WO1991012823A1 - Diagnostic aid - Google Patents
Diagnostic aid Download PDFInfo
- Publication number
- WO1991012823A1 WO1991012823A1 PCT/GB1991/000247 GB9100247W WO9112823A1 WO 1991012823 A1 WO1991012823 A1 WO 1991012823A1 GB 9100247 W GB9100247 W GB 9100247W WO 9112823 A1 WO9112823 A1 WO 9112823A1
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- WO
- WIPO (PCT)
- Prior art keywords
- microcapsules
- process according
- gas
- microcapsule
- emulsion
- Prior art date
Links
- 239000003094 microcapsule Substances 0.000 claims abstract description 67
- 238000000034 method Methods 0.000 claims abstract description 39
- 102000009027 Albumins Human genes 0.000 claims abstract description 22
- 108010088751 Albumins Proteins 0.000 claims abstract description 22
- 238000005354 coacervation Methods 0.000 claims abstract description 11
- 239000007788 liquid Substances 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 9
- 238000004945 emulsification Methods 0.000 claims abstract description 7
- 239000000463 material Substances 0.000 claims description 17
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 239000002775 capsule Substances 0.000 claims description 4
- 238000002405 diagnostic procedure Methods 0.000 claims description 2
- 244000118350 Andrographis paniculata Species 0.000 claims 1
- 238000001704 evaporation Methods 0.000 claims 1
- 230000008020 evaporation Effects 0.000 claims 1
- 238000004108 freeze drying Methods 0.000 claims 1
- 210000000056 organ Anatomy 0.000 claims 1
- 239000008194 pharmaceutical composition Substances 0.000 claims 1
- 239000000839 emulsion Substances 0.000 abstract description 42
- 239000003921 oil Substances 0.000 abstract description 13
- 239000000341 volatile oil Substances 0.000 abstract description 13
- 229960004624 perflexane Drugs 0.000 abstract description 12
- ZJIJAJXFLBMLCK-UHFFFAOYSA-N perfluorohexane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F ZJIJAJXFLBMLCK-UHFFFAOYSA-N 0.000 abstract description 12
- 238000002592 echocardiography Methods 0.000 abstract description 8
- 239000000126 substance Substances 0.000 abstract description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 24
- 102000008100 Human Serum Albumin Human genes 0.000 description 19
- 108091006905 Human Serum Albumin Proteins 0.000 description 19
- 239000000203 mixture Substances 0.000 description 16
- 238000003756 stirring Methods 0.000 description 12
- 235000019198 oils Nutrition 0.000 description 11
- 239000000243 solution Substances 0.000 description 11
- 235000012424 soybean oil Nutrition 0.000 description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 239000007764 o/w emulsion Substances 0.000 description 9
- 239000000047 product Substances 0.000 description 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 8
- 239000002245 particle Substances 0.000 description 8
- 239000003208 petroleum Substances 0.000 description 7
- 239000011148 porous material Substances 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 6
- 229920001993 poloxamer 188 Polymers 0.000 description 5
- 239000004094 surface-active agent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- HZAXFHJVJLSVMW-UHFFFAOYSA-N 2-Aminoethan-1-ol Chemical compound NCCO HZAXFHJVJLSVMW-UHFFFAOYSA-N 0.000 description 4
- AFABGHUZZDYHJO-UHFFFAOYSA-N 2-Methylpentane Chemical compound CCCC(C)C AFABGHUZZDYHJO-UHFFFAOYSA-N 0.000 description 4
- 108010010803 Gelatin Proteins 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- NWGKJDSIEKMTRX-AAZCQSIUSA-N Sorbitan monooleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@@H](O)[C@H]1OC[C@H](O)[C@H]1O NWGKJDSIEKMTRX-AAZCQSIUSA-N 0.000 description 4
- HQPMKSGTIOYHJT-UHFFFAOYSA-N ethane-1,2-diol;propane-1,2-diol Chemical compound OCCO.CC(O)CO HQPMKSGTIOYHJT-UHFFFAOYSA-N 0.000 description 4
- 229920000159 gelatin Polymers 0.000 description 4
- 239000008273 gelatin Substances 0.000 description 4
- 235000019322 gelatine Nutrition 0.000 description 4
- 235000011852 gelatine desserts Nutrition 0.000 description 4
- 239000004005 microsphere Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 3
- 238000007792 addition Methods 0.000 description 3
- 238000005054 agglomeration Methods 0.000 description 3
- 230000002776 aggregation Effects 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 3
- 239000004006 olive oil Substances 0.000 description 3
- 235000008390 olive oil Nutrition 0.000 description 3
- 229950011087 perflunafene Drugs 0.000 description 3
- -1 perfluoro compound Chemical class 0.000 description 3
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 description 3
- 238000002360 preparation method Methods 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- HRZFUMHJMZEROT-UHFFFAOYSA-L sodium disulfite Chemical compound [Na+].[Na+].[O-]S(=O)S([O-])(=O)=O HRZFUMHJMZEROT-UHFFFAOYSA-L 0.000 description 3
- 239000004296 sodium metabisulphite Substances 0.000 description 3
- 235000010262 sodium metabisulphite Nutrition 0.000 description 3
- 239000006228 supernatant Substances 0.000 description 3
- QIROQPWSJUXOJC-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,5,6-undecafluoro-6-(trifluoromethyl)cyclohexane Chemical compound FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)F QIROQPWSJUXOJC-UHFFFAOYSA-N 0.000 description 2
- 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 2
- ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 2,3-dimethylbutane Chemical compound CC(C)C(C)C ZFFMLCVRJBZUDZ-UHFFFAOYSA-N 0.000 description 2
- PFEOZHBOMNWTJB-UHFFFAOYSA-N 3-methylpentane Chemical compound CCC(C)CC PFEOZHBOMNWTJB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 description 2
- 244000068988 Glycine max Species 0.000 description 2
- 235000010469 Glycine max Nutrition 0.000 description 2
- 240000007817 Olea europaea Species 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000012634 fragment Substances 0.000 description 2
- 238000000265 homogenisation Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- 235000010445 lecithin Nutrition 0.000 description 2
- 239000000787 lecithin Substances 0.000 description 2
- 229940067606 lecithin Drugs 0.000 description 2
- 238000000386 microscopy Methods 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- LOQGSOTUHASIHI-UHFFFAOYSA-N perfluoro-1,3-dimethylcyclohexane Chemical compound FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(C(F)(F)F)C1(F)F LOQGSOTUHASIHI-UHFFFAOYSA-N 0.000 description 2
- 229920001184 polypeptide Polymers 0.000 description 2
- 102000004196 processed proteins & peptides Human genes 0.000 description 2
- 108090000765 processed proteins & peptides Proteins 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000007762 w/o emulsion Substances 0.000 description 2
- GHBZJUJZNRLHBI-UHFFFAOYSA-N 1,1,2,2,3,3,4,4,5,6-decafluoro-5,6-bis(trifluoromethyl)cyclohexane Chemical compound FC(F)(F)C1(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C1(F)C(F)(F)F GHBZJUJZNRLHBI-UHFFFAOYSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- ZORQXIQZAOLNGE-UHFFFAOYSA-N 1,1-difluorocyclohexane Chemical compound FC1(F)CCCCC1 ZORQXIQZAOLNGE-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OQNWUUGFAWNUME-UHFFFAOYSA-N 2-[2-(2-hydroxyethoxy)propoxy]