EP0892806A1 - Organo phosphorous compounds - Google Patents
Organo phosphorous compoundsInfo
- Publication number
- EP0892806A1 EP0892806A1 EP97916556A EP97916556A EP0892806A1 EP 0892806 A1 EP0892806 A1 EP 0892806A1 EP 97916556 A EP97916556 A EP 97916556A EP 97916556 A EP97916556 A EP 97916556A EP 0892806 A1 EP0892806 A1 EP 0892806A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- phosphonic acid
- acid
- organo phosphonic
- organo
- preparing
- 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.)
- Ceased
Links
- 150000002903 organophosphorus compounds Chemical class 0.000 title description 10
- 229940058344 antitrematodals organophosphorous compound Drugs 0.000 title description 5
- -1 organo phosphonic acids Chemical class 0.000 claims abstract description 22
- 239000002253 acid Substances 0.000 claims abstract description 14
- 238000000034 method Methods 0.000 claims abstract description 14
- QQVDJLLNRSOCEL-UHFFFAOYSA-N (2-aminoethyl)phosphonic acid Chemical compound [NH3+]CCP(O)([O-])=O QQVDJLLNRSOCEL-UHFFFAOYSA-N 0.000 claims abstract description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims abstract description 8
- DBVJJBKOTRCVKF-UHFFFAOYSA-N Etidronic acid Chemical compound OP(=O)(O)C(O)(C)P(O)(O)=O DBVJJBKOTRCVKF-UHFFFAOYSA-N 0.000 claims abstract description 7
- 125000004432 carbon atom Chemical group C* 0.000 claims abstract description 7
- 239000003814 drug Substances 0.000 claims abstract description 7
- 229940079593 drug Drugs 0.000 claims abstract description 7
- NGNBDVOYPDDBFK-UHFFFAOYSA-N 2-[2,4-di(pentan-2-yl)phenoxy]acetyl chloride Chemical compound CCCC(C)C1=CC=C(OCC(Cl)=O)C(C(C)CCC)=C1 NGNBDVOYPDDBFK-UHFFFAOYSA-N 0.000 claims abstract description 5
- 125000001931 aliphatic group Chemical group 0.000 claims abstract description 4
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 claims abstract description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims abstract description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract description 4
- UIQSKEDQPSEGAU-UHFFFAOYSA-N 1-Aminoethylphosphonic Acid Chemical compound CC(N)P(O)(O)=O UIQSKEDQPSEGAU-UHFFFAOYSA-N 0.000 claims abstract description 3
- 125000001312 palmitoyl group Chemical group O=C([*])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 abstract 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000049 pigment Substances 0.000 claims description 6
- 235000019730 animal feed additive Nutrition 0.000 claims description 5
- 239000012736 aqueous medium Substances 0.000 claims description 5
- 238000012377 drug delivery Methods 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 5
- 238000009360 aquaculture Methods 0.000 claims description 4
- 244000144974 aquaculture Species 0.000 claims description 4
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000010521 absorption reaction Methods 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 150000003007 phosphonic acid derivatives Chemical class 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000000047 product Substances 0.000 abstract description 26
- 235000015097 nutrients Nutrition 0.000 abstract description 4
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 210000000170 cell membrane Anatomy 0.000 abstract description 2
- 239000007795 chemical reaction product Substances 0.000 abstract 1
- 241000251468 Actinopterygii Species 0.000 description 26
- 235000019688 fish Nutrition 0.000 description 26
- 239000000243 solution Substances 0.000 description 17
- 235000005911 diet Nutrition 0.000 description 16
- 230000037213 diet Effects 0.000 description 16
- 210000004027 cell Anatomy 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 238000006243 chemical reaction Methods 0.000 description 10
- JEBFVOLFMLUKLF-IFPLVEIFSA-N Astaxanthin Natural products CC(=C/C=C/C(=C/C=C/C1=C(C)C(=O)C(O)CC1(C)C)/C)C=CC=C(/C)C=CC=C(/C)C=CC2=C(C)C(=O)C(O)CC2(C)C JEBFVOLFMLUKLF-IFPLVEIFSA-N 0.000 description 9
- 235000013793 astaxanthin Nutrition 0.000 description 9
- MQZIGYBFDRPAKN-ZWAPEEGVSA-N astaxanthin Chemical compound C([C@H](O)C(=O)C=1C)C(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)[C@@H](O)CC1(C)C MQZIGYBFDRPAKN-ZWAPEEGVSA-N 0.000 description 9
- 229940022405 astaxanthin Drugs 0.000 description 9
- 239000001168 astaxanthin Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 8
- ARBOVOVUTSQWSS-UHFFFAOYSA-N hexadecanoyl chloride Chemical compound CCCCCCCCCCCCCCCC(Cl)=O ARBOVOVUTSQWSS-UHFFFAOYSA-N 0.000 description 8
- 239000000787 lecithin Substances 0.000 description 8
- 235000010445 lecithin Nutrition 0.000 description 8
- IIZPXYDJLKNOIY-JXPKJXOSSA-N 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/CCCCC IIZPXYDJLKNOIY-JXPKJXOSSA-N 0.000 description 7
- 229940067606 lecithin Drugs 0.000 description 7
- IPCSVZSSVZVIGE-UHFFFAOYSA-N palmitic acid group Chemical group C(CCCCCCCCCCCCCCC)(=O)O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 7
- 239000007787 solid Substances 0.000 description 7
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 238000002360 preparation method Methods 0.000 description 5
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 4
- 229920001202 Inulin Polymers 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- FFUAGWLWBBFQJT-UHFFFAOYSA-N hexamethyldisilazane Chemical compound C[Si](C)(C)N[Si](C)(C)C FFUAGWLWBBFQJT-UHFFFAOYSA-N 0.000 description 4
- 230000006872 improvement Effects 0.000 description 4
