WO1998057735A1 - Surfactant compositions - Google Patents
Surfactant compositions Download PDFInfo
- Publication number
- WO1998057735A1 WO1998057735A1 PCT/GB1998/001767 GB9801767W WO9857735A1 WO 1998057735 A1 WO1998057735 A1 WO 1998057735A1 GB 9801767 W GB9801767 W GB 9801767W WO 9857735 A1 WO9857735 A1 WO 9857735A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- block copolymer
- composition
- copolymer surfactant
- polyalkyleneglycol
- metal ion
- Prior art date
Links
- 239000004094 surface-active agent Substances 0.000 title claims abstract description 65
- 239000000203 mixture Substances 0.000 title claims description 50
- 229920001400 block copolymer Polymers 0.000 claims abstract description 60
- 229910021645 metal ion Inorganic materials 0.000 claims abstract description 40
- 229920001515 polyalkylene glycol Polymers 0.000 claims abstract description 25
- 238000000034 method Methods 0.000 claims abstract description 19
- 238000010525 oxidative degradation reaction Methods 0.000 claims description 11
- 150000002500 ions Chemical class 0.000 claims description 9
- 229920001983 poloxamer Polymers 0.000 claims description 6
- 238000002560 therapeutic procedure Methods 0.000 claims description 5
- 229910052742 iron Inorganic materials 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000002736 metal compounds Chemical class 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical group C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 claims description 2
- 238000003745 diagnosis Methods 0.000 claims description 2
- 229910052759 nickel Inorganic materials 0.000 claims description 2
- 229960000502 poloxamer Drugs 0.000 claims description 2
- 229920001987 poloxamine Polymers 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 229910001428 transition metal ion Inorganic materials 0.000 claims description 2
- 229910052726 zirconium Inorganic materials 0.000 claims description 2
- 230000015556 catabolic process Effects 0.000 abstract description 10
- 238000006731 degradation reaction Methods 0.000 abstract description 10
- 230000000087 stabilizing effect Effects 0.000 abstract description 6
- 230000008901 benefit Effects 0.000 abstract description 3
- 229920002517 Poloxamer 338 Polymers 0.000 description 20
- 239000000243 solution Substances 0.000 description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- 230000006641 stabilisation Effects 0.000 description 6
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 5
- 239000003963 antioxidant agent Substances 0.000 description 5
- 239000012535 impurity Substances 0.000 description 5
- 229920000642 polymer Polymers 0.000 description 5
- 238000011105 stabilization Methods 0.000 description 5
- 229920002534 Polyethylene Glycol 1450 Polymers 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- -1 Zr4+ Chemical compound 0.000 description 4
- 239000002537 cosmetic Substances 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- 238000003998 size exclusion chromatography high performance liquid chromatography Methods 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000003708 ampul Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000012071 phase Substances 0.000 description 3
- 238000003860 storage Methods 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 239000007983 Tris buffer Substances 0.000 description 2
- 125000002947 alkylene group Chemical group 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 229910052802 copper Inorganic materials 0.000 description 2
- 239000010949 copper Substances 0.000 description 2
- 238000000354 decomposition reaction Methods 0.000 description 2
- 239000007857 degradation product Substances 0.000 description 2
- 238000012377 drug delivery Methods 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 229910052751 metal Inorganic materials 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 241000271566 Aves Species 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 206010034972 Photosensitivity reaction Diseases 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- GOOHAUXETOMSMM-UHFFFAOYSA-N Propylene oxide Chemical compound CC1CO1 GOOHAUXETOMSMM-UHFFFAOYSA-N 0.000 description 1
- 206010040642 Sickle cell anaemia with crisis Diseases 0.000 description 1
- 229920002359 Tetronic® Polymers 0.000 description 1
- QCWXUUIWCKQGHC-UHFFFAOYSA-N Zirconium Chemical compound [Zr] QCWXUUIWCKQGHC-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001299 aldehydes Chemical class 0.000 description 1
- 230000002009 allergenic effect Effects 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 238000011088 calibration curve Methods 0.000 description 1
