GB2415699A - Seal material for a dispensing apparatus - Google Patents
Seal material for a dispensing apparatus Download PDFInfo
- Publication number
- GB2415699A GB2415699A GB0519174A GB0519174A GB2415699A GB 2415699 A GB2415699 A GB 2415699A GB 0519174 A GB0519174 A GB 0519174A GB 0519174 A GB0519174 A GB 0519174A GB 2415699 A GB2415699 A GB 2415699A
- Authority
- GB
- United Kingdom
- Prior art keywords
- seal
- accelerator
- valve
- polymer
- cross
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000000463 material Substances 0.000 title description 15
- 239000000203 mixture Substances 0.000 claims abstract description 80
- 229920000642 polymer Polymers 0.000 claims abstract description 35
- 229920001021 polysulfide Polymers 0.000 claims abstract description 30
- 150000001875 compounds Chemical class 0.000 claims abstract description 28
- 239000003431 cross linking reagent Substances 0.000 claims abstract description 27
- 229920001577 copolymer Polymers 0.000 claims abstract description 23
- 150000001993 dienes Chemical class 0.000 claims abstract description 17
- SKOLWUPSYHWYAM-UHFFFAOYSA-N carbonodithioic O,S-acid Chemical class SC(S)=O SKOLWUPSYHWYAM-UHFFFAOYSA-N 0.000 claims abstract description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 38
- -1 polyethylene Polymers 0.000 claims description 31
- 238000000034 method Methods 0.000 claims description 30
- 230000008569 process Effects 0.000 claims description 28
- 239000000243 solution Substances 0.000 claims description 24
- 239000003380 propellant Substances 0.000 claims description 21
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 20
- 239000005864 Sulphur Substances 0.000 claims description 15
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 claims description 14
- 239000004927 clay Substances 0.000 claims description 14
- 238000004132 cross linking Methods 0.000 claims description 13
- 239000012530 fluid Substances 0.000 claims description 11
- MSFGZHUJTJBYFA-UHFFFAOYSA-M sodium dichloroisocyanurate Chemical compound [Na+].ClN1C(=O)[N-]C(=O)N(Cl)C1=O MSFGZHUJTJBYFA-UHFFFAOYSA-M 0.000 claims description 10
- 239000000454 talc Substances 0.000 claims description 10
- 229910052623 talc Inorganic materials 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 9
- 239000007788 liquid Substances 0.000 claims description 8
- ZWWQICJTBOCQLA-UHFFFAOYSA-N o-propan-2-yl (propan-2-yloxycarbothioyldisulfanyl)methanethioate Chemical compound CC(C)OC(=S)SSC(=S)OC(C)C ZWWQICJTBOCQLA-UHFFFAOYSA-N 0.000 claims description 8
- 239000005995 Aluminium silicate Substances 0.000 claims description 7
- 235000012211 aluminium silicate Nutrition 0.000 claims description 7
- 239000003963 antioxidant agent Substances 0.000 claims description 7
- 239000011787 zinc oxide Substances 0.000 claims description 7
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000000443 aerosol Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000000460 chlorine Substances 0.000 claims description 6
- 229910052801 chlorine Inorganic materials 0.000 claims description 6
- 239000000725 suspension Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- 239000004698 Polyethylene Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- FZHAPNGMFPVSLP-UHFFFAOYSA-N silanamine Chemical compound [SiH3]N FZHAPNGMFPVSLP-UHFFFAOYSA-N 0.000 claims description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 claims description 4
- 229910000323 aluminium silicate Inorganic materials 0.000 claims description 4
- 230000003078 antioxidant effect Effects 0.000 claims description 4
- 125000001309 chloro group Chemical group Cl* 0.000 claims description 4
- 230000000977 initiatory effect Effects 0.000 claims description 4
- 239000012764 mineral filler Substances 0.000 claims description 4
- 239000004014 plasticizer Substances 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 claims description 3
- 239000000391 magnesium silicate Substances 0.000 claims description 3
- 235000019792 magnesium silicate Nutrition 0.000 claims description 3
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 3
- 229910052757 nitrogen Inorganic materials 0.000 claims description 3
- 239000000377 silicon dioxide Substances 0.000 claims description 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 claims description 2
- 239000004614 Process Aid Substances 0.000 claims description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 claims description 2
- 239000011230 binding agent Substances 0.000 claims description 2
- 239000007767 bonding agent Substances 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 238000000748 compression moulding Methods 0.000 claims description 2
- IHGWHZVHHHLEQR-UHFFFAOYSA-L dimagnesium oxygen(2-) carbonate Chemical compound C([O-])([O-])=O.[Mg+2].[O-2].[Mg+2] IHGWHZVHHHLEQR-UHFFFAOYSA-L 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- 238000001746 injection moulding Methods 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 229910052751 metal Inorganic materials 0.000 claims description 2
- 229910052698 phosphorus Inorganic materials 0.000 claims description 2
- 239000011574 phosphorus Substances 0.000 claims description 2
- 239000000049 pigment Substances 0.000 claims description 2
- 229920000573 polyethylene Polymers 0.000 claims description 2
- 230000002787 reinforcement Effects 0.000 claims description 2
- 239000011347 resin Substances 0.000 claims description 2
- 229920005989 resin Polymers 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 claims description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- 108700024827 HOC1 Proteins 0.000 claims 1
- 101100178273 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) HOC1 gene Proteins 0.000 claims 1
- 229920001971 elastomer Polymers 0.000 description 40
- 239000005060 rubber Substances 0.000 description 36
- 238000009472 formulation Methods 0.000 description 25
- 229920001084 poly(chloroprene) Polymers 0.000 description 24
- 239000003814 drug Substances 0.000 description 17
- 150000002978 peroxides Chemical class 0.000 description 17
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 16
- 229920005557 bromobutyl Polymers 0.000 description 16
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 16
- 230000032683 aging Effects 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000003599 detergent Substances 0.000 description 11
- 230000008901 benefit Effects 0.000 description 10
- AFZSMODLJJCVPP-UHFFFAOYSA-N dibenzothiazol-2-yl disulfide Chemical compound C1=CC=C2SC(SSC=3SC4=CC=CC=C4N=3)=NC2=C1 AFZSMODLJJCVPP-UHFFFAOYSA-N 0.000 description 10
- 239000000945 filler Substances 0.000 description 10
- 238000007789 sealing Methods 0.000 description 10
- VQTUBCCKSQIDNK-UHFFFAOYSA-N Isobutene Chemical group CC(C)=C VQTUBCCKSQIDNK-UHFFFAOYSA-N 0.000 description 9
- 238000001723 curing Methods 0.000 description 8
- 239000000284 extract Substances 0.000 description 8
- 229920005549 butyl rubber Polymers 0.000 description 7
- 239000000047 product Substances 0.000 description 7
- 230000000052 comparative effect Effects 0.000 description 6
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 6
- KUAZQDVKQLNFPE-UHFFFAOYSA-N thiram Chemical compound CN(C)C(=S)SSC(=S)N(C)C KUAZQDVKQLNFPE-UHFFFAOYSA-N 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 230000000704 physical effect Effects 0.000 description 5
- 230000003068 static effect Effects 0.000 description 5
- OPNUROKCUBTKLF-UHFFFAOYSA-N 1,2-bis(2-methylphenyl)guanidine Chemical compound CC1=CC=CC=C1N\C(N)=N\C1=CC=CC=C1C OPNUROKCUBTKLF-UHFFFAOYSA-N 0.000 description 4
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical class C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
- 239000013583 drug formulation Substances 0.000 description 4
- 239000000806 elastomer Substances 0.000 description 4
- 238000002290 gas chromatography-mass spectrometry Methods 0.000 description 4
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical compound ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 description 4
- IUJLOAKJZQBENM-UHFFFAOYSA-N n-(1,3-benzothiazol-2-ylsulfanyl)-2-methylpropan-2-amine Chemical compound C1=CC=C2SC(SNC(C)(C)C)=NC2=C1 IUJLOAKJZQBENM-UHFFFAOYSA-N 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 229960002447 thiram Drugs 0.000 description 4
