fabric have a monofilament linear density of 1 .3 to 5 decitex, and a strength of 1 .2 to 1 .8 cN/dtex, and the fabric has a thickness of 30 to 210g/m2 or more (pre- absorption if the fibres are of a water-absorbent material.)
55. A composition according to claim 1 , wherein the carrier is at least one piece of an open-cell foam.
56. A composition according to claim 55, wherein the foam has a mean pore size of 1 to 85 microns.
57. An absorbent antimicrobial device comprising a solid substantially water- insoluble antimicrobial composition according to claim 1 .
58. A device according to claim 57 which is a wound dressing.
59. An absorbent antimicrobial wound dressing which comprises a composition according to claim 1 .
60. A dressing according to claim 59 wherein the composition is essentially or is comprised in an absorbent material of the dressing lying in fluidic contact with the wound in use.
61 . A dressing according to claim 60 wherein the carrier in the composition is a particulate, a random assembly of flexible fibres in the form of at least one piece of wadding, at least one piece of woven fabric or non-woven, optionally spun-bonded fabric, or at least one piece of an open-cell foam, irremovably attached directly or indirectly to a dressing backing layer and in which in use does not adhere to a wound on removal of the wound dressing from the wound.
62 A dressing according to claim 60 wherein the composition and/or absorbent material is comprised in a conformable container.
63. A dressing according to claim 60 wherein the container is formed by a wound- facing layer or sheet cover that is permeable to wound fluid and irremovably attached directly or indirectly to a dressing backing layer and in use does not adhere to a wound on removal of the wound dressing from the wound.
64. A dressing according to claim 60 wherein the container is a stand-alone envelope, pouch or sachet, with a wound-facing layer or sheet cover that is permeable to wound fluid and in use does not adhere to a wound on removal of the wound dressing from the wound, and is irremovably attached directly or indirectly to a dressing backing.
65. A dressing according to claim 60 wherein the container is a stand-alone envelope, pouch or sachet, and is an inner container within an outer container which is formed by a wound-facing layer or sheet cover that is permeable to wound fluid, is irremovably attached directly or indirectly to a dressing backing layer and in use does not adhere to a wound on removal of the wound dressing from the wound.
66.A dressing according to claim 60 wherein the container is a stand-alone envelope, pouch or sachet, and is an inner container within an outer container which is a stand-alone envelope, pouch or sachet, with a wound- facing layer or sheet cover that is permeable to wound fluid and in use does not adhere to a wound on removal of the wound dressing from the wound, which is irremovably attached directly or indirectly to a dressing backing layer.
67. A dressing according to any of claims 60 to 64, wherein the composition is essentially or is comprised in a wound-facing layer or sheet cover that is permeable to wound fluid of a a conformable container.
68. A process for producing a solid substantially water-insoluble antimicrobial composition according to claim 1 , which comprises treating a solid substantially water-insoluble carrier with a fluid medium comprising
i) a water-soluble therapeutically active derivatised quaternary ammonium salt, wherein the quaternary ammonium salt is N-substituted by a group of formula (I)
R1 (R2) (R3) Si-(R4) - (I) and a group R5
in which each of R1, R2, R3 and R4 , and R5 are as defined in claim 1 , and
ii) a at least one salt of a cationic antimicrobial, which is not derivatised by a group of formula (I). 69. A process according to claim 68, which comprises immersing the carrier in the liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt.
.A process according to claim 68, which comprises spraying a surface of the carrier with an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, optionally also comprising a volatile non-aqueous liquid which is a water-miscible non- solvent for the carrier.
71 .A process according to claim 68, which comprises electrospraying a surface of the carrier with an aerosol comprising the aqueous solution of the derivatised quaternary ammonium salt and the cationic antimicrobial salt, optionally also comprising a volatile non-aqueous liquid which is a water- miscible non-solvent for the carrier.
72. A process according to any of claims 68 to 71 , which comprises treating a solid substantially water-insoluble carrier in a precursor form to that of the
final form of the antimicrobial composition for an antimicrobial device with an aqueous liquid medium comprising the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt, and then processing the treated precursor into the final form for the antimicrobial composition for an antimicrobial device.
73. A method of treatment or prophylaxis of microbial infections using an antimicrobial composition according to claim 1 .
74. A method of treatment or prophylaxis of microbial infections and underlying pathologies in wounds, comprising administering a therapeutically effective amount of a composition according to claim 1 to a wound.