- 238000012668 chain scission Methods 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 239000000599 controlled substance Substances 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- ARUVKPQLZAKDPS-UHFFFAOYSA-L copper(II) sulfate Chemical compound [Cu+2].[O-][S+2]([O-])([O-])[O-] ARUVKPQLZAKDPS-UHFFFAOYSA-L 0.000 description 1
- 239000008380 degradant Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000013583 drug formulation Substances 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 1
- 229940117927 ethylene oxide Drugs 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000006260 foam Substances 0.000 description 1
- 239000004088 foaming agent Substances 0.000 description 1
- 239000002778 food additive Substances 0.000 description 1
- 235000013373 food additive Nutrition 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229920001519 homopolymer Polymers 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 239000011261 inert gas Substances 0.000 description 1
- 239000000468 intravenous fat emulsion Substances 0.000 description 1
- 239000002085 irritant Substances 0.000 description 1
- 231100000021 irritant Toxicity 0.000 description 1
- 239000005351 kimble Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- PJUIMOJAAPLTRJ-UHFFFAOYSA-N monothioglycerol Chemical compound OCC(O)CS PJUIMOJAAPLTRJ-UHFFFAOYSA-N 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 150000002978 peroxides Chemical class 0.000 description 1
- 230000036211 photosensitivity Effects 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 229920000233 poly(alkylene oxides) Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000005464 sample preparation method Methods 0.000 description 1
- 150000003378 silver Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 239000003643 water by type Substances 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- DUNKXUFBGCUVQW-UHFFFAOYSA-J zirconium tetrachloride Chemical class Cl[Zr](Cl)(Cl)Cl DUNKXUFBGCUVQW-UHFFFAOYSA-J 0.000 description 1
- GBNDTYKAOXLLID-UHFFFAOYSA-N zirconium(4+) ion Chemical compound [Zr+4] GBNDTYKAOXLLID-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
- C09K23/42—Ethers, e.g. polyglycol ethers of alcohols or phenols
-
- C—CHEMISTRY; METALLURGY
- C09—DYES; PAINTS; POLISHES; NATURAL RESINS; ADHESIVES; COMPOSITIONS NOT OTHERWISE PROVIDED FOR; APPLICATIONS OF MATERIALS NOT OTHERWISE PROVIDED FOR
- C09K—MATERIALS FOR MISCELLANEOUS APPLICATIONS, NOT PROVIDED FOR ELSEWHERE
- C09K23/00—Use of substances as emulsifying, wetting, dispersing, or foam-producing agents
Definitions
- This invention relates to surfactants and in particular to block copolymer surfactants stabilized by the presence of metal ions.
- Block copolymer surfactants have a wide variety of uses in a number of industries. They are used as food additives, have applications in the cosmetic industry and have also been proposed as defoamers, anti-static agents, detergents, gelling agents, foam controllers, dispersants and dye levellers. However, due to their diversity and physiological safety for both external and internal administration, block copolymer surfactants are of particular importance in the pharmaceutical industry.
- block copolymer surfactants are employed as emulsifying agents, e.g. in intravenous fat emulsions, wetting agents e.g. for antibiotics, thickening agents, coatings e.g. for tablets, solubilisers e.g. to maintain clarity in elixirs and syrups, dispersion enhancers and foaming agents.
- emulsifying agents e.g. in intravenous fat emulsions
- wetting agents e.g. for antibiotics, thickening agents
- coatings e.g. for tablets
- solubilisers e.g. to maintain clarity in elixirs and syrups
- dispersion enhancers and foaming agents e.g. to maintain clarity in elixirs and syrups
- foaming agents e.g. to maintain clarity in elixirs and syrups
- These polymers have also been used as bases for ointments and suppositories, as tablet
- block copolymer surfactants have also been found to have their own therapeutic application. For example some block copolymer surfactants have been shown to act as adjuvants or hypolemic agents whilst Poloxa ers 182LF and F188 have therapeutic applications as a pharmaceutic aid and a cathartic respectively. F188 is also being investigated for its ability to improve blood flow in myocardial infarction and in sickle cell crisis and for potential application for the treatment of burns. A comprehensive discussion of medical applications of Poloxamers can be found in "Poloxamers in the Pharmaceutical Industry", Schmolka I.R., Polymers for Controlled Drug Delivery, Ed. Peter Tarcha, CRC Press, Boca Raton 1991, pages 189-214 which is incorporated herein by reference.