- JWZZKOKVBUJMES-UHFFFAOYSA-N (+-)-Isoprenaline Chemical compound CC(C)NCC(O)C1=CC=C(O)C(O)=C1 JWZZKOKVBUJMES-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- PDQAZBWRQCGBEV-UHFFFAOYSA-N Ethylenethiourea Chemical compound S=C1NCCN1 PDQAZBWRQCGBEV-UHFFFAOYSA-N 0.000 description 3
- IOVCWXUNBOPUCH-UHFFFAOYSA-M Nitrite anion Chemical compound [O-]N=O IOVCWXUNBOPUCH-UHFFFAOYSA-M 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- NDAUXUAQIAJITI-UHFFFAOYSA-N albuterol Chemical compound CC(C)(C)NCC(O)C1=CC=C(O)C(CO)=C1 NDAUXUAQIAJITI-UHFFFAOYSA-N 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000000338 in vitro Methods 0.000 description 3
- 239000000395 magnesium oxide Substances 0.000 description 3
- 238000000465 moulding Methods 0.000 description 3
- 150000004005 nitrosamines Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000003566 sealing material Substances 0.000 description 3
- 229920003051 synthetic elastomer Polymers 0.000 description 3
- XWTYSIMOBUGWOL-UHFFFAOYSA-N (+-)-Terbutaline Chemical compound CC(C)(C)NCC(O)C1=CC(O)=CC(O)=C1 XWTYSIMOBUGWOL-UHFFFAOYSA-N 0.000 description 2
- KWGRBVOPPLSCSI-WPRPVWTQSA-N (-)-ephedrine Chemical compound CN[C@@H](C)[C@H](O)C1=CC=CC=C1 KWGRBVOPPLSCSI-WPRPVWTQSA-N 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical group CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- XMNIXWIUMCBBBL-UHFFFAOYSA-N 2-(2-phenylpropan-2-ylperoxy)propan-2-ylbenzene Chemical compound C=1C=CC=CC=1C(C)(C)OOC(C)(C)C1=CC=CC=C1 XMNIXWIUMCBBBL-UHFFFAOYSA-N 0.000 description 2
- UPMLOUAZCHDJJD-UHFFFAOYSA-N 4,4'-Diphenylmethane Diisocyanate Chemical compound C1=CC(N=C=O)=CC=C1CC1=CC=C(N=C=O)C=C1 UPMLOUAZCHDJJD-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- RRHGJUQNOFWUDK-UHFFFAOYSA-N Isoprene Chemical compound CC(=C)C=C RRHGJUQNOFWUDK-UHFFFAOYSA-N 0.000 description 2
- 229910017976 MgO 4 Inorganic materials 0.000 description 2
- GIIZNNXWQWCKIB-UHFFFAOYSA-N Serevent Chemical compound C1=C(O)C(CO)=CC(C(O)CNCCCCCCOCCCCC=2C=CC=CC=2)=C1 GIIZNNXWQWCKIB-UHFFFAOYSA-N 0.000 description 2
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 229940092705 beclomethasone Drugs 0.000 description 2
- NBMKJKDGKREAPL-DVTGEIKXSA-N beclomethasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@H](C)[C@@](C(=O)CO)(O)[C@@]1(C)C[C@@H]2O NBMKJKDGKREAPL-DVTGEIKXSA-N 0.000 description 2
- 239000007844 bleaching agent Substances 0.000 description 2
- GZUXJHMPEANEGY-UHFFFAOYSA-N bromomethane Chemical compound BrC GZUXJHMPEANEGY-UHFFFAOYSA-N 0.000 description 2
- OROGSEYTTFOCAN-DNJOTXNNSA-N codeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)=C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC OROGSEYTTFOCAN-DNJOTXNNSA-N 0.000 description 2
- 238000011109 contamination Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=C(C)\C([C@H](C/2(C)C)CCC(N)=O)=N\C\2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 239000000645 desinfectant Substances 0.000 description 2
- DMBHHRLKUKUOEG-UHFFFAOYSA-N diphenylamine Chemical compound C=1C=CC=CC=1NC1=CC=CC=C1 DMBHHRLKUKUOEG-UHFFFAOYSA-N 0.000 description 2
- 229960000676 flunisolide Drugs 0.000 description 2
- WMWTYOKRWGGJOA-CENSZEJFSA-N fluticasone propionate Chemical compound C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@]1(F)[C@@H]2[C@@H]2C[C@@H](C)[C@@](C(=O)SCF)(OC(=O)CC)[C@@]2(C)C[C@@H]1O WMWTYOKRWGGJOA-CENSZEJFSA-N 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 229920005555 halobutyl Polymers 0.000 description 2
- 229940088597 hormone Drugs 0.000 description 2
- 239000005556 hormone Substances 0.000 description 2
- WQYVRQLZKVEZGA-UHFFFAOYSA-N hypochlorite Chemical compound Cl[O-] WQYVRQLZKVEZGA-UHFFFAOYSA-N 0.000 description 2
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 2
- 239000012633 leachable Substances 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 description 2
- 229920003052 natural elastomer Polymers 0.000 description 2
- 229920001194 natural rubber Polymers 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- 239000005022 packaging material Substances 0.000 description 2
- 230000002028 premature Effects 0.000 description 2
- 230000002265 prevention Effects 0.000 description 2
- 230000002685 pulmonary effect Effects 0.000 description 2
- 238000004080 punching Methods 0.000 description 2
- MIXMJCQRHVAJIO-TZHJZOAOSA-N qk4dys664x Chemical compound O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O.C1([C@@H](F)C2)=CC(=O)C=C[C@]1(C)[C@@H]1[C@@H]2[C@@H]2C[C@H]3OC(C)(C)O[C@@]3(C(=O)CO)[C@@]2(C)C[C@@H]1O MIXMJCQRHVAJIO-TZHJZOAOSA-N 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000010058 rubber compounding Methods 0.000 description 2
- 229960002052 salbutamol Drugs 0.000 description 2
- SUKJFIGYRHOWBL-UHFFFAOYSA-N sodium hypochlorite Chemical compound [Na+].Cl[O-] SUKJFIGYRHOWBL-UHFFFAOYSA-N 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 229940124530 sulfonamide Drugs 0.000 description 2
- 150000003456 sulfonamides Chemical class 0.000 description 2
- 239000005061 synthetic rubber Substances 0.000 description 2
- 239000008399 tap water Substances 0.000 description 2
- 235000020679 tap water Nutrition 0.000 description 2
- 229960000195 terbutaline Drugs 0.000 description 2
- 231100000027 toxicology Toxicity 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- 230000037317 transdermal delivery Effects 0.000 description 2
- AKNNEGZIBPJZJG-MSOLQXFVSA-N (-)-noscapine Chemical compound CN1CCC2=CC=3OCOC=3C(OC)=C2[C@@H]1[C@@H]1C2=CC=C(OC)C(OC)=C2C(=O)O1 AKNNEGZIBPJZJG-MSOLQXFVSA-N 0.000 description 1
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 description 1
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- 238000011049 filling Methods 0.000 description 1
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- 239000012458 free base Substances 0.000 description 1
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- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 description 1
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- 239000000383 hazardous chemical Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
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- 229920000669 heparin Polymers 0.000 description 1
- 239000007970 homogeneous dispersion Substances 0.000 description 1
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 1
- 229960000890 hydrocortisone Drugs 0.000 description 1
- 229960001067 hydrocortisone acetate Drugs 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229960001410 hydromorphone Drugs 0.000 description 1
- WVLOADHCBXTIJK-YNHQPCIGSA-N hydromorphone Chemical compound O([C@H]1C(CC[C@H]23)=O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O WVLOADHCBXTIJK-YNHQPCIGSA-N 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000002664 inhalation therapy Methods 0.000 description 1
- 229940125396 insulin Drugs 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 229940039009 isoproterenol Drugs 0.000 description 1
- 229940001447 lactate Drugs 0.000 description 1
- 229940099584 lactobionate Drugs 0.000 description 1
- JYTUSYBCFIZPBE-AMTLMPIISA-N lactobionic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O JYTUSYBCFIZPBE-AMTLMPIISA-N 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- IWYDHOAUDWTVEP-UHFFFAOYSA-M mandelate Chemical compound [O-]C(=O)C(O)C1=CC=CC=C1 IWYDHOAUDWTVEP-UHFFFAOYSA-M 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 229940126601 medicinal product Drugs 0.000 description 1
- LMOINURANNBYCM-UHFFFAOYSA-N metaproterenol Chemical compound CC(C)NCC(O)C1=CC(O)=CC(O)=C1 LMOINURANNBYCM-UHFFFAOYSA-N 0.000 description 1
- HNJJXZKZRAWDPF-UHFFFAOYSA-N methapyrilene Chemical compound C=1C=CC=NC=1N(CCN(C)C)CC1=CC=CS1 HNJJXZKZRAWDPF-UHFFFAOYSA-N 0.000 description 1
- 229960001869 methapyrilene Drugs 0.000 description 1
- 229940102396 methyl bromide Drugs 0.000 description 1
- LRMHVVPPGGOAJQ-UHFFFAOYSA-N methyl nitrate Chemical compound CO[N+]([O-])=O LRMHVVPPGGOAJQ-UHFFFAOYSA-N 0.000 description 1
- JZMJDSHXVKJFKW-UHFFFAOYSA-M methyl sulfate(1-) Chemical compound COS([O-])(=O)=O JZMJDSHXVKJFKW-UHFFFAOYSA-M 0.000 description 1
- 229960001664 mometasone Drugs 0.000 description 1