- JYJIGFIDKWBXDU-MNNPPOADSA-N inulin Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)OC[C@]1(OC[C@]2(OC[C@]3(OC[C@]4(OC[C@]5(OC[C@]6(OC[C@]7(OC[C@]8(OC[C@]9(OC[C@]%10(OC[C@]%11(OC[C@]%12(OC[C@]%13(OC[C@]%14(OC[C@]%15(OC[C@]%16(OC[C@]%17(OC[C@]%18(OC[C@]%19(OC[C@]%20(OC[C@]%21(OC[C@]%22(OC[C@]%23(OC[C@]%24(OC[C@]%25(OC[C@]%26(OC[C@]%27(OC[C@]%28(OC[C@]%29(OC[C@]%30(OC[C@]%31(OC[C@]%32(OC[C@]%33(OC[C@]%34(OC[C@]%35(OC[C@]%36(O[C@@H]%37[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O%37)O)[C@H]([C@H](O)[C@@H](CO)O%36)O)[C@H]([C@H](O)[C@@H](CO)O%35)O)[C@H]([C@H](O)[C@@H](CO)O%34)O)[C@H]([C@H](O)[C@@H](CO)O%33)O)[C@H]([C@H](O)[C@@H](CO)O%32)O)[C@H]([C@H](O)[C@@H](CO)O%31)O)[C@H]([C@H](O)[C@@H](CO)O%30)O)[C@H]([C@H](O)[C@@H](CO)O%29)O)[C@H]([C@H](O)[C@@H](CO)O%28)O)[C@H]([C@H](O)[C@@H](CO)O%27)O)[C@H]([C@H](O)[C@@H](CO)O%26)O)[C@H]([C@H](O)[C@@H](CO)O%25)O)[C@H]([C@H](O)[C@@H](CO)O%24)O)[C@H]([C@H](O)[C@@H](CO)O%23)O)[C@H]([C@H](O)[C@@H](CO)O%22)O)[C@H]([C@H](O)[C@@H](CO)O%21)O)[C@H]([C@H](O)[C@@H](CO)O%20)O)[C@H]([C@H](O)[C@@H](CO)O%19)O)[C@H]([C@H](O)[C@@H](CO)O%18)O)[C@H]([C@H](O)[C@@H](CO)O%17)O)[C@H]([C@H](O)[C@@H](CO)O%16)O)[C@H]([C@H](O)[C@@H](CO)O%15)O)[C@H]([C@H](O)[C@@H](CO)O%14)O)[C@H]([C@H](O)[C@@H](CO)O%13)O)[C@H]([C@H](O)[C@@H](CO)O%12)O)[C@H]([C@H](O)[C@@H](CO)O%11)O)[C@H]([C@H](O)[C@@H](CO)O%10)O)[C@H]([C@H](O)[C@@H](CO)O9)O)[C@H]([C@H](O)[C@@H](CO)O8)O)[C@H]([C@H](O)[C@@H](CO)O7)O)[C@H]([C@H](O)[C@@H](CO)O6)O)[C@H]([C@H](O)[C@@H](CO)O5)O)[C@H]([C@H](O)[C@@H](CO)O4)O)[C@H]([C@H](O)[C@@H](CO)O3)O)[C@H]([C@H](O)[C@@H](CO)O2)O)[C@@H](O)[C@H](O)[C@@H](CO)O1 JYJIGFIDKWBXDU-MNNPPOADSA-N 0.000 description 4
- 229940029339 inulin Drugs 0.000 description 4
- 239000002502 liposome Substances 0.000 description 4
- 229910052760 oxygen Inorganic materials 0.000 description 4
- 239000001301 oxygen Substances 0.000 description 4
- 238000001228 spectrum Methods 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 235000021314 Palmitic acid Nutrition 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 235000019439 ethyl acetate Nutrition 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 150000003904 phospholipids Chemical class 0.000 description 3
- PTMHPRAIXMAOOB-UHFFFAOYSA-N phosphoramidic acid Chemical compound NP(O)(O)=O PTMHPRAIXMAOOB-UHFFFAOYSA-N 0.000 description 3
- UQRXMVAOHFLEIH-UHFFFAOYSA-N 1-(hexadecanoylamino)ethylphosphonic acid Chemical compound CCCCCCCCCCCCCCCC(=O)NC(C)P(O)(O)=O UQRXMVAOHFLEIH-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001805 chlorine compounds Chemical class 0.000 description 2
- 239000012153 distilled water Substances 0.000 description 2
- 230000001804 emulsifying effect Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- UMGDCJDMYOKAJW-UHFFFAOYSA-N thiourea Chemical compound NC(N)=S UMGDCJDMYOKAJW-UHFFFAOYSA-N 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- HVLLSGMXQDNUAL-UHFFFAOYSA-N triphenyl phosphite Chemical compound C=1C=CC=CC=1OP(OC=1C=CC=CC=1)OC1=CC=CC=C1 HVLLSGMXQDNUAL-UHFFFAOYSA-N 0.000 description 2
- 125000000022 2-aminoethyl group Chemical group [H]C([*])([H])C([H])([H])N([H])[H] 0.000 description 1
- IKHGUXGNUITLKF-UHFFFAOYSA-N Acetaldehyde Chemical compound CC=O IKHGUXGNUITLKF-UHFFFAOYSA-N 0.000 description 1
- 241000972773 Aulopiformes Species 0.000 description 1
- 239000012981 Hank's balanced salt solution Substances 0.000 description 1
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 1
- 229930182816 L-glutamine Natural products 0.000 description 1
- 235000000365 Oenanthe javanica Nutrition 0.000 description 1
- 240000008881 Oenanthe javanica Species 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 241000277263 Salmo Species 0.000 description 1
- 241000277284 Salvelinus fontinalis Species 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Natural products NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 238000005273 aeration Methods 0.000 description 1
- 229940064734 aminobenzoate Drugs 0.000 description 1
- 230000003444 anaesthetic effect Effects 0.000 description 1
- 210000004102 animal cell Anatomy 0.000 description 1
- 230000001857 anti-mycotic effect Effects 0.000 description 1
- 239000002543 antimycotic Substances 0.000 description 1
- 235000019789 appetite Nutrition 0.000 description 1
- 230000036528 appetite Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 238000004364 calculation method Methods 0.000 description 1
- 238000004113 cell culture Methods 0.000 description 1
- DDKMFOUTRRODRE-UHFFFAOYSA-N chloromethanone Chemical compound Cl[C]=O DDKMFOUTRRODRE-UHFFFAOYSA-N 0.000 description 1
- ZPUCINDJVBIVPJ-LJISPDSOSA-N cocaine Chemical class O([C@H]1C[C@@H]2CC[C@@H](N2C)[C@H]1C(=O)OC)C(=O)C1=CC=CC=C1 ZPUCINDJVBIVPJ-LJISPDSOSA-N 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 235000020940 control diet Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000011928 denatured alcohol Substances 0.000 description 1
- 238000009795 derivation Methods 0.000 description 1
- XQRLCLUYWUNEEH-UHFFFAOYSA-N diphosphonic acid Chemical compound OP(=O)OP(O)=O XQRLCLUYWUNEEH-UHFFFAOYSA-N 0.000 description 1
- 229940042400 direct acting antivirals phosphonic acid derivative Drugs 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- POULHZVOKOAJMA-UHFFFAOYSA-N dodecanoic acid ester group Chemical class C(CCCCCCCCCCC)(=O)O POULHZVOKOAJMA-UHFFFAOYSA-N 0.000 description 1
- 238000004836 empirical method Methods 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- RIFGWPKJUGCATF-UHFFFAOYSA-N ethyl chloroformate Chemical compound CCOC(Cl)=O RIFGWPKJUGCATF-UHFFFAOYSA-N 0.000 description 1
- 230000004907 flux Effects 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 238000000265 homogenisation Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000004941 influx Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 229930014626 natural product Natural products 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 235000021231 nutrient uptake Nutrition 0.000 description 1
- 239000007764 o/w emulsion Substances 0.000 description 1
- REEZZSHJLXOIHL-UHFFFAOYSA-N octanoyl chloride Chemical compound CCCCCCCC(Cl)=O REEZZSHJLXOIHL-UHFFFAOYSA-N 0.000 description 1
- 150000008105 phosphatidylcholines Chemical class 0.000 description 1
- 230000019612 pigmentation Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 244000062645 predators Species 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 235000019515 salmon Nutrition 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 239000003039 volatile agent Substances 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002569 water oil cream Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3839—Polyphosphonic acids
- C07F9/386—Polyphosphonic acids containing hydroxy substituents in the hydrocarbon radicals
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/105—Aliphatic or alicyclic compounds
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/179—Colouring agents, e.g. pigmenting or dyeing agents