- Block copolymer surfactants are quite unstable undergoing degradation both in the solid phase and in aqueous or organic solutions. In solution, this degradation is faster under more neutral pH and is accelerated by high temperature and photoradiation. Solid phase degradation is also caused by light, thus further illustrating the photosensitivity of block copolymer surfactants.
- Block copolymer surfactant preparations also generally contain impurities along with degradation products which may also accelerate decomposition. Although it is possible to remove impurities such as aldehydes and peroxides from solution phase block copolymer surfactant compositions it would be highly advantageous if such procedures were not necessary.
- the degradation is believed to occur via a free-radical initiated autoxidative mechanism and its rate is dependent on the nature of the block copolymer surfactant.
- oxidation is particularly significant in polymers containing tertiary hydrogen atoms and chain scission at weak links, such as those at branching sites, is a concern in some polymers.
- antioxidants to inhibit the radical decomposition reaction.
- an antioxidant such as monothioglycerol
- protection from oxidation given by antioxidants is limited due to the finite supply of antioxidant material present in the formulation or other composition.
- Another method of stabilizing block copolymer surfactants may involve storing the compounds under an inert gas or in the absence of light, however these methods are undesirable and impractical for most block copolymer surfactant compositions.
- block copolymer surfactants can be stabilized by the presence of small quantities of certain metal ions and/or a polyalkyleneglycol .
- the metal ions afford block copolymer surfactant stability at very low concentration of metal ion and safety advantages over conventional stabilizing techniques.
- the present invention is all the more surprising in view of the prior art which clearly indicates that metal ions would be expected to accelerate autoxidative degradation. It is envisaged that metal ions and/or a polyalkyleneglycol could be used to stabilise compositions intended for both medical and non-medical usage.
- the invention provides a composition comprising a block copolymer surfactant and a metal ion wherein said metal ion is present in an amount sufficient to inhibit oxidative degradation of said block copolymer surfactant, particularly compositions which consist essentially of surfactant (and optionally impurities and degradation products conventionally associated with the particular surfactant), metal ions, optionally counter ions for the metal ions, and optionally a liquid solvent system, e.g. water or an organic solvent or a mixture of two or more solvents .
- a liquid solvent system e.g. water or an organic solvent or a mixture of two or more solvents .
- the invention provides a process for the preparation of a stabilized block copolymer surfactant composition comprising adding a metal ion to a block copolymer surfactant composition in an amount sufficient to inhibit oxidative degradation of said block copolymer surfactant .
- the invention provides the use of a metal compound for the manufacture of a composition comprising a block copolymer surfactant wherein ions of said metal are present in an amount sufficient to inhibit oxidative degradation of said block copolymer surfactant .
- the invention provides a method of therapy or diagnosis of a human or non-human animal (preferably a vascularised animal, e.g. a mammalian or avian animal) body, said method comprising administering to said body a therapeutically or diagnostically effective amount of a composition comprising a physiologically tolerable block copolymer surfactant and a physiologically tolerable amount of metal ion wherein said metal ion is present in an amount sufficient to inhibit oxidative degradation of said block copolymer surfactant.
- a human or non-human animal preferably a vascularised animal, e.g. a mammalian or avian animal
- the metal ion is used in a sufficient amount to achieve a stabilizing affect, e.g. a concentration sufficient to stabilize the composition for therapeutic or diagnostic administration.
- a stabilizing affect e.g. a concentration sufficient to stabilize the composition for therapeutic or diagnostic administration.
- the quantity of metal ion used in the composition will depend on the nature and quantity of the block copolymer surfactant and other excipients present, the use of the composition, e.g. for therapy or diagnostic use or cosmetic use, the nature of the active agent and the like but the necessary amount may be readily determined by the person skilled in the art.
- the concentration of metal ion employed relative to the block copolymer surfactant will be in the range 1 x 10 "6 M to 1 x 10 "3 M, preferably of the order of 10 "4 to 10 "5 M.