- QLIIKPVHVRXHRI-CXSFZGCWSA-N mometasone Chemical compound C1CC2=CC(=O)C=C[C@]2(C)[C@]2(Cl)[C@@H]1[C@@H]1C[C@@H](C)[C@@](C(=O)CCl)(O)[C@@]1(C)C[C@@H]2O QLIIKPVHVRXHRI-CXSFZGCWSA-N 0.000 description 1
- 229960005181 morphine Drugs 0.000 description 1
- PLPRGLOFPNJOTN-UHFFFAOYSA-N narcotine Natural products COc1ccc2C(OC(=O)c2c1OC)C3Cc4c(CN3C)cc5OCOc5c4OC PLPRGLOFPNJOTN-UHFFFAOYSA-N 0.000 description 1
- XKLJHFLUAHKGGU-UHFFFAOYSA-N nitrous amide Chemical compound ON=N XKLJHFLUAHKGGU-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960002657 orciprenaline Drugs 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 235000019161 pantothenic acid Nutrition 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229960001802 phenylephrine Drugs 0.000 description 1
- SONNWYBIRXJNDC-VIFPVBQESA-N phenylephrine Chemical compound CNC[C@H](O)C1=CC=CC(O)=C1 SONNWYBIRXJNDC-VIFPVBQESA-N 0.000 description 1
- DLNKOYKMWOXYQA-APPZFPTMSA-N phenylpropanolamine Chemical compound C[C@@H](N)[C@H](O)C1=CC=CC=C1 DLNKOYKMWOXYQA-APPZFPTMSA-N 0.000 description 1
- 229960000395 phenylpropanolamine Drugs 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000021317 phosphate Nutrition 0.000 description 1
- 229960005414 pirbuterol Drugs 0.000 description 1
- 229920002587 poly(1,3-butadiene) polymer Polymers 0.000 description 1
- 229920001083 polybutene Polymers 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229960005205 prednisolone Drugs 0.000 description 1
- OIGNJSKKLXVSLS-VWUMJDOOSA-N prednisolone Chemical compound O=C1C=C[C@]2(C)[C@H]3[C@@H](O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 OIGNJSKKLXVSLS-VWUMJDOOSA-N 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 239000003507 refrigerant Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 229960001457 rimiterol Drugs 0.000 description 1
- IYMMESGOJVNCKV-SKDRFNHKSA-N rimiterol Chemical compound C([C@@H]1[C@@H](O)C=2C=C(O)C(O)=CC=2)CCCN1 IYMMESGOJVNCKV-SKDRFNHKSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 229960004017 salmeterol Drugs 0.000 description 1
- 229960005018 salmeterol xinafoate Drugs 0.000 description 1
- 229960002646 scopolamine Drugs 0.000 description 1
- STECJAGHUSJQJN-FWXGHANASA-N scopolamine Chemical compound C1([C@@H](CO)C(=O)O[C@H]2C[C@@H]3N([C@H](C2)[C@@H]2[C@H]3O2)C)=CC=CC=C1 STECJAGHUSJQJN-FWXGHANASA-N 0.000 description 1
- 229910000077 silane Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 229910021653 sulphate ion Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229910052714 tellurium Inorganic materials 0.000 description 1
- PORWMNRCUJJQNO-UHFFFAOYSA-N tellurium atom Chemical compound [Te] PORWMNRCUJJQNO-UHFFFAOYSA-N 0.000 description 1
- KFVSLSTULZVNPG-UHFFFAOYSA-N terbutaline sulfate Chemical compound [O-]S([O-])(=O)=O.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1.CC(C)(C)[NH2+]CC(O)C1=CC(O)=CC(O)=C1 KFVSLSTULZVNPG-UHFFFAOYSA-N 0.000 description 1
- IWVCMVBTMGNXQD-UHFFFAOYSA-N terramycin dehydrate Natural products C1=CC=C2C(O)(C)C3C(O)C4C(N(C)C)C(O)=C(C(N)=O)C(=O)C4(O)C(O)=C3C(=O)C2=C1O IWVCMVBTMGNXQD-UHFFFAOYSA-N 0.000 description 1
- 150000003512 tertiary amines Chemical class 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 239000004753 textile Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 150000003557 thiazoles Chemical class 0.000 description 1
- 150000003585 thioureas Chemical class 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000009602 toxicology test Methods 0.000 description 1
- 229960001322 trypsin Drugs 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K5/00—Use of organic ingredients
- C08K5/0008—Organic ingredients according to more than one of the "one dot" groups of C08K5/01 - C08K5/59
- C08K5/0025—Crosslinking or vulcanising agents; including accelerators
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08K—Use of inorganic or non-macromolecular organic substances as compounding ingredients
- C08K3/00—Use of inorganic substances as compounding ingredients
- C08K3/34—Silicon-containing compounds
- C08K3/346—Clay
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L11/00—Compositions of homopolymers or copolymers of chloroprene
Landscapes
- Chemical & Material Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Organic Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
A seal for a valve for use in a pharmaceutical dispensing device, which seal is formed from an elastomeric composition comprising: <SL> <LI>(a) a chlorine-substituted diene polymer or co-polymer thereof; <LI>(b) a cross-linking agent for the chlorine-substituted diene polymer or co-polymer thereof; and <LI>(c) an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof. </SL>
Description
i 2415699 . - 1 - Seal Material for a Dispensing Apparatus The present
invention relates to a seal material and, in particular, to an elastomeric seal material which may be used in a dispensing apparatus for dispensing pressurised fluid in the form of an aerosol. Such an apparatus may be used for dispensing medicine or products in solution or suspension in an alcohol base.
It is known from GB-1201918 to provide a dispensing apparatus in which pressurized fluid from a pressurised dispensing container is released by a valve in a substantially controlled manner, the valve including elastomeric seals which are annular and which co-operate with a sliding valve stem to open and close fluid ports.
Known rubber compounds for sealing pharmaceutical metered dose aerosol inhalers are based on the traditional technology of vulcanising a synthetic or natural rubber polymer.
The required material properties necessary for good seal performance for pharmaceutical applications include: chemical compatibility (swell), tensile strength, permanent compression set, stress relaxation, elastic modulus, regulatory compliance, low extractives (i.e. cleaner materials), and stable properties after extraction.
Products to be dispensed are commonly provided in solution or suspension in an alcohol base, this being particularly common in the dispensing of medicinal compounds for inhalation therapy. 2 -
A typical apparatus includes a CFC volatile propellant having a liquid phase in which the product together with the alcohol carrier is readily soluble within the container. A typical material for the valve seal is a synthetic rubber such as nitrite rubber.
Recent trends in the production of aerosol dispensers have moved away from CFC propellants because of their environmental hazards and HFC propellants are now being introduced. A problem with such propellants is that alcohol is less soluble in the liquid phase of such propellants and tends to separate within the container, thereby exposing the valve seals to a much greater concentration of alcohol than was formerly the case. Seal materials such as nitrite rubber allow alcohol vapour to escape by permeation over extended storage periods so that the remaining quantity of alcohol is significantly depleted.
Accelerators are compounds which reduce the time required for curing/cross-linking of natural and synthetic rubbers. Accelerators may also act to improve the ageing characteristics and other physical properties of the rubber. Known accelerators include sulphenamides, guanidines, thioureas, thiazoles, dithiocarbamates (eg tellurium diethyldithio carbamate), thiuram sulphides (eg dipentamethylene thiuram hexasulphide and tetramethylthiuram disulphide), zinc oxide and tertiary amines.
The most important commercial cure accelerators are the mercaptobenzothiazole derivatives for example MATS (dibenzthiazyle disulphide). As delayed-action primary accelerators, these derivatives provide good - 3 - scorch protection, i.e. resistance to premature crosslinking, especially in polychloroprene rubbers.
Bromobutyl and butyl rubbers may be cured using a sulphur curing agent, together with MBTS and optionally thiuram (TMTD, tetramethyl thiuram disulphide). However, the combination of MBTS and TMTD can lead to the formation of nitrosamines which are undesirable in seals for pharmaceutical applications. The use of MBTS on its own can result in an MBT-type (2-mercaptobenzthiazole) residue as the by-product of the cross linking reaction. Such a residue is undesirable because it can leach out of the sealing material and migrate into the drug media. MBT also has a bitter taste.