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K50/00—Feeding-stuffs specially adapted for particular animals
- A23K50/80—Feeding-stuffs specially adapted for particular animals for aquatic animals, e.g. fish, crustaceans or molluscs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/127—Liposomes
- A61K9/1271—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers
- A61K9/1272—Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers with substantial amounts of non-phosphatidyl, i.e. non-acylglycerophosphate, surfactants as bilayer-forming substances, e.g. cationic lipids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/28—Phosphorus compounds with one or more P—C bonds
- C07F9/38—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)]
- C07F9/3804—Phosphonic acids [RP(=O)(OH)2]; Thiophosphonic acids ; [RP(=X1)(X2H)2(X1, X2 are each independently O, S or Se)] not used, see subgroups
- C07F9/3808—Acyclic saturated acids which can have further substituents on alkyl
Definitions
- the present invention relates to organo phosphorous compounds that provide improved bio-availability of drugs and nutrients by permiabilising cell membranes.
- the compounds may be used as animal feed additives to increase nutrient uptake, pigment abso ⁇ tion in aqua-cultures and for the nanoencapsulation of drugs for drug delivery in vivo, in a way similar to lysophospholipids and phospholipids.
- a suggested mechanism for the improvement in bio-availability is given in the paper by David Garnett and Robin Jones in The Genetic Engineer and Biotechnologist, Vol.13, No.2, 1993 and in International Application W094/22324.
- the organo-phosphorous compounds of the present invention are phosphonolipids preferably prepared by the reaction of a long chain alkyl acid chloride with an organophosphonic acid derivative preferably including a reactive hydroxy or amino residue.
- the present invention provides an organo phosphonic acid compound having the formula: -
- n 0 or 1
- R 3 an alkyl group containing
- R 4 is a methyl group.
- the alkyl acid chlorides have a chain length of 10 or more carbon atoms and preferably not more than about 20 carbon atoms; particularly suitable are the acid chlorides of palmitic and lauric acids.
- Particularly suitable phosphonic acid derivatives are ethane- 1- hydroxy-1 , 1-diphosphonic acid (Etidronic acid) and 1 and 2 amino-ethyl phosphonic acids.
- the present invention provides a method for preparing the organo phosphorous compounds of the present invention suitable for use as animal feed additives, pigment absorption in aqua-culture and nanoencapsulation drugs for drug delivery in vivo, comprising reacting an acid chloride of a long chain aliphatic acid with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in a non-aqueous medium, preferably chloroform, at low temperatures, washing with cold water and subsequently drying.
- reaction temperature is kept below 5°C and most preferably in the range 3-5°C.
- the reactants are employed in stoichiometric proportions.
- the invention also provides an organophosphonic acid as defined above for use as an animal feed additive,, to improve pigment absorption in aqua culture or for the nanoencapsulation of drugs for drug delivery in vivo.
- the invention provides an organo phosphorous compound of the present invention capable of being used as an animal feed additive prepared by the reaction of ethane- 1 -hydroxy- 1 , 1- diphosphonic acid and palmitoyl chloride in a non-aqueous medium at temperatures below 5°C.
- the invention provides a method for the manufacture of an organo-phosphonic acid derivative of the present invention suitable for use in the nano-encapsulation of drugs for drug delivery in vivo by the reaction of 1 or 2-amino ethyl phosphonic acid and palmitoyl chloride in a non-aqueous medium at temperatures below 5°C.
- Example 1 is illustrative but non-limitative of the present invention.
- a glass 5-litre 3 necked reacton flask equipped with a stirrer is charged through one neck with 206 grams of Etidonic acid (ethane- 1- hydroxy-1 , 1-diphosphonic acid) dissolved in 1 litre of chloroform and the solution cooled to a temperature in the range 3 to 5°C.
- 275 grams of palmitoyl chloride are added slowly through one neck with vigorous stirring whilst maintaining the temperature at 3-5°C.
- Hydrochloric acid evolved in the reaction is withdrawn through the other neck and passed through a sodium hydroxide scrubber. Stirring is continued for 60 minutes after the addition of the palmitoyl chloride is complete.
- the contents of the reaction flask are poured into cold water and the chlorifofm and unreacted palmitoyl chloride, in the form of palmitic acid (a wax) separated off.
- the resultant product is further washed with cold water to remove any trace of unreacted etidonic acid. After repeated washing the product is filtered off and dried under vacuum.
- the product is soluble in water at about 70°C to provide a solution of pH 10.5 and is characterised by a Near Infra Red (NIR) spectra
- Example 1 The process of Example 1 was repeated except that the etidonic acid was replaced by 125 grams of 2-amino-ethyl phosphonic acid.
- the product yield was 90% of theoretical.
- the product dissolved in water at 60°C to provide a solution having a pH of 3.33.
- Example 2 was repeated using 1 amino ethyl phosphonic acid in place of 2 amino ethyl phosphonic acid.
- the product yield was 60% and had an NIR spectra as shown in Figure 3.
- the product was soluble in water at 60°C to give a solution of pH 3.76 and is believed to have the structure shown below:
- Example 1 was repeated except that the palmitoyl chloride was replaced by 219 grams of lauroyl chloride.
- the product yield was 23.2% of theoretical and the product dissolved in water at 60°C to give a solution having a pH of 10.42.
- the product is identified by is NIR spectra shown in Figure 4 and is believed to have the structure shown below :-
- Example 3 was repeated replacing palmitoyl chloride with 219 gram of lauroyl chloride.
- the product yield was 20% of theoretical.
- Example 6 The in vitro effect of the product of Example 1 on Inulin uptake in BHK cells is shown in Example 7 below.