- the metal ions of the invention can be any ion which stabilizes a block copolymer surfactant.
- Particularly preferred metal ions include ions having stable lower valence states i.e. reducible ions such as transition metal ions, in particular ions of iron, zirconium, Nickel and cobalt, e.g. Fe 3+ , Zr 4+ , Ni 2+ and Co 2+ .
- the compositions of the present invention also encompass compositions utilising one or more metal ions to stabilise one or more block copolymer surfactants present in the same composition.
- the metal ion is present in a physiologically tolerable concentration. It is envisaged that the metal ions useful according to the invention can be bound to a chelating agent prior to administration although in view of the very low concentrations of metal ion required for stabilisation, this is not a necessity and this comprises a further advantage of the present invention.
- the block copolymer surfactants of the present invention are preferably non-ionic and may be for example block alkylene oxide copolymers, for example poloxamers such as the pluronics (e.g. Pluronic F68 and 108 which are block copolymer surfactants of ethyleneoxide and propyleneoxide) or poloxamines such as the tetronics .
- pluronics e.g. Pluronic F68 and 108 which are block copolymer surfactants of ethyleneoxide and propyleneoxide
- poloxamines such as the tetronics .
- the molecular weight of the block copolymer surfactants to be stabilised conveniently range from 1000 to 20,000, preferably 1550 to 15000, most preferably 2000 to 15000 atomic mass units.
- the block copolymer surfactants of the invention can be prepared by standard polymerisation procedures, e.g. under conditions of high temperature and pressure in an inert anhydrous atmosphere, but are readily available commercially.
- the quantity of block copolymer surfactant used in the composition will depend on the nature and quantity of the other excipients present, the use of the composition, e.g. for therapy or diagnostic use or cosmetic use, the nature of the active agent, the specific use of the block copolymer surfactant e.g. whether as an emulsifier or a coating agent, but the necessary amount may be readily determined by the person skilled in the art. It has also been surprisingly found that the addition of small amounts of a polyalkyleneglycol (i.e. polyalkyleneoxide) to a block copolymer surfactant composition may increase the stability of the composition.
- a polyalkyleneglycol i.e. polyalkyleneoxide
- the invention provides a composition comprising a block copolymer surfactant and a polyalkyleneglycol wherein said polyalkyleneglycol is present in an amount sufficient to inhibit oxidative degradation of said block copolymer surfactant .
- the invention provides the use of a polyalkyleneglycol for the manufacture of a composition comprising a block copolymer surfactant wherein the polyalkyleneglycol is present in an amount sufficient to inhibit oxidative degradation of said block copolymer surfactant.
- polyalkyleneglycol is used in conjunction with a metal ion and this forms a yet further aspect of the invention.
- the polyalkyleneglycol can be a block copolymer or a homopolymer, preferably having C 2 , C 3 or C 4 alkylene units especially C 2 or C 3 units. It is preferably a polyethyleneglycol .
- the molecular weight of the polyalkyleneglycol ranges from 300 to 10,000 atomic mass units, preferably, 400 to 2000 atomic mass units.
- the quantity of polyalkyleneglycol used in the composition will depend on the nature and quantity of the block copolymer surfactant and other excipients present, the use of the composition, e.g. for therapy or diagnostic use or cosmetic use, the nature of the active agent and the like but the necessary amount may be readily determined by the person skilled in the art. In general , the amount of polyalkyleneglycol used ranges from 1 to 30%, preferably 5 to 20%, most preferably 10 to 20% by weight of the composition. Where the composition is for medical use, the polyalkyleneglycol will be present in a physiologically tolerable amount. The use of one or more polyalkyleneglycols to stabilise one or more block copolymer surfactants is also envisaged in the present invention.
- polyalkyleneglycols of the invention are readily prepared by standard polymerisation techniques and are readily available commercially.
- Two size-exclusion HPLC methods were developed to analyze Poloxamer 338 using a refractive index detector.
- a Superose 12 column (30 cm x 7.8 mm) from Pharmacia was used with a flow rate of 0.8 mL/min.