Polychloroprer.e elastomers require accelerators for a practical cure reaction. A known accelerator is
-
2-mercaptoimidazoline (NA-22). However, there are concerns concerning the toxicity of this accelerator.
In addition, this accelerator suffers from scorch, i.e. premature crosslinking. While MBTS and/or TMTD may be used in combination with NA-22 to alleviate such problems, there still exists the problem of undesirable byproduct formation.
Peroxides such as dicumyl peroxide can also be used to cure polychloroprene. However, the curing reaction can be variable and this may affect the material properties; in extreme cases, the material can become brittle. Moreover the products of the reaction have to be removed as they can deteriorate Elastomer properties, for example ageing. Another problem is that peroxides are deactivated by antioxidants. Antioxidants are often required to enhance the ageing properties of the elastomer. 4
In most pharmaceutical applications it is also necessary to extract or wash the cured elastomer in order to remove surface residues and byproducts resulting from the cure reaction and moulding process.
The aforementioned conventional cure/accelerator systems require relatively lengthy extraction times (typically 50 to 70 hours). Prolonged extraction times have been found to result in a deterioration in material properties.
It is an object of the present invention to provide a seal material for a dispensing apparatus which addresses at least some of the problems
associated with the prior art.
Accordingly, in a first aspect the present invention provides a seal for a valve for use in a pharmaceutical dispensing device, which seal is formed from an elastomeric composition comprising: (a) an isobutylene polymer or co-polymer thereof; (b) a cross-linking agent for the isobutylene polymer or co-polymer thereof; and (c) an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof.
The elastomeric composition preferably comprises one or more of polyisobutylene, polybutene, butyl rubber, halogenated butyl rubber, including derivatives thereof. More preferably, the elastomeric composition comprises butyl rubber or bromobutyl rubber. Butyl rubber is a copolymer made from isobutylene and a small amount of a diolefin such as, for example, isoprene (2-methylbuta-1,3-diene). - 5 -
Typically, butyl rubber comprises approximately 97% isobutylene and approximately 3% isoprene, and it may be polymerized using an aluminium chloride catalyst.
Halogenated butyl rubbers such as bromobutyl rubber and chlorobutyl rubber may be made by treating isoprene-isobutylene rubber with bromine/chlorine.
It will be appreciated that the elastomeric composition may comprise a blend of an isobutylene polymer or co-polymer thereof with another polymer, such as a chlorine-substituted diene polymer. For example, a blend of butyl and polychloroprene may be used. Blending of polychloroprene with the non-polar butyl is advantageous as it allows dissipation of static charge. Static charge builds up during the automated valve assembly process and can cause seats to self adhere and pose problems in valve assembly.
In a second aspect the present invention provides a seal for a valve for use in a pharmaceutical dispensing device, which seal is formed from an elastomeric composition comprising: (a) a chlorine-substituted diene polymer or co polymer thereof; (b) a cross-linking agent for the chlorine substituted diene polymer or co-polymer thereof; and (c) an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof.
In the second aspect the elastomeric composition preferably comprises a chlorine-substituted butadiene polymer, more preferably 2-chlorobuta-1,3diene (i.e. polychloroprene, also known as Neoprene). Again, it will be appreciated that the elastomeric composition 6 - may comprise a blend of a chlorine-substituted diene polymer or co- polymer thereof with another polymer.
For example, a blend of butyl and polychloroprene may be used.
In both the first and second aspects the seal may be used in a valve for use in a pharmaceutical dispensing device, such as, for example, a nasal, pulmonary or transdermal delivery device. A preferred use of the seal is in a pharmaceutical metered dose aerosol inhaler device.
The term pharmaceutical as used herein is intended to encompass any pharmaceutical, compound, composition, medicament, agent or product which can be delivered or administered to a human being or animal, for example pharmaceuticals, drugs, biological and medicinal products. Examples include antiallergics, analgesics, bronchodilators, antihistamines, therapeutic proteins and peptides, antitussives, anginal preparations, antibiotics, anti-inflammatory preparations, hormones, or sulfonamides, such as, for example, a vasoconstrictive amine, an enzyme, an alkaloid, or a steroid, including combinations of two or more thereof. In particular, examples include isoproterenol [alpha-(isopropylaminomethyl) protocatechuyl alcohol], phenylephrine, phenylpropanolamine, glucagon, adrenochrome, trypsin, epinephrine, ephedrine, narcotine, codeine, atropine, heparin, morphine, dihydromorphinone, ergotamine, scopolamine, methapyrilene, cyanocobalamin, terbutaline, rimiterol, salbutamol, flunisolide, colchicine, pirbuterol, beclomethasone, orciprenaline, fentanyl, and diamorphine, streptomycin, penicillin, procaine penicillin, tetracycline, chlorotetracycline and hydroxytetracycline, adrenocorticotropic hormone and adrenocortical hormones, such as cortisone, - 7 - hydrocortisone, hydrocortisone acetate and prednisolone, insulin, cromolyn sodium, and mometasone, including combinations of two or more thereof.
The pharmaceutical may be used as either the free base or as one or more salts conventional in the art, such as, for example, acetate, benzenesulphonate, benzoate, bircarbonate, bitartrate, bromide, calcium edetate, camsylate, carbonate, chloride, citrate, dihydrochloride, edetate, edisylate, estolate, esylate, fumarate, fluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrobromide, hydrochloride, hydroxynaphthoate, iodide, isethionate, lactate, lactobionate, malate, maleate, mandelate, mesylate, methylbromide, methylnitrate, methylsulphate, mucate, napsylate, nitrate, pamoate, (embonate), pantothenate, phosphate, diphosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, sulphate, tannate, tartrate, and triethiodide, including combinations of two or more thereof. Cationic salts may also be used, for example the alkali metals, e.g. Na and K, and ammonium salts and salts of amines known in the art to be pharmaceutically acceptable, for example glycine, ethylene diamine, choline, diethanolamine, triethanolamine, octadecylamine, diethylamine, triethylamine, 1-amino-2-propanol-amino-2(hydroxymethyl)propane-1,3-diol, and 1-(3,4 dihydroxyphenyl)-2 isopropylaminoethanol.
The pharmaceutical will typically be one which is suitable for inhalation and may be provided in any suitable form for this purpose, for example as a powder or as a solution or suspension in a solvent or carrier liquid, for example ethanol. 8 -
The pharmaceutical may, for example, be one which is suitable for the treatment of asthma. Examples include salbutamol, beclomethasone, salmeterol, fluticasone, formoterol, terbutaline, sodium chromoglycate, budesonide and flunisolide, and physiologically acceptable salts (for example salbutamol sulphate, salmeterol xinafoate, fluticasone propionate, beclomethasone dipropionate, and terbutaline sulphate), solvates and esters, including combinations of two or more thereof. Individual isomers such as, for example, R-salbutamol, may also be used. As will be appreciated, the pharmaceutical may comprise of one or more active ingredients, an example of which is flutiform, and may optionally be provided together with a suitable carrier, for example a liquid carrier. One or more surfactants may be included if desired.
In both the first and second aspects the cross linking agent (also known as a curing agent) provides or facilitates network formation to result in a three- dimensional polymer network structure. The cross- linking agent may act by reacting with the functional groups on the polymer chain. The cross-linking agent will typically comprise sulphur or a sulphurcontaining compound. The cross-linking agent is preferably substantially free of any peroxide curing agents such as, for example, dicumyl peroxide.
In both the first and second aspects the polysulphide compound is preferably derived from a substituted xanthic acid or derivative thereof, preferably of the type ROC(S)SH, in which R is typically an alkyl radical. The substituted group in the polysulphide compound typically comprises an isopropyl group. - 9 -
The polysulphide compound preferably comprises three or more bridging sulphur atoms, more preferably 3, 4 or 5 bridging sulphur atoms.
The polysulphide compound is preferably substantially free from nitrogen, phosphorus and metallic elements.
Advantageously, the polysulphide compound comprises or consists of diisopropyl xanthogen polysulphide.
In both the first and second aspects the elastomeric composition typically comprises up to 3 wt.% of the accelerator based on the total weight of the accelerator and polymer in the composition, more typically up to 1.5 wt.% of the accelerator based on the total weight of the accelerator and polymer in the composition, still more typically up to 1 wt.% of the accelerator based on the total weight of the accelerator and polymer.
In both the first and second aspects the weight ratio of the accelerator to the cross-linking agent in the elastomeric composition is preferably in the range of from 1:1 to 3:1, more preferably from 1:1 to 2:1.