- Example 6 The in vitro effect of the product of Example 1 on Inulin uptake in BHK cells is shown in Example 7 below.
- the preparation was conducted in three steps.
- Step 3 A solution of palmitic acid (13.18g,51.4 mmol) in dry ethyl acetate (80ml) was stirred at -5°C then treated sequentially with triethylamine (17.15ml,5.4mmol) and ethyl chloroformate (5.57g,51.4mmol) , the latter added dropwise. The resulting cloudy mixture was stirred at -5°C for 0.5h, then a solution of tris-silyl derivative B in ethyl acetate (35ml) was added dropwise and the resulting mixture stirred at the same temperature for 2h, then for 2h without cooling and finally for 3h at 80°C. The volatiles were removed from the cooled mixture by rotary evaporation.
- the residue was dissolved in saturated aqueous sodium bicarbonate and the resulting solution acidified to pH 2 using 10% hydrochloric acid and the precipitated acylamino-acid C filtered off.
- the crude solid was washed with methanol to remove residual palmitic acid then dried under high vacuum to leave the 1-Palmitoylaminoethylphosphonic acid C (16.0g,86%) as a white solid.
- BHK 21 (clonel3)cells were cultured in the normal way using G-MEM (Sigma G5154) supplemented with 10% FBS (Sigma F2442), lOml/L of 200mM L-Glutamine (Sigma G7513) 5% TSB (Sigma T8159) and 10 ml/L antibiotic/antimycotic solution (Sigma A9909) .
- the cells were cultured at 37°C with 5%C0 2 .
- the cell line was sourced from the European Collection of Animal Cell Cultures at the Centre for Applied Microbiology and Research at Porton Down.
- the Eppendorf s are then re-spun and aliquots of the D-water (lOO ⁇ ) were then removed and mixed with SigmaFluor Scintillation cocktail (Sigma S4398) and read in a scintillation counter. Results are converted into DPM per mg/cell weight after the Eppendorfs are re-weighed.
- Results are plotted on the graph shown in Figure 6 and clearly show a bi-phasic response, where at very low concentrations the flux of Inulin into the cells is reduced and at higher doses the influx is dramatically increased whilst Inulin is a large compound and is not particularly typical of compounds which one might wish to preferentailly absorb. The same effect can be observed with other sized molecules. Inferences about the emulsion forming properties of phosphonolipids and phosphonolipid mixtures can be made from the determination of the emulsifying power of Lecithin formulations. An Empirical method that determines the percentage of oil in water emulsion that is stable for an excess of 24 hours is as follows :-
- Example 8 The improvement in stability of Miscelles formed the inclusion of the product of Example 2 is indicated in Example 8 below.
- Liposomes were created as follows: -
- aqueous 1% v / v dispersion of the product of Example 2 was prepared by homogenisation using an Utra-Turrex T25 homogeniser operating at 14,000 rpm for approximately 30 seconds. Two sets of liposomes were created, the first test sample was formed using pure phosphatidylcholines and the second set made using 10% of the product of Example 2 in the formulation. Liposome concentration was determined spectro-photometrically using a Cecil Series 2 Machine at 500 NM wavelength. The liposome preparations were examined microscopically to ensure calibration of the spectrophotometer. The miscelle preparations were subject to a 30°C heat regime for periods of 10 minutes and 3 hours and 60°C for 30 minutes using a heated water bath. The results of the analysis are given below.
- Construction Concrete tanks set into ground with flat base and smooth internal finish
- Inlet A Single 100mm inlet on tank surface directing incoming water round edge of tank. Water flow controlled with butterfly valve - maximum capacity 2000 litres per minute
- Outlet A 0.6m x 0.6m diameter flat scree in middle of tank base leading into 150mm discharge pipe.
- B 0.5m x 0.8m diameter flat scree in middle of tank base leading to a 200mm discharge tank.
- a Tank inlets fed from an llkw centrifugal pump (with standby) drawing water from main salt water header tank. Header tank fed by two separate pumping systems drawing water from a minimum depth of 3m below surface. Salinity 27ppt to 31ppt. Water screened with 15mm grid before entering pump. Water passes once through tanks (no recirculation) with a retention time of less than one hour.
- Each tank fitted with a single 3kg capacity clockwork feeder suspended above the water at edge of tank.
- the fish were fed to appetite three times a day by hand and supplemented with automatic feeding. About 50% of the total daily intake as calculated from standard commercial feeding tables was supplied by hand. Suitable adjustments were made to the feed rate calculation on a weekly basis to allow for the increasing weight of the fish.
- the water flow into the tank was switched off and the level dropped to 20cm. Oxygen levels were maintained with a diffuser placed inside the tank. Anaesthetic (ethylp-amino benzoate dissolved in methylated spirit) was then added to the water to sedate the fish. The fish were then netted into a 40 litre capacity bucket, containing 15 Iites of water and weighed in bulk using a Salter 50kg capacity hanging spring balance. In this way stress levels and physical damage were kept to a minimum.
- the diets of the fish were as follows :-
- the 350 fish were split equally between the five tanks (70 fish per tank). Diet A was fed to tanks 1 and 3; Diet B was fed to tanks 2 and 4 (all type A tanks); Diet C was fed to the sea site tank (Type B tank). The pellet size of the fish diets ws 6.5mm.
- Table 1 tabulates the statistics recorded throughout the trial.
- Figure 7 is a graphical representation of the weight of the fish fed on each of the three diets at the end of the trial.
- Figure 8 is a graphical representation of the Roche Fan scores of the fish fed on each of the three diets at the end of the trial.
- Figure 7 shows that the fish fed the nutrient, astaxanthin, together with the organo-phosphorous compound, Corbinol, exhibited a greater increase in weight than the fish fed on the diets not including the organo- phosphorous compound.
- Figure 8 shows that the fish fed the nutrient, astaxanthin, together with the organo-phosphorous compound, Corbinol, exhibited a higher Roche Fan score than those fish fed diets not including the organo phosphorous compound.
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Abstract
Disclosed are organo phosphonic acids having formula (I) where: n = 0 or 1; R1 = H or (a); R2 = (b) or (c); R3 = an alkyl group containing > 10 carbon atoms; and R4 = H or CH3, that provide improved bio-availability of drugs and nutrients by permiabilising cell membranes. The products are prepared by the method of reacting an acid chloride of long chain aliphatic acid having 10-20 carbon atoms with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in chloroform at temperatures below 5 °C. Especially useful are the reaction products of palmitoyl or lauroyl chloride with ethane-1-hydroxy-1,1-diphosphonic acid, 2-amino-ethyl phosphonic acid or 1-amino-ethyl phosphonic acid.