75. A method of treatment or prophylaxis of microbial infections and underlying pathologies in wounds, comprising applying a wound dressing comprising a therapeutically effective amount of a composition according to claim 1 to a wound.
76. A method of treatment or prophylaxis of microbial infections comprising applying a composition according to claim 1 to a human body surface.
77. A method of treatment or prophylaxis of microbial infections comprising applying a personal care device comprising a composition according to claim 1 to a human body surface.
78. A device according to claim 57 which is a personal care device.
79. A method of removal of bodily fluid (excluding wound exudate) from a body surface (including the skin and internal mucosa) of a human or animal, comprising applying a non-medical absorbent device which is a personal care device, according to claim 78 to the body surface.
80 A conformable cushioning device for application to a human or animal body, which consists essentially of or comprises a substantially water-insoluble antimicrobial composition according to claim 1 , which comprises a carrier made of a soft, pliable plastics material.
81 . A cushioning device according to claim 80, which is a cushioning medical device which in use relieves the pressure on the skin of the patient and makes a water-insoluble form of the derivatised quaternary ammonium salt and the cationic antimicrobial salt available to the skin and/or the tissue underlying it.
82. A cushioning device according to claim 80, wherein the derivatised quaternary ammonium salt and the cationic antimicrobial salt is attached to and/or dispersed within the solid substantially water-insoluble carrier.
83. A cushioning device according to claim 80 wherein the carrier comprises a material selected from the following synthetic polymeric materials:
elastomers, based on one or more of ethylene, propylene, butylene and styrene and combinations thereof;
thermoplastic polyurethanes;
copolyesters and polyamides, or combinations thereof; and
foamed thermoplastic polyurethane foam, foamed natural rubber or any other foam material.
84. A cushioning device according to claim 80, where in the carrier is in the form of at least one layer or sheet optionally bonded to each other and optionally bonded to a backing layer which optionally has a pressure-sensitive adhesive around its periphery.
85. A cushioning device according to claim 84, wherein the layer or sheet is inherently self-adhesive to skin.
86. A cushioning device according to claim 84, characterised in that the cushioning device has a constant thickness of from 0.3 to 0.5 cm.
87. A cushioning device as claimed in claim 80, characterised in that the cushioning device is shaped to conform in use to a pressure-sensitive part of the body.
88. A cushioning device as claimed in claim 87, characterised in that the cushioning device has a thickness of from 1 to 1 .5 cm, with an increased
thickness at the point where it is required to cushioning device the pressure- sensitive part of the body.
89. A cushioning device as claimed in claim 80, characterised in that the carrier has a moisture vapour permeability (MVP) that falls between 282 to 4 820 g/m2/87hr.
90. A process for producing a solid substantially water-insoluble antimicrobial cushioning device according to claim 80, which comprises dispersing the water-soluble therapeutically active derivatised quaternary ammonium salt and the cationic antimicrobial salt in a fluid precursor of the carrier, followed by solidification of the precursor of the carrier to form the carrier.
91 .A method of treatment or prophylaxis of a pressure-sensitive part of the body of a patient at risk of developing wound precursors and/or wounds, comprising applying a medical device, which is a cushioning device according to claim 80 to the part of the body at risk.
92. A method of treatment or prophylaxis of microbial infections in a pressure- sensitive part of the body of a patient at risk of developing wound precursors and/or wounds, comprising applying a medical device, which is a cushioning device according to claim 80 to the part of the body at risk.
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GBGB1213782.4A GB201213782D0 (en) | 2012-08-02 | 2012-08-02 | Process and dressing |
GB1213782.4 | 2012-08-02 |
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CN106188419A (en) * | 2016-07-25 | 2016-12-07 | 东南大学 | Graft polymers and the preparation method of antibacterial soft lens based on surface grafting |
CN107041965A (en) * | 2016-12-26 | 2017-08-15 | 广东海洋大学 | A kind of efficient styptic sponge and preparation method thereof |
EP3632477A4 (en) * | 2017-05-23 | 2020-06-17 | Huizhou Foryou Medical Devices Co., Ltd. | Antibacterial wound dressing and preparation method and application thereof |
CN111775519A (en) * | 2020-05-22 | 2020-10-16 | 沈百荣 | Super gentle medical treatment non-woven fabrics |
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