In both the first and second aspects the seal advantageously further includes a filler, preferably a mineral filler. Mineral fillers are preferable to carbon black in order to minimise the formation of polyouclear aromatic hydrocarbon compounds. Suitable examples include any of magnesium silicate, aluminium silicate, silica, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, - 10 talc, kaolin and clay, including combinations of two or more thereof. Preferably, the filler is or comprises one or more of magnesium silicate, talc, calcined clay, kaolin and/or amino silane coated clay.
In both the first and second aspects the seal further preferably further includes a process aid, preferably a low molecular weight polyethylene.
In both the first and second aspects the seal may further comprise any of a reinforcement agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agents, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonants, a secondary accelerator or an activator, including combinations of two or more thereof. Examples of antioxidants are 2:2'-methylene-bis(6-(1-methyl-cyclohexyl)-para- creosol) and octylated diphenylamine. An advantage of
-
the seal according to the present invention is that it can be essentially free of an antioxidant if desired.
It will be appreciated that certain constituents may have more than one effect. For example, zinc oxide may act as an activator and as a filler.
Similarly, magnesium oxide may act as an acid absorber and as a filler.
The term seal as used herein is intended to encompass any sealing member or portion thereof present in a pharmaceutical dispensing device, including, but not limited to, gaskets and seals whether static or dynamic.
The present invention also provides a valve for use in a pharmaceutical dispensing device and having a seal as herein described with reference to either the first or second aspect of the invention.
It will be appreciated that the seal may be provided as a separate component or may be formed integrally with the valve.
The present invention also provides a pharmaceutical dispensing device having a valve as herein described. The pharmaceutical dispensing device may be, for example, a nasal, pulmonary or transdermal delivery device. A preferred device is a pharmaceutical metered dose aerosol inhaler device.
The present invention also provides a dispensing apparatus for dispensing pressurized fluid comprising a valve body defining a chamber, a valve member extending movably through the chamber and through at least one annular seal co-operating with the valve member and the body to regulate the discharge of fluid, wherein the or at least one of the seals is as herein described with reference to either the first or second aspect of the invention.
Such a device may be used for dispensing medicine, pharmaceuticals, biological agents, drugs and/or products in solution or suspension as herein described.
In a preferred embodiment, the dispensing apparatus comprises a pressurized dispensing container having a valve body provided with two annular valve seals through which a valve member is axially slidable, the seals being disposed at inlet and outlet apertures of a valve chamber so that the valve functions as a metering valve.
The dispensing apparatus as herein described may comprise a pressurised dispensing container operatively connected to the valve body and containing - 12 the fluid to be dispensed and a hydrofluorocarbon propellant comprising propellant type 134a or 227.
The designation of propellant types referred to in the present application is as specified in British
Standard BS4580:1970 "Specification for number
designations of organic refrigerants". Accordingly, propellant 134a is: 1, 1,1,2-tetrafluoroethane CH2F-CF3 and propellant 227 is: 1,1,1,2,3,3,3 heptafluoropropane CF3-CHF-CF3.
The fluid to be dispensed typically comprises a liquid or particulate product as a solution or suspension in a carrier liquid. The carrier liquid preferably comprises an alcohol such as ethanol. One or more surfactants may be present.
The present invention provides particularly favourable results when used in conjunction with a hydrofluorocarbon propellant in the aerosol device.
The present invention also provides a seal for a valve for use in a pharmaceutical dispensing device, which seal comprises a vulcanisate of an isobutylene polymer or co-polymer thereof, a cross-linking agent for the isobutylene polymer or co-polymer thereof, and an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof.
The present invention also provides a seal for a valve for use in a pharmaceutical dispensing device, which seal comprises a vulcanisate of a chlorine substituted diene polymer or co-polymer thereof, a 3S cross-linking agent for the chlorine-substituted diene polymer or copolymer thereof, and an accelerator for the cross-linking agent, wherein the accelerator - 13 includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof.
In relation to the first aspect, the present invention also provides a process for the preparation of a seal for a valve for use in a pharmaceutical dispensing device, the process comprising: (i) forming a composition comprising a mixture of an isobutylene polymer or co-polymer thereof, a cross-linking agent for the isobutylene polymer or co- polymer thereof, and an accelerator for the cross- linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof; (ii) initiating a cross-linking reaction in the mixture to form a cross- linked elastomeric composition; and (iii) either before or after (ii) forming the composition into a seal.
In relation to the second aspect, the present invention also provides a process for the preparation of a seal for a valve for use in a pharmaceutical dispensing device, the process comprising: (i) forming a composition comprising a mixture of a chlorine-substituted diene polymer or co-polymer thereof, a cross-linking agent for the chlorine substituted diene polymer or co-polymer thereof, and an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof; (ii) initiating a cross-linking reaction in the mixture to form a cross- linked elastomeric composition; and (iii) either before or after (ii) forming the composition into a seal. - 14
In both of the above-described processes the step of forming the composition into a seal may involve one or more forming techniques such as compression moulding, injection moulding and/or extrusion.
The initiation of the cross-linklog reaction may be achieved by any of the known conventional techniques, for example heating the formulation to at least the curing reaction temperature, which is typically in the range of from 130 to 200 C. A preferred process involves forming rubber compound strips (typically of approximately 1 mm thickness) by compression moulded. The moulding temperature is typically in the range 160 -180 C. The cure time is typically in the range 1-10 minutes. The moulded strips are preferably post cured in an air oven for typically 1 hour at 150 C.
The strips may then be made into gaskets (seats) using a punching device.
The thus formed rubber components may be washed using, for example, a detergent solution. This has been found, however, to have many disadvantages, particularly self adhering of components after the wash cycle, thereby making the valve assembly process difficult, and in extreme cases impossible. To address this the rubber components may alternatively (or in combination with a detergent wash) be immersed in an aqueous chlorinated solution such as, for example, a solution comprising water and bleach.
Examples of bleach include sodium hypochlorite (NaOCl) and calcium hypochlorite (Ca(OCl) 2) . Solutions of hypochlorous acid (HOCl) and/or hypochlorite solutions (i.e. an aqueous solution of a metallic salt of hypochlorous acid) may also be used. It is preferred that the aqueous chlorinated solution comprises water - 15 and hypochlorous acid. More preferably, it has been found that a dilute solution of a commonly used disinfectant in hospitals and clinical environments, sodium dichloroisocyanurate (NaDCC), gives substantially adhesion-free components and also advantages in the maintenance of drug solution stability. The process may be carried out using a commercial washing machine. The washed components are preferably then rinsed in water and then dried. The dried components are advantageously free from rubber debris.
This process has a surprising advantage over using a detergent in the wash cycle. In particular, it has been found that washing the components in a solution of NaDCC results in substantially adhesion- free components. Furthermore, there is always the possibility of non- rinsed detergent residue remaining on the seat surface after the wash cycle using conventional methods. Such residue can be carried over into the drug dispensing device. Drug formulations contain surfactants for achieving solution stability, which is important for the consistency of delivered dose, and detergent residues may interfere with stabilization mechanisms. Unstable drug formulation can also prevent device function by blockage of valve. The washing of components in NaDCC has yielded advantages in an automated valve assembly process and the prevention of contamination of drug mixtures by residual detergent.
The rubber components may optionally be ethanol extracted to reduce the level of leachable species that could migrate into drug mixtures. In this process, the components are loaded into a glass column and washed by refluxing ethanol.
The use of the accelerator as herein described in the elastomeric compositions according to the present invention can eliminate the need for free sulphur in the cross-linking process. The accelerator as herein described is preferably provided as a liquid and is preferably miscible with the polymer to provide a homogeneous dispersion. It has been found that the use of such an accelerator facilitates filler dispersion and can obviate the need for a separate plasticizer. The presence of plasticisers is undesirable in that they tend to leach out of the material. In contrast, the accelerator as herein described forms or is part of the cross-linked network and therefore does not leach out into the drug media.
In the seal compositions according to the present invention the accelerator is typically almost totally consumed during the cross-linking reaction. This results in a cleaner rubber and the extractables are reduced. Typically, substantially no nitrosamines are generated during the cross-linking reaction.
Furthermore, the compositions according to the present invention show improved ageing characteristics compared with conventional Neoprene and Butyl rubber formulations. Most or substantially all of any by products resulting from the cross-linking reaction may be volatiles.