- the injection volume was 10 ⁇ l and the mobile phase contained 10% methanol and 25 mM NaCl .
- Solution samples were typically diluted with water to below 2% concentration before injection.
- the samples were first dissolved in methanol and further diluted with 80% methanol to the appropriate concentration before injection.
- the method uses a TSK G2000SWXL column from Supelco (30 cm x 7.8 mm) and a mobile phase containing six parts methanol and four parts 62.5 mM NaCl .
- Figure la depicts typical chromatograms of the NF grade and purified Poloxamer 338.
- Poloxamer 338 as obtained from BASF showed a higher molecular weight (HMW) parent peak and a lower molecular weight impurity/degradant peak with nominal molecular weights of 14.6K and 3K respectively. As evident, the lower molecular weight peak was reduced significantly upon purification by membrane diafiltration.
- Figure lb shows typical chromatograms of poloxamer 338 samples in solution degraded under 40°C storage to different extents. Degradation of poloxamer 338 in solution manifested itself initially in a decrease of the parent peak and a corresponding increase of the lower molecular weight peak. No new peak was observed.
- Figure 2a shows the standard curve of Poloxamer 338 parent peak area versus concentration (% w/v) .
- Figure 2b shows the calibration curve of the SE- HPLC system for molecular weight determination using polyethylene glycol molecular weight standards and a Waters GPC software. Since the degradation of Poloxamer 338 is manifested in a gradual loss of the parent peak, the HPLC data of stability samples are expressed as percent of area under the parent peak.
- Poloxamer 338 appears to be more stable under acidic (pH ⁇ 4) and alkaline (pH >8) conditions and less stable at the pH region in between.
- Poloxamer 338 A study of the effect of metal ions on the stability of Poloxamer 338 was carried out with 3% aqueous solution Poloxamer 338 and 2 x 10 ⁇ 4 M (11-12 ppm) of metal ion.
- the SE-HPLC results are listed in the following table.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU81163/98A AU8116398A (en) | 1997-06-19 | 1998-06-17 | Surfactant compositions |
EP98930875A EP0989906A1 (en) | 1997-06-19 | 1998-06-17 | Surfactant compositions |
JP50397599A JP2002507932A (en) | 1997-06-19 | 1998-06-17 | Surfactant composition |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9712981.1 | 1997-06-19 | ||
GBGB9712981.1A GB9712981D0 (en) | 1997-06-19 | 1997-06-19 | Compositions |
US5707597P | 1997-08-27 | 1997-08-27 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1998057735A1 true WO1998057735A1 (en) | 1998-12-23 |
Family
ID=10814598
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1998/001767 WO1998057735A1 (en) | 1997-06-19 | 1998-06-17 | Surfactant compositions |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0989906A1 (en) |
JP (1) | JP2002507932A (en) |
AU (1) | AU8116398A (en) |
GB (1) | GB9712981D0 (en) |
WO (1) | WO1998057735A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1368813A2 (en) * | 2000-12-15 | 2003-12-10 | The Arizona Board of Regents on Behalf of the University of Arizona | Method for patterning metal using nanoparticle containing precursors |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993023087A1 (en) * | 1992-05-19 | 1993-11-25 | Cox James P | Stabilization of biowastes |
EP0601619A2 (en) * | 1992-12-04 | 1994-06-15 | NanoSystems L.L.C. | Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization |
EP0602700A2 (en) * | 1992-12-17 | 1994-06-22 | NanoSystems L.L.C. | Novel formulations for nanoparticulate X-ray blood pool contrast agents using high molecular weight surfactants |
EP0605024A2 (en) * | 1992-12-16 | 1994-07-06 | NanoSystems L.L.C. | Use of purified surface modifiers to prevent particle aggregation during sterilization |
-
1997
- 1997-06-19 GB GBGB9712981.1A patent/GB9712981D0/en active Pending
-
1998
- 1998-06-17 JP JP50397599A patent/JP2002507932A/en active Pending
- 1998-06-17 WO PCT/GB1998/001767 patent/WO1998057735A1/en not_active Application Discontinuation