Description
ORGANO PHOSPHOROUS COMPOUNDS
The present invention relates to organo phosphorous compounds that provide improved bio-availability of drugs and nutrients by permiabilising cell membranes. In particular the compounds may be used as animal feed additives to increase nutrient uptake, pigment absoφtion in aqua-cultures and for the nanoencapsulation of drugs for drug delivery in vivo, in a way similar to lysophospholipids and phospholipids. A suggested mechanism for the improvement in bio-availability is given in the paper by David Garnett and Robin Jones in The Genetic Engineer and Biotechnologist, Vol.13, No.2, 1993 and in International Application W094/22324.
Compounds of the type referred to above are available as purified natural compounds and as a result are substantially impure. There is, therefore, a need for compounds of higher purity, such as may be obtained by chemical synthesis, which will have improved thermal stability and resistance to enzymatic attack, when compared to phospholipids.
The organo-phosphorous compounds of the present invention are phosphonolipids preferably prepared by the reaction of a long chain alkyl acid chloride with an organophosphonic acid derivative preferably including a reactive hydroxy or amino residue.
From one aspect the present invention provides an organo phosphonic acid compound having the formula: -
where:-
n = 0 or 1
OH
R3 = an alkyl group containing
> 10 carbon atoms
Preferably R4 is a methyl group.
The alkyl acid chlorides have a chain length of 10 or more carbon atoms and preferably not more than about 20 carbon atoms; particularly suitable are the acid chlorides of palmitic and lauric acids.
Particularly suitable phosphonic acid derivatives are ethane- 1- hydroxy-1 , 1-diphosphonic acid (Etidronic acid) and 1 and 2 amino-ethyl phosphonic acids.
From another aspect, therefore, the present invention provides a method for preparing the organo phosphorous compounds of the present
invention suitable for use as animal feed additives, pigment absorption in aqua-culture and nanoencapsulation drugs for drug delivery in vivo, comprising reacting an acid chloride of a long chain aliphatic acid with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in a non-aqueous medium, preferably chloroform, at low temperatures, washing with cold water and subsequently drying.
Preferably the reaction temperature is kept below 5°C and most preferably in the range 3-5°C.
Preferably also the reactants are employed in stoichiometric proportions.
The invention also provides an organophosphonic acid as defined above for use as an animal feed additive,, to improve pigment absorption in aqua culture or for the nanoencapsulation of drugs for drug delivery in vivo.
From another aspect the invention provides an organo phosphorous compound of the present invention capable of being used as an animal feed additive prepared by the reaction of ethane- 1 -hydroxy- 1 , 1- diphosphonic acid and palmitoyl chloride in a non-aqueous medium at temperatures below 5°C.
From a further aspect the invention provides a method for the manufacture of an organo-phosphonic acid derivative of the present invention suitable for use in the nano-encapsulation of drugs for drug delivery in vivo by the reaction of 1 or 2-amino ethyl phosphonic acid and palmitoyl chloride in a non-aqueous medium at temperatures below 5°C.
The following examples are illustrative but non-limitative of the present invention.
Example 1
Preparation of Ethane-l-Palmitoyl-1 , 1 Diphosphonic Acid
A glass 5-litre 3 necked reacton flask equipped with a stirrer is charged through one neck with 206 grams of Etidonic acid (ethane- 1- hydroxy-1 , 1-diphosphonic acid) dissolved in 1 litre of chloroform and the solution cooled to a temperature in the range 3 to 5°C. 275 grams of palmitoyl chloride are added slowly through one neck with vigorous stirring whilst maintaining the temperature at 3-5°C. Hydrochloric acid evolved in the reaction is withdrawn through the other neck and passed through a sodium hydroxide scrubber. Stirring is continued for 60 minutes after the addition of the palmitoyl chloride is complete. At the end of the reaction the contents of the reaction flask are poured into cold water and the chlorifofm and unreacted palmitoyl chloride, in the form of palmitic acid (a wax) separated off. The resultant product is further washed with cold water to remove any trace of unreacted etidonic acid. After repeated washing the product is filtered off and dried under vacuum.
The product yield was 90% of theoretical.
The product is soluble in water at about 70°C to provide a solution of pH 10.5 and is characterised by a Near Infra Red (NIR) spectra
(measured on an NIR Systems Seris 5000 spectrometer) , shown inFigure 1. It is believed that the product has the structure:-
0H
I
0 0 • i '■■ P OH
CHjtCH-),. — C -
CH3 0
The effect of Ethane-l-Palmitoyl-l , l-Diphosphonic Acid on pigment uptake in fish is shown in example 9 below.
Example 2
The process of Example 1 was repeated except that the etidonic acid was replaced by 125 grams of 2-amino-ethyl phosphonic acid.
The product yield was 90% of theoretical. The product dissolved in water at 60°C to provide a solution having a pH of 3.33.
The product had a NIR spectra as shown in Figure 2 and is believed to have the structure:
o o
CHj(CH2),4 — I CI — NH CH, — CH2 — I PI — OH
OH
Example 3
Example 2 was repeated using 1 amino ethyl phosphonic acid in place of 2 amino ethyl phosphonic acid. The product yield was 60% and had an NIR spectra as shown in Figure 3. The product was soluble in water at 60°C to give a solution of pH 3.76 and is believed to have the structure shown below:
0
II
CHj(CH2),4- c — NH - CH— P - OH i 1
CH, OH
Example 4
Example 1 was repeated except that the palmitoyl chloride was replaced by 219 grams of lauroyl chloride.
The product yield was 23.2% of theoretical and the product dissolved in water at 60°C to give a solution having a pH of 10.42. The product is identified by is NIR spectra shown in Figure 4 and is believed to have the structure shown below :-
OH
I
0— P OH
Example 5
Example 3 was repeated replacing palmitoyl chloride with 219 gram of lauroyl chloride. The product yield was 20% of theoretical.
The product is believed to have a structure as shown below :-
/ ° CH,(CH2),.- C-NH — CH— P- OH
\ I
CH, OH
The use of octanoyl chloride in place of palmitoyl chloride with either etidronic acid or 2 amino ethyl phosphonic acid did not produce any useful product.
The in vitro effect of the product of Example 1 on Inulin uptake in BHK cells is shown in Example 7 below.
Example 6
Preparation of 1 -Palmitoylaminoethylphosphonic Acid
The preparation was conduced in three steps.