The present invention will now be further described with reference to the following non-limiting examples and drawings, provided by way of example, in which: Figure 1 is a plot of ageing at 110 C for Example EF147 (a polychloroprene formulation according to the present invention) compared with a conventional polychloroprene (EF134); - 17 Figure 2 is a plot of ageing at 150 C for Example EF147 (a polychloroprene formulation according to the present invention) compared with a conventional polychloroprene(EFl34) Figure 3 is a plot of ageing at 130 C for Example EF147 (a polychloroprene formulation according to the present invention) compared with a conventional polychloroprene; Figure 4 is a plot of ageing (% Elongation against time) at 150 C for Example EF150 (a bromobutyl formulation according to the present invention); Figure 5 is a plot of ageing (% EB against time) at 110 C for Example EF150; Figure 6 is a plot of ageing (% EB against time) at 130 C for Example EF150; Figure 7 shows an ageing profile of time to reach 50% of original % EB against temperature for Example EF150; and Figure 8 is a plot of shot weight against No. of packs for Example EF166 (a bromobutyl formulation according to the present invention) and EFMBTS (a Comparative Example). - 18
Table 1A
_
Ingredlents Formulabon EF147 EF134 EF15014B) EF151(14A) EF149 Bromobutyl 0 100 100 100 Polychloroprene 100 100 0. _ 0 Clay 40 40 40 40 30 S'lane treated 0 0 0 0 0 Clay Talc 30 30 0 0 0
_
S'lca filler 0 0 0 0 0 Platey Talc 0 0 1 80 80 80 Steanc Acid 1 1 1 1 1 Octaamne 0 1 0 0 0 Anboxdant 1 0 0 0 0 Robac AS100 1 0 1 1 1 5 MBTS 0 0 0 0 0 DPG 0 0 0 5 0 0.5 2 0 TBBS (PM 75%) 0 0 0 1 33 0 DOTS 0 5 0 0 0 0 Sulphur 0 5 0 0 5 0 5 0 75 Peroxide 0 4 0 0 0 Peroxide 0 0 0 0 0 2 5 Coagent TAC MgO 4 4 0 0 0 ZnO 5 5 2 3 5 Low MW PE O O 1 2 2 - 19
Table 1 B
Ingredients Formulabon Formulation EF152 EFMBTS EF166 EF168 EF172 Bromobutyl 100 100 100 100 80 Polychhroprene 0 0 0 20 Clay 30 40 0 35 30 S'iane treated 80 0 Clay Talc 0 0 35 0 80 SlLca Beer 0 0 5 5 0 Platey Talc 80 80 80 80 0 Stearic Aad 1 1 1 1 1 Octaamlne O Antioxidant O O O O O Robac AS100 1 METS 0 2 0 0 0 2 0 DPG 0 0 0.5 0 0.5 TBBS (PM 75%) 0 DOTG 0 0 0 0 0 Sulphur 0 75 0.5 0. 5 0 0.5 Peroxide 0 2 5 Peroxide o o o 1 o Coagent TAC MgO 0 0 0 0 0 ZnO 5 2 3 2 2 Low MW PE 2 2 1 2 1
Table 2
__ _
Ingredents Form' labon_ eF12s EFt26 EF127; Flie EF129 EF130 EF131 EF132 EFl33 EF135 PoychIoroprene 00 00 00 00 00 00 00 00 00 00 Clay 40 40 40 50 40 40 40 40 40 30 Talc 40 40 40 30 40 40 40 50 40 30 Stearic Acid 0 0 0 0 0 1 1 0 1 1
_ _ __ ___
Peroxide 6 6 5 5 6 6 6 5 5 5 4 MgO 4 4 0 0 4 0 4 0 4 4 ZnO __ 5 5 5 5 5 5 5 5 5 Kev EF147: Neoprene with sulphur/diisopropyl xanthogen polysulphide cure system (invention) EF125: Neoprene with peroxide cure system - EF135 (comparative) EF150: Bromobutyl rubber with sulphur/diisopropyl (14B) xanthogen polysulphide cure system (invention) EF151: Bromobutyl rubber with sulphur/diisopropyl (14A) xanthogen polysulphide cure system (invention) EF149: Bromobutyl rubber with sulphur/diisopropyl xanthogen polysulphide cure system (invention) EF152: Bromobutyl rubber withsulphur/diisopropyl xanthogen polysulphide cure system (invention) - 21 EFMBTS: Bromobutyl rubber with sulphur/MBTS cure system (comparative) EF166: Bromobutyl rubber with amino silane treated clay as a filler sulphur/diisopropyl xanthogen polysulphide cure system (invention) EF168: Bromobutyl rubber with peroxide cure system (comparative) EF172: Bromobutyl and polychloroprene rubber blend with sulphur/diisopropyl xanthogen polysulphide cure system (invention) Bromobutyl: Exxon 2246 Polychloroprene: Neoprene W Clay: Polestar 20OR Talc: Magsil 2628 Platey talc: Mistron Vapour RP6D Robac AS100: A diisopropyl xanthogen polysulphide available from Robinson Brothers Ltd. MBTS: bis(2-benzathiazoyle disulphide) (rubber accelerator) DPG: diphenylquanidine (rubber accelerator)- Ekaland DPG Pd (Powder) Silica: Sipernet 2200 available from Degussa TAC: Alcapudre 70, Triallyl Cyanurate, available from Akzo Nobel Silane treated clay: Clay with amino silane treatment - 22 TBBS: N-tertiary butyl 2 benzothiazoyle sulfonamide Robac TBBS (75% active polymer masterbatch) DOTG: di-o-tolylguanidine (rubber accelerator) - Ekaland DOTG Pd (Powder) Sulphur: AKM 300# GSS 2. 5% (magnesium coated sulphur) Peroxide: 40% di(2-tert butylperoxyisopropyl-2 benzene, his peroxide) Luperco / Peroximon / Perkadox Magnesium Oxide: Maglite Y or DE Low MW PE: PE AC617A or Luwax The rubber formulations were mixed using a Francis Shaw 1.2 l laboratory Banbury Mixer using speed setting 1 (long rotor speed 117 rpm), a friction ratio 1:1.125, and cooling waters circulated through the body, jacket and rotors. Mixing quality and consistency may be controlled by the time of mixing and the temperature of mixing and the energy used.
Rubber compound strips of approximately 1 mm thickness were compression moulded using a press with electrically heated platens. The moulding temperature was in the range 160 -180 C. The cure time was determined from rheometer traces and was in the range 1-10 minutes. The moulded strips were post cured in an air oven for 1 hour at 150 C.
The strips were made into gaskets (seats) using a punching device.
The seats were washed initially using a detergent solution. This was found to have many disadvantages - 23 such as self adhering of components after the wash cycle, making the valve assembly process difficult, and in extreme cases impossible. It was found that a dilute solution of a commonly used disinfectant in hospitals and clinical environments, Sodium dichloroisocyanurate (NaDCC), gave essentially adhesion-free components and also advantages in the maintenance of drug solution stability. The process was carried out using a commercial washing machine.
The machine was loaded with about 1 kg of seats contained in a textile mesh bag. 9 tablets of NaDCC (2.5g weight) were dissolved in 1 liter of tap water.
The solution was added to the machine's water inlet, and a further 30 litres of hot water at 30 C was introduced. The components were washed for 20 minute after which the water was discharged. The components were then rinsed using 30 liters of tap water at 30 C for about 10 minutes and the water discharged. The components were tumble dried for about 30 minutes.
The dried components were free from rubber debris.
This process has a surprising advantage over using a detergent in the wash cycle. The components do not adhere to each other and are thus easily assembled in to valves.
There is always the possibility of non-rinsed detergent residue remaining on the seat surface after the wash cycle. This can be carried over into the drug dispensing device. Drug formulations contain surfactants for achieving solution stability, which is important for the consistency of delivered dose, and detergent residues can also interfere with stabilization mechanisms. Unstable drug formulation can also prevent device function by blockage of valve. - 24
The NaDCC washing of components has yielded advantages in an automated valve assembly process and the prevention of contamination of drug mixtures by residual detergent.
The rubber components may optionally be ethanol extracted to reduce the level of leachable species that could migrate into drug mixtures. In this process, the components are loaded into a glass column and washed by refluxing ethanol.