- 1998-06-17 AU AU81163/98A patent/AU8116398A/en not_active Abandoned
- 1998-06-17 EP EP98930875A patent/EP0989906A1/en not_active Withdrawn
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1993023087A1 (en) * | 1992-05-19 | 1993-11-25 | Cox James P | Stabilization of biowastes |
EP0601619A2 (en) * | 1992-12-04 | 1994-06-15 | NanoSystems L.L.C. | Use of non-ionic cloud point modifiers to minimize nanoparticle aggregation during sterilization |
EP0605024A2 (en) * | 1992-12-16 | 1994-07-06 | NanoSystems L.L.C. | Use of purified surface modifiers to prevent particle aggregation during sterilization |
EP0602700A2 (en) * | 1992-12-17 | 1994-06-22 | NanoSystems L.L.C. | Novel formulations for nanoparticulate X-ray blood pool contrast agents using high molecular weight surfactants |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1368813A2 (en) * | 2000-12-15 | 2003-12-10 | The Arizona Board of Regents on Behalf of the University of Arizona | Method for patterning metal using nanoparticle containing precursors |
EP1368813A4 (en) * | 2000-12-15 | 2005-03-23 | Univ Arizona | Method for patterning metal using nanoparticle containing precursors |
US7252699B2 (en) | 2000-12-15 | 2007-08-07 | The Arizona Board Of Regents | Method for patterning metal using nanoparticle containing precursors |
US8557017B2 (en) | 2000-12-15 | 2013-10-15 | The Arizona Board Of Regents | Method for patterning metal using nanoparticle containing precursors |
US8779030B2 (en) | 2000-12-15 | 2014-07-15 | The Arizona Board of Regents, The University of Arizone | Method for patterning metal using nanoparticle containing precursors |
Also Published As
Publication number | Publication date |
---|---|
AU8116398A (en) | 1999-01-04 |
EP0989906A1 (en) | 2000-04-05 |
GB9712981D0 (en) | 1997-08-27 |
JP2002507932A (en) | 2002-03-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP0576612B1 (en) | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity | |
EP1539122B1 (en) | Aqueous 2,6-diisopropylphenol pharmaceutical compositions | |
US5674911A (en) | Antiinfective polyoxypropylene/polyoxyethylene copolymers and methods of use | |
US5567859A (en) | Polyoxypropylene/polyoxyethylene copolymers with improved biological activity | |
EP0722313B1 (en) | Viscoelastic compositions of fluorinated organic compounds | |
IE45321B1 (en) | Sprayable germicidal foam compositions | |
AU2007227091B2 (en) | Stabilized ophthalmic compositions comprising oxidatively unstable components | |
EP0143478B1 (en) | Stable, aqueous, acidic solution of cis-platinum, suitable for injection | |
US20230293494A1 (en) | Liquid pharmaceutical formulation | |
JP2003525231A (en) | Anesthetic preparations | |
KR0130644B1 (en) | Stabilizing packaged iodophor and minimizing leaching of iodine through packaging | |
CN108883064B (en) | Ophthalmic compositions comprising PVP-I | |
WO2014013903A1 (en) | Liquid composition containing taxane-based active ingredient, process for producing same, and liquid medicinal preparation | |
WO2017085687A1 (en) | Stable formulation of phenobarbital sodium injection | |
EP0989906A1 (en) | Surfactant compositions | |
JP2827295B2 (en) | Eye drops containing vitamin A | |
CZ63395A3 (en) | Composition based on polyoxyethylene-polyoxypropylene block co-polymers and a tank containing thereof | |
WO2023287316A1 (en) | Gas transmission emulsion for intravenous administration |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AL AM AT AU AZ BA BB BG BR BY CA CH CN CU CZ DE DK EE ES FI GB GE GH GM GW HU ID IL IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT UA UG US UZ VN YU ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW SD SZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 81163/98 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1998930875 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1998930875 Country of ref document: EP |
|
REG | Reference to national code |
Ref country code: DE Ref legal event code: 8642 |
|
NENP | Non-entry into the national phase |
Ref country code: CA |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 1998930875 Country of ref document: EP |