Step 1
Thiourea (9.89g.l30 mmol) was added to a solution of acetaldhyde(18.57 ml.325 mmol) and triphenylphosphite (68.13 ml, 325 mmol) in acetic acid (130 ml) and the resulting solution stirred and heated at 80°C for lhr to give an orange solution. Acetic anhydride (325 ml) was then added and the resulting solution refluxed for 2h to give a dark brown solution. 37% Aqueous hydrogen bromide (325 ml) was then added very carefully dropwise, via the condenser, and the resulting solution refluxed for 8h then cooled and rotary evaporated. The dark residue was dissolved in ethanol (260 ml) and methyloxirane added slowly until pH6 was reached. This addition resulted in the immediate precipitation of the aminophosphonic acid A shown as the product of the reactions outlined below. The solid was allowed to settle and the liquid supernatant decanted. Fresh ethanol (250 ml) was added and the mixture briefly refluxed, then cooled and the ethanol decanted. This washing was repeated until most of the brown coloration was removed. The solid was finally dried under high vacuum to give the aminophosphonic acid A (8.23g,50.6%) as a slightly coloured solid, m.p.<290°C(dec).
reflui, 8h; evaporate
Step 2
A mixture of the aminophosphonic acid A (8.23g.65.8 mmol) and hexamethyldisilazane
(55.5ml, 263 mmol) was heated on an oil bath at 150-160°C until all the solid dissolved (2-5h). Excess hexamethyldisilazane was evaporated and the residue was distilled to give the N,0,0-trisily derivative B (17.50g,86%), as a colourless oil, b.p.l40°C at 15mm Hg, the structure of which is outlined in the reaction illustrated below.
Step 3 A solution of palmitic acid (13.18g,51.4 mmol) in dry ethyl acetate (80ml) was stirred at -5°C then treated sequentially with triethylamine (17.15ml,5.4mmol) and ethyl chloroformate (5.57g,51.4mmol) , the latter added dropwise. The resulting cloudy mixture was stirred at -5°C for 0.5h, then a solution of tris-silyl derivative B in ethyl acetate (35ml) was
added dropwise and the resulting mixture stirred at the same temperature for 2h, then for 2h without cooling and finally for 3h at 80°C. The volatiles were removed from the cooled mixture by rotary evaporation. The residue was dissolved in saturated aqueous sodium bicarbonate and the resulting solution acidified to pH 2 using 10% hydrochloric acid and the precipitated acylamino-acid C filtered off. The crude solid was washed with methanol to remove residual palmitic acid then dried under high vacuum to leave the 1-Palmitoylaminoethylphosphonic acid C (16.0g,86%) as a white solid.
Step 3
O 0
° ClCO.Et, Et3N
R OH EtOAc. -5*C, 0.5h O OEi
-5' C' . 2h. 20*C. 2h,
The NMR spectra for the resultant lysophosphonolipid is shown in Fig.5.
Example 7
BHK 21 (clonel3)cells were cultured in the normal way using G-MEM (Sigma G5154) supplemented with 10% FBS (Sigma F2442), lOml/L of 200mM L-Glutamine (Sigma G7513) 5% TSB (Sigma T8159) and 10 ml/L antibiotic/antimycotic solution (Sigma A9909) . The cells were cultured at 37°C with 5%C02. The cell line was sourced from the European Collection of Animal Cell Cultures at the Centre for Applied Microbiology and Research at Porton Down.
These cells were cultured in 24 well plates (Sigma M9655). All experiments were performed in triplicate.
Cells in the wells were exposed to lμCi of C-1 Inulin (Sigma
30,480-8) prepared in Hanks Balanced Salt Solution (Sigma H9394) from a 75μCi stock solution. These were co-exposed to varying concentrations of the product of Example 1. The cultures were left for 1 hr and then the media was removed by aspiration. The adhered cells were then washed twice in Hanks' solution and then the cells were trypsinised using Trypsin-EDTA solution (Sigma T5775) and centrifuged to a pellet at lOOOrpm in pre- weighed Eppendorf tubes. The cell pellet was then lysed using distilled water. The Eppendorf s are then re-spun and aliquots of the D-water (lOOμ) were then removed and mixed with SigmaFluor Scintillation cocktail (Sigma S4398) and read in a scintillation counter. Results are converted into DPM per mg/cell weight after the Eppendorfs are re-weighed.
Results are plotted on the graph shown in Figure 6 and clearly show a bi-phasic response, where at very low concentrations the flux of Inulin into the cells is reduced and at higher doses the influx is dramatically increased whilst Inulin is a large compound and is not particularly typical of compounds which one might wish to preferentailly absorb. The same effect can be observed with other sized molecules.
Inferences about the emulsion forming properties of phosphonolipids and phosphonolipid mixtures can be made from the determination of the emulsifying power of Lecithin formulations. An Empirical method that determines the percentage of oil in water emulsion that is stable for an excess of 24 hours is as follows :-
Measure 100 ml amounts of distilled water and vegetable oil into a beaker. Add the test sample of lecithins (normally 1 gram). Using the high speed rotor action blender homogenise the mixture for 1 minute at 25°C. Immediately empty the container into a measuring flask and leave at 25°C for 24 hours. At the end of 24 hours calculate the percentage oil-water emulsion remaining.
An assay carried out comparing lecithin with a 90% lecithin - 10% of example 1 product gave the following results :-
Contol 0.0010 Lecithin 0.1948 90% Lecithin - 10% product Example 1 - 0.222
These results show a 12.3% improvement in the emulsifying power.
The improvement in stability of Miscelles formed the inclusion of the product of Example 2 is indicated in Example 8 below.
Example 8
Liposomes were created as follows: -
An aqueous 1% v/v dispersion of the product of Example 2 was prepared by homogenisation using an Utra-Turrex T25 homogeniser operating at 14,000 rpm for approximately 30 seconds. Two sets of
liposomes were created, the first test sample was formed using pure phosphatidylcholines and the second set made using 10% of the product of Example 2 in the formulation. Liposome concentration was determined spectro-photometrically using a Cecil Series 2 Machine at 500 NM wavelength. The liposome preparations were examined microscopically to ensure calibration of the spectrophotometer. The miscelle preparations were subject to a 30°C heat regime for periods of 10 minutes and 3 hours and 60°C for 30 minutes using a heated water bath. The results of the analysis are given below.
10 minutes 3 hours 60°C-30 mins
Lecithin Lecithin + 10% 1.31 1.288 0.975
Product of
Example 2 1.34 1.338 1.062
Net Increase 0.022% 3.88% 8.92%
The results indicate that there is a significant improvement in the stability of miscelles at elevated temperatures in the presence of phospholipids formed according to the present invention.
Example 9
Effect of Ethane-1 -Palmitoyl- 1 , 1-Diphosphonic Acid (Corbinol) on pigment uptake in salmon.
350 post smolt Atlantic salmon originating from a pure Mowi mixed sex stock, aged 24 months from hatch and being an initial average weight of 1.2kg were used in this trial.