Table 3A
EF147 EF134 EF150 I EF151 14B 14A Acetone extracts <2% 4 2% <2% c2% HPLC No DOTG Will be No DPG MET above lima peroxide above lima detected at of 0 005% residues by of 0 005% 0 007%
_ GC-MS
GC-MS on acetone N/a N/a 4 ppm of N/a extracts DPG residue 2 0 HPLC N/a N/a N/a N/a
_
I nitrosamne,opb N/a N/a N/a N/a nitrosamine ppb N/a N/a None 1 detected Comparative N/a N/a 3 me in 14 N/a Scaling (ambient) days 2 5 1 Propellant 1 34a loss I _ l _ | Sealing (ambient) 10-14 me in N/a 2- 11 me in N/a Propellant 1 34a toss 6 months | 3 months | Sealing 694 me in N/a 6-30 mg in N/a (40.C/75%RH)) 6 months 3 months 3 0 Propellant 134a bee I l USP<8P In vitro 1 N/a 0 N/a Toxicology rating (ethanol extracted samples) _ _ 3 5 USP<87> In vitro N/a N/a 1 N/a Toxicology rating (non ethanol extracted samples) . _. - 25
Table 3B
Black nnale EFMBTS EF166 EF172 Acetone extracts 8 5-10% 3% 1 35% N/a HPLC N/a N/a N/a N/a GC-MS on acetone N/a MBTS resdues No DPG N/a extracts detected at resdue venous levels 32, 59, 91 ppm _ HPLC MBT, ZDMC N/a N/a N/a detected at venous levels ntrosamne ppb Vanous levels N/a N/a N/a 1 7, 83 I I nitrosamne ppb N/a N/a N/a N/a ComparaNve N/a 2 mg n 14 2 mg in 14 N/a Seahng (ambient) days days Propellant 134a loss Sealng (ambenl) N/a N/a N/a N/a Propellant 134a bss Sealing N/a Nla N/a N/a 2 0 (40 Cn5%RH)) Propellant 134a loss USP<87> In vdro N/a Nla O 1 Toxcology rabng (ethanol extracted 2 5 samples) . . USP<87> In vitro Nla N/a Nla N/a Toxcology rabng (non ethanol extracted samples) __ - 26
Table 4
Formulabon Cure Temp T90 Tlme to 90% Hardness Tensile Strength % ED cure mm-sees (MPa) EF1M 170 C 8 98 75 7 273 EF147 170 C 9 91 75 12 390 EF149 170 C 4 05 60 5.6 430 EF150 170 C 3.8 58 6 1 690 EFMBTS 170 C 8. 1 54 6 5 580 EF 151 170 C 4 6 56 6 520 EF152 170 C 2 04 58 6 5 390 EF 166 170 C 4.93 57 6 1 490 EF168 170 C 3 54 47 4 9 740 EF 172 170 C 4 74 60 5 9 600 Discussion 1. With reference to Tables 3A and 3B, the acetone extracts in respect of the formulations according to the invention are lower than black nitrite.
2. With reference to formulations EF147, EF150 and EF151, the Robac AS100 concentration is so small that it is not detected by HPLC. The accelerator is therefore almost totally consumed during the cross-linking reaction with the corollary of a cleaner rubber.
3. With reference to formulations EF150, EF166, their acetone extract analysis by GC-MS shows that very low levels of DPG accelerator residues were detected. In contrast, there were significant levels of accelerator MBTS in EFMBTS. Hence Robac AS100 accelerated rubbers are cleaner. - 27
4. The acetone extracts for the Butyl formulations containing Robac AS100 (i.e. EF150, EF151 and EF166) are approximately half those obtained for the non-Robac AS100 cured butyl material (i.e. EFMBTS). EF147 and EF134 are polychloroprene compositions differing only in the type of crosslinking system. EF147 has the Robac AS100 cure system and its acetone extract is half that for the peroxide cured EF134 formulation.
5. The use of Robac AS100 in Butyl, polychloroprene and their blends is also acceptable as non toxic rubbers are produced. According to the US Pharmacopoeia Commission, monograph USP<87> in vitro toxicology test, EF147, EF150 and EF166 have rating of 0, i.e. the rubbers are non toxic (see Tables 3A and 3B). Ethanol extracting of rubber components is not always necessary. EF154 non extracted gave a USP<87> rating of 1 (non/slight toxic).
6. With reference to Table 4, the formulation EF152 gave a satisfactory rate of cure even in the absence of a secondary accelerator.
7. With reference to Table 4, the physical properties of the formulations according to the invention are not affected by the use of the Robac AS100 accelerator. Compared with MBTS, the EF152 formulation gave a shorter T90 time.
8. With reference to Table 4, the physical properties of the formulations according to the invention are not affected by the use of Robac AS100 accelerator when compared with equivalent formulations cured with peroxide. EF147 (Robac AS100) has equivalent physical properties to EF134 (peroxide cured) and - 28 has a comparable T90 time. Butyl formulations EF149, EF150, EFl51, EFl52 and EF166 also have a higher Tensile Strength than the equivalent peroxide cured butyl EFl68 formulation.
9. With reference to Table 4, Butyl formulation EFl66 includes amino silane coated clay as a filler.
Silane coated fillers offer advantages in achieving good filler - rubber interactions, which can offer benefits in sealing and mechanical properties. The formulation is cured using Robac AS100.
10. EF172 is a blend of butyl and polychloroprene and is cured using Robac AS100. Blending of polychloroprene with the non-polar Butyl is advantageous as it allows dissipation of static - charge. Static charge builds up during the automated valve assembly process and can cause seats to self adhere and pose problems in valve assembly. The blend cured with Robac AS100 has good physical properties (i.e. hardness, TS and DEB) that are comparable to the Butyl composition EF150. Its T90 cure time is also similar to EF150.
11. With reference to Tables 3A and 3B and the formulations according to the invention (i.e.EF147, EF149, EF150 and EF151, EF152, EF166, EF172), no nitrosamines were generated.
12. Sealing of rubber materials was investigated by filling MDI packs (having the sealing material) with 134a propellant/ethanol. The fill weights were 134a/Ethanol = 18.0g + 0.2g / 0.95g + 0.02g.
The packs were stored in an inverted position at ambient and 40 C/75% RH. Before and after storage - 29 the packs were weighed to 3 decimal places to calculate the loss of propellant and hence the sealing capacity. From Tables 3A and 3B, a comparison of EF150, EF166 and EFMBTS shows that using Robac AS100 does not detract the good sealing properties of Butyl. Tables 3A and 3B also shows longer term sealing behavior of Robac AS100 cured rubbers. In all cases the leakage rates are very low.
13. PMDI devices must have consistent shot weights (dose) and the standard deviation (SD) of shots should be low. The shot weights of packs using EF166 and EFMBTS as sealing materials were determined. Packs were stored for 14 days in valve down position and the shot weights determined. Figure 8 shows shot weights of test packs. Each pack was fired 10 times and the mean shot weight calculated. EF166 has a very consistent shot weight with a SD of 1.2. In comparison EFMBTS has an inconsistent shot weight and a SD of 9.9.
14. Butyl rubber cured with Robac AS100 has thus given an unexpected advantage, that is a very consistent shot weight. The reason why Butyl EFMBTS cured with a traditional dibenzthiazyl disulphide accelerator gave poor, unacceptable shot weights is not understood.
15. With reference to Figures 1 to 3, the formulations according to the invention show improved ageing characteristics compared with the comparative formulations.
16. With reference to Figures 4 to 7, the Butyl formulation EF150 shows good ageing using Robac - 30 AS100. The useful life of EF150 at 30 C is based on the time to decay to 50% of its original elongation at break and is predicted as approximately 6.5 years. This should be taken as an approximate indication in view of the number of data points used to determine the accelerated ageing profiles. - 31
Claims (31)
- CLAIMS: 1. A seal for a valve for use in a pharmaceutical dispensingdevice, which seal is formed from an elastomeric composition comprising: (a) a chlorine-substituted diene polymer or co- polymer thereof; (b) a cross-linking agent for the chlorine- substituted diene polymer or co-polymer thereof; and (c) an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof.
- 2. A seal as claimed in claim l, wherein the elastomeric composition comprises a chlorine
- 3. A seal as claimed in claim 2, wherein the elastomeric composition comprises 2-chlorobuta-l,3- diene.
- 4. A seal as claimed in any one of the preceding claims, wherein the cross-linking agent comprises sulphur or a sulphur-donating compound.
- 5. A seal as claimed in any one of the preceding claims, wherein said polysulphide compound is derived from a substituted xanthic acid or derivative thereof.
- 6. A seal as claimed in any one of the preceding claims, wherein the substituted group in said polysulphide compound comprises or consists of an isopropyl group.
- 7. A seal as claimed in any one of the preceding S claims, wherein said polysulphide compound comprises or consists of diisopropyl xanthogen polysulphide.
- 8. A seal as claimed in any one of the preceding claims, wherein said polysulphide compound comprises lo three or more bridging sulphur atoms.
- 9. A seal as claimed in any one of the preceding claims, wherein said polysulphide compound is substantially free from nitrogen, phosphorus and IS metallic elements.
- 10. A seal as claimed in any one of the preceding claims, wherein the elastomeric composition comprises up to 3 wt.% of the accelerator based on the total weight of the accelerator and polymer in the composition.