The details of the five holding facilities used are given below:
A-Four adjacent 5m trial tanks
B-One 12m production tank (sea site control)
A B Diameter 5.0m 12.0m Wall depth 1.2m 1.8m Water depth 0.9m 1.6m Cubic capacity 17.6m 180.0m
Construction: Concrete tanks set into ground with flat base and smooth internal finish
Inlet: A Single 100mm inlet on tank surface directing incoming water round edge of tank. Water flow controlled with butterfly valve - maximum capacity 2000 litres per minute
B Single 200mm inlet on tank surface directing incoming water round edge of tank. Water flow controlled with slide valve - maximum capacity 2000 litres per minute.
Outlet: A 0.6m x 0.6m diameter flat scree in middle of tank base leading into 150mm discharge pipe. B 0.5m x 0.8m diameter flat scree in middle of tank base leading to a 200mm discharge tank.
Water Supply:
A Tank inlets fed from an llkw centrifugal pump (with standby) drawing water from main salt water header tank. Header tank fed by two separate pumping systems drawing water from a minimum depth of 3m below surface. Salinity 27ppt to 31ppt. Water screened with 15mm grid before entering pump. Water passes once through tanks (no recirculation) with a retention time of less than one hour.
B Tank inlet fed directly from main salt water header tank.
Aeration: Each tank fed by its own air diffuser supplied with air from the main farm blower. These can be used to elevate the oxygen levels in normal conditions and would keep the fish alive for several hours in the event of a water supply failure.
Level Control A External stand pipe in shared drain sump, adjacent to tank. B External stand pipe.
Jump netting 85% shade netting 200mm high around tank circumference and predator lines.
System failure indication: Low level float switch in each tank. Both connected to central alarm monitored 24 hrs. a day.
Automatic feeds:
Each tank fitted with a single 3kg capacity clockwork feeder suspended above the water at edge of tank.
The fish were fed to appetite three times a day by hand and supplemented with automatic feeding. About 50% of the total daily intake as calculated from standard commercial feeding tables was supplied by hand. Suitable adjustments were made to the feed rate calculation on a weekly basis to allow for the increasing weight of the fish.
Mortalities were removed immediately, their individual weights recorded and the cause of death assessed. Any disease treatments considered necessary through the course of the trial were applied to all tanks to minimise possible differences between tanks caused by the treatments.
Water flows through the tanks were maintained to ensure minimum dissolved oxygen levels of 7.0mg/litre. Oxygen levels were monitored
daily and if necessary water flows adjusted to maintain the tanks in balance. The tanks were brushed regularly to prevent the build-up of waste material and high levels of suspended solids.
Water temperature was recorded daily.
When the fish were weighed the following procedure was adopted :-
The water flow into the tank was switched off and the level dropped to 20cm. Oxygen levels were maintained with a diffuser placed inside the tank. Anaesthetic (ethylp-amino benzoate dissolved in methylated spirit) was then added to the water to sedate the fish. The fish were then netted into a 40 litre capacity bucket, containing 15 Iites of water and weighed in bulk using a Salter 50kg capacity hanging spring balance. In this way stress levels and physical damage were kept to a minimum.
The diets of the fish were as follows :-
Diet A - 55ppm astaxanthin Diet B - 55ppm astaxanthin + Corbinol (Ethane-1 -Palmitoyl- 1
1-Diphosphonic Acid) Diet C - Standard trouw 75ppm Astaxanthin (Control).
The 350 fish were split equally between the five tanks (70 fish per tank). Diet A was fed to tanks 1 and 3; Diet B was fed to tanks 2 and 4 (all type A tanks); Diet C was fed to the sea site tank (Type B tank). The pellet size of the fish diets ws 6.5mm.
The experiment ran for 36 days.
Total weights of the fish in each tank were taken at the beginning of the trial and at the end of the trial. Samples of fish for carcass analysis were taken after 4 weeks.
Samping was carried out at the following times :-
10 fish at start of trial for baseline;
10 fish from each tank after four weeks;
All remaining fish to be sampled at end of 36 day period.
Samples were analysed for HPLC astaxanthin level immediately after culling.
After the fourth week analysis was conducted and showed greatest spread of pigmentation in group 1 and consequently more fish were selected from group one to analyse with HPLC. HPLC analysis was carried out on 25% of the fish whilst a Roche Fan score was determined for all fish.
Table 1 tabulates the statistics recorded throughout the trial.
Figure 7 is a graphical representation of the weight of the fish fed on each of the three diets at the end of the trial.
Figure 8 is a graphical representation of the Roche Fan scores of the fish fed on each of the three diets at the end of the trial.
The results shown in figures 7 and 8 were calculated using standard derivation methods and allowed for the difference in the number of fish fed the control diet compared to those fed diets A and B.
Figure 7 shows that the fish fed the nutrient, astaxanthin, together with the organo-phosphorous compound, Corbinol, exhibited a greater increase in weight than the fish fed on the diets not including the organo- phosphorous compound.
Figure 8 shows that the fish fed the nutrient, astaxanthin, together with the organo-phosphorous compound, Corbinol, exhibited a higher Roche Fan score than those fish fed diets not including the organo phosphorous compound.
TABLE 1
Trial Statistics for example 9
Tank 1 2 3 4 Seasite
Diet A B A B C
Start Date 27.2.95
Finish Date 4.4.95
Number of Days 36 36 36 36 36
Start number 70 70 70 70 70
Number of mortalities 0 0 0 0 0
Final number 70 70 70 70 70
Start Total weight 80.4 84.7 82.8 86.5 68.6
Finish Total weight 97.5 99.5 96.1 106.2 86.1
Mortality weight 0 0 0 0 0
Gain in weight 17.1 14.8 13.3 19.7 17.5
Start average weight 1.149 1.210 1.183 1.236 0.980
Finish average weight 1.393 1.421 1.373 1.517 1.230
% increase 21.3 17.5 16.1 22.8 25.5
Specific growth rate (%day) 0.54 0.45 0.410 0.57 0.63
Feed consumed kgs 15.8 14.2 15.5 18.0 0
Feed conversion ratio 0.92 0.96 1.17 0.91 0
Average temperature 7.9
Diets: A Trouw 65, 55ppm astaxanthin
B Trouw 65, 55ppm astaxanthin + corbinol C Control Trouw 65, 75ppm astaxanthin
Diets supplied direct from Trouw
Corbinol (Ethane-l-Palmitoyl-l,l-Diρhosphonic acid)
OH
I o-v — OH
CH, O
Claims
1. An organo phosphonic acid compound having the formula:
where:
n = 0 or 1
OH 1
R. = H or p OH il 0
0 O H
I) II I R2 = [Rj- C-01- or [Rj - C — NH
R, = an alkyi group containing > 10 carbon atoms
R4 = H or CHj
2. An organo phosphonic acid compound according to claim 1 wherein R4 is a methyl group
3. An organo phosphonic acid according to claim 2 having the formula: -
OH
I
0 0= P — OH
CH,(CH2)M— C C p ^
J || ^^ OH
CH, 0
4. An organo phosphonic acid according to claim 2 having the formula: -
5. An organo phosphonic acid according to claim 2 having the formula: -
o o
If II
CH3(CH2)10— C — NH — CH — P — OH
I I
CH, OH
6. An organo phosphonic acid according to claim 1 having the formula: -
o o
II II
CH,(CHj)u— C — NH — CH2 - CH2 — P — 0H i 0 H
7. An organo phosphonic acid according to claim 2 having the formula:-
CH,(CH2)u — I CI — NH — CH — I PI — OH
I I
CH, OH
8. A method for preparing the organo phosphonic acid compounds of claim 1 comprising reacting an acid chloride of a long chain aliphatic acid with an alkyl phosphonic acid derivative containing an active amino or hydroxy group in a non-aqueous medium at low temperatures, washing with water and drying.