- 11. A seal as claimed in claim 10, wherein the elastomeric composition comprises up to 1.5 wt.% of the accelerator based on the total weight of the accelerator and polymer in the composition.
- 12. A seal as claimed in any one of the preceding claims, wherein the weight ratio of the accelerator to the cross-linking agent in the elastomeric composition is in the range of from 1:1 to 3:1.
- 13. A seal as claimed in any one of the preceding claims, wherein the seal further includes a mineral filler.
- 14. A seal as claimed in claim 13, wherein the mineral filler is selected from one or more of magnesium silicate, aluminium silicate, silica, titanium oxide, zinc oxide, calcium carbonate, magnesium oxide magnesium carbonate, magnesium aluminium silicate, aluminium hydroxide, talc, kaolin, clay and amino silane coated clay.
- 15. A seal as claimed in any one of the preceding claims, wherein the seal further includes a process aid, preferably a low molecular weight polyethylene.
- 16. A seal as claimed in any one of the preceding claims, further comprising one or more of a reinforcement agent, a plasticizer, a binder, a stabilizer, a retarder, a bonding agents, an antioxidant, a lubricant, a pigment, a wax, a resin, an antiozonants, a secondary accelerator or an activator.
- 17. A valve for use in a pharmaceutical dispensing device having a seal as defined in any one of claims 1 to 16.
- 18. A pharmaceutical dispensing device having a valve as claimed in claim 17.
- 19. A pharmaceutical dispensing device as claimed in claim 18 which is a pharmaceutical metered dose aerosol inhaler device.
- 20. A dispensing apparatus for dispensing pressurised fluid comprising a valve body defining a chamber, a valve member extending movably through the chamber and through at least one annular seal co-operating with the valve member and the body to regulate the discharge of fluid, wherein the or at least one of the seals is as defined in any one of claims 1 to 16.
- 21. A dispensing apparatus which comprises a pressurised dispensing container having a valve body provided with two annular valve seals through which a valve member is axially slidable, said seals being disposed at inlet and outlet apertures of a valve chamber so that the valve functions as a metering valve, wherein at least one of the annular valve seals is as defined in any one of claims 1 to 16.
- 22. A dispensing apparatus as claimed in claim 20 or claim 21, comprising a pressurized dispensing container operatively connected to the valve body and containing the fluid to be dispensed and a hydrofluorocarbon propellant comprising propellant type 134a or 227.
- 23. A dispensing apparatus as claimed in any one of claims 20 to 22, wherein the fluid to be dispensed comprises a liquid or particulate product as a solution or suspension in a carrier liquid comprising alcohol.
- 24. A dispensing apparatus as claimed in claim 23, wherein the alcohol comprises ethanol.
- 25. A seal for a valve for use in a pharmaceutical dispensing device, which seal comprises a vulcanisate of a chlorine-substituted diene polymer or co-polymer thereof, a cross-linking agent for the chlorine- substituted diene polymer or co-polymer thereof, and an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof.
- 26. A process for the preparation of a seal for a valve for use in a pharmaceutical dispensing device, the process comprising: (i) forming a composition comprising a mixture of a chlorine-substituted diene polymer or co-polymer thereof, a cross-linking agent for the chlorine substituted diene polymer or co-polymer thereof, and an accelerator for the cross-linking agent, wherein the accelerator includes a polysulphide compound derived from a substituted dithiocarbonic acid or derivative thereof; (ii) initiating a cross-linking reaction in the mixture to form a cross- linked elastomeric composition; and (iii) either before or after (ii) forming the composition into a seal. - 36
- 27. A process as claimed in claim 26, wherein the step of forming the composition into a seal involves one or more forming techniques selected from compression moulding, injection moulding and extrusion.
- 28. A process as claimed in claim 26 or claim 27, wherein the process also involves washing the seals.
- 29. A process as claimed in any one of claims 26 to 28, wherein the seals are immersed in an aqueous chlorinated solution.
- 30. A process as claimed in claim 29, wherein the aqueous chlorinated solution comprises water and HOC1.
- 31. A process as claimed in any one of claims 26 to 30, wherein the seals are immersed in a solution comprising water and sodium dichloroisocyanurate (NaDCC).
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB0206354A GB0206354D0 (en) | 2002-03-18 | 2002-03-18 | Seal material for a dispensing apparatus |
GB0303451A GB0303451D0 (en) | 2003-02-14 | 2003-02-14 | Seal material for a dispensing apparatus |
GB0306160A GB2386601B (en) | 2002-03-18 | 2003-03-18 | Seal material for a dispensing apparatus |
Publications (2)
Publication Number | Publication Date |
---|---|
GB0519174D0 GB0519174D0 (en) | 2005-10-26 |
GB2415699A true GB2415699A (en) | 2006-01-04 |
Family
ID=35500768
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
GB0519174A Withdrawn GB2415699A (en) | 2002-03-18 | 2003-03-18 | Seal material for a dispensing apparatus |
Country Status (1)
Country | Link |
---|---|
GB (1) | GB2415699A (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2585289A4 (en) * | 2010-06-25 | 2015-05-06 | Allegiance Corp | Vulcanization composition having reduced allergenic potential |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111751456B (en) * | 2019-09-10 | 2023-04-28 | 上海市食品药品包装材料测试所 | Method for simultaneously and quantitatively detecting nitrosamine and nitrosamine producibility in elastomer sealing element |
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JPS52127953A (en) * | 1976-04-20 | 1977-10-27 | Denki Kagaku Kogyo Kk | Method for accelerating curing of liquid chloroprene polymers |
JPS5529547A (en) * | 1978-08-21 | 1980-03-01 | Dainichi Nippon Cables Ltd | Crosslinkable chlorine-containing elastomer composition |
JPS5887139A (en) * | 1981-11-18 | 1983-05-24 | Mitsuboshi Belting Ltd | Rubber compounding composition |
US4695609A (en) * | 1984-10-25 | 1987-09-22 | Robinson Brothers Limited | Vulcanizable rubber compositions containing xanthogen polysulfide and xanthate compounds |
EP0597362A2 (en) * | 1992-11-12 | 1994-05-18 | Bayer Rubber Inc. | Butyl elastomeric compositions |
WO1997001611A1 (en) * | 1995-06-27 | 1997-01-16 | Bespak Plc | Dispensing apparatus |
EP0866096A1 (en) * | 1996-10-04 | 1998-09-23 | Kuraray Co., Ltd. | Thermoplastic polymer composition |
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2003
- 2003-03-18 GB GB0519174A patent/GB2415699A/en not_active Withdrawn
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JPS52127953A (en) * | 1976-04-20 | 1977-10-27 | Denki Kagaku Kogyo Kk | Method for accelerating curing of liquid chloroprene polymers |
JPS5529547A (en) * | 1978-08-21 | 1980-03-01 | Dainichi Nippon Cables Ltd | Crosslinkable chlorine-containing elastomer composition |
JPS5887139A (en) * | 1981-11-18 | 1983-05-24 | Mitsuboshi Belting Ltd | Rubber compounding composition |
US4695609A (en) * | 1984-10-25 | 1987-09-22 | Robinson Brothers Limited | Vulcanizable rubber compositions containing xanthogen polysulfide and xanthate compounds |
EP0597362A2 (en) * | 1992-11-12 | 1994-05-18 | Bayer Rubber Inc. | Butyl elastomeric compositions |
WO1997001611A1 (en) * | 1995-06-27 | 1997-01-16 | Bespak Plc | Dispensing apparatus |
EP0866096A1 (en) * | 1996-10-04 | 1998-09-23 | Kuraray Co., Ltd. | Thermoplastic polymer composition |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
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EP2585289A4 (en) * | 2010-06-25 | 2015-05-06 | Allegiance Corp | Vulcanization composition having reduced allergenic potential |
US9260623B2 (en) | 2010-06-25 | 2016-02-16 | Allegiance Corporation | Vulcanization composition having reduced allergenic potential, and elastomeric articles formed therewith |
US9550906B2 (en) | 2010-06-25 | 2017-01-24 | Allegiance Corporation | Vulcanization composition having reduced allergenic potential, and elastomeric articles formed therewith |
US10125239B2 (en) | 2010-06-25 | 2018-11-13 | Allegiance Corporation | Vulcanization composition having reduced allergenic potential, and elastomeric articles formed therewith |
EP4233771A3 (en) * | 2010-06-25 | 2023-09-27 | Allegiance Corporation | Vulcanization composition having reduced allergenic potential |
Also Published As
Publication number | Publication date |
---|---|
GB0519174D0 (en) | 2005-10-26 |
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