9. A method for preparing organo phosphonic acid compounds according to claim 8 wherein the non-aqueous medium is chloroform.
10. A method of preparing organo phosphonic acid compounds according to claims 8 or 9 wherein the temperature is kept below 5°C.
11. A method of preparing organo phosphonic acid compounds according to claim 10 wherein the temperature is in the range of 3-5°C.
12. A method of preparing organo phosphonic acid compounds according to any one of claims 8-11 wherein said long chain aliphatic acid chloride contains less than 20 carbon atoms in the chain.
13. A method for preparing organo phosphonic acid compounds ccording to claim 12 wherein the acid chloride is palmitoyl or lauroyl chloride.
14. A method for preparing organo phosphonic acid compounds according to any of claims 8-13 wherein the phosphonic acid derivative is ethane-1 -hydroxy- 1 , 1-diphosphonic acid (Etidonic acid) or 1 or 2 aminoethylphosphonic acid.
15. A method of preparing organo phosphonic acid compounds according to any of claims 8-14 wherein the reactants are employed in stoichiometric proportions.
16. The organo phosphonic acid compound of any one of claims 1-7, when used as an animal feed additive, to improve pigment absorption in aqua culture or for the nanoencapsulation of drugs for drug delivery in vivo.
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9607583 | 1996-04-12 | ||
GBGB9607583.3A GB9607583D0 (en) | 1996-04-12 | 1996-04-12 | Organo phosphorous compounds |
GB9617729 | 1996-08-23 | ||
GB9617729A GB2311991B (en) | 1996-04-12 | 1996-08-23 | Organo phosphorus compounds |
PCT/GB1997/001020 WO1997039004A1 (en) | 1996-04-12 | 1997-04-14 | Organo phosphorous compounds |
Publications (1)
Publication Number | Publication Date |
---|---|
EP0892806A1 true EP0892806A1 (en) | 1999-01-27 |
Family
ID=26309109
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97916556A Ceased EP0892806A1 (en) | 1996-04-12 | 1997-04-14 | Organo phosphorous compounds |
Country Status (6)
Country | Link |
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EP (1) | EP0892806A1 (en) |
CN (1) | CN1218477A (en) |
BR (1) | BR9708660A (en) |
GB (1) | GB2323089B (en) |
NO (1) | NO984671L (en) |
WO (1) | WO1997039004A1 (en) |
Families Citing this family (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB0400988D0 (en) * | 2004-01-16 | 2004-02-18 | Oxoid Ltd | Therapeutically useful antibacterial compounds |
DE102004032781A1 (en) | 2004-01-23 | 2005-08-11 | Mcs Micro Carrier Systems Gmbh | New lipid-modified bis-phosphonic acid derivatives, useful e.g. for transporting therapeutic or diagnostic agents, with affinity for bone, also as corrosion inhibitors |
WO2010039897A2 (en) * | 2008-10-03 | 2010-04-08 | Life Technologies Corporation | Nanocrystals with functional ligands |
CN107602610A (en) * | 2017-09-09 | 2018-01-19 | 南通意特化工有限公司 | It is a kind of can reuse sulfuric acid wastewater containing organic phospho acid production technology |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US2304156A (en) * | 1940-03-07 | 1942-12-08 | Du Pont | Organic compound and process of preparing the same |
DE2530139C3 (en) * | 1975-04-30 | 1979-06-21 | Joh. A. Benckiser Gmbh, 6700 Ludwigshafen | N-acyl-1-aminoalkane-1,1-diphosphonic acids, their preparation and use |
DE2651048A1 (en) * | 1976-11-09 | 1978-05-18 | Hoechst Ag | PLASTIC DISPERSION WITH HIGH WET ADHESION AND METHOD FOR THEIR PRODUCTION |
JP2612619B2 (en) * | 1988-12-14 | 1997-05-21 | 財団法人相模中央化学研究所 | Transdermal absorption enhancer consisting of phosphorus-containing compound |
EP0550385A1 (en) * | 1991-12-19 | 1993-07-07 | Ciba-Geigy Ag | Oral pharmaceutical compositions containing derivatives of methane-diphosphonic acid and 18-crown-6 ethers |
GB2267033B (en) * | 1992-03-07 | 1996-01-24 | David Garnett | Lysophospholipid Animal Feed Supplement |
US5523430A (en) * | 1994-04-14 | 1996-06-04 | Bristol-Myers Squibb Company | Protein farnesyl transferase inhibitors |
-
1996
- 1996-08-23 GB GB9726184A patent/GB2323089B/en not_active Expired - Fee Related
-
1997
- 1997-04-14 CN CN97194522A patent/CN1218477A/en active Pending
- 1997-04-14 BR BR9708660-6A patent/BR9708660A/en not_active Application Discontinuation
- 1997-04-14 WO PCT/GB1997/001020 patent/WO1997039004A1/en not_active Application Discontinuation
- 1997-04-14 EP EP97916556A patent/EP0892806A1/en not_active Ceased
-
1998
- 1998-10-06 NO NO984671A patent/NO984671L/en not_active Application Discontinuation
Non-Patent Citations (1)
Title |
---|
See references of WO9739004A1 * |
Also Published As
Publication number | Publication date |
---|---|
CN1218477A (en) | 1999-06-02 |
NO984671L (en) | 1998-12-04 |
BR9708660A (en) | 2000-01-04 |
WO1997039004A1 (en) | 1997-10-23 |
GB9726184D0 (en) | 1998-02-11 |
NO984671D0 (en) | 1998-10-06 |
GB2323089B (en) | 1999-02-10 |
GB2323089A8 (en) | 1998-09-24 |
GB2323089A (en) | 1998-09-16 |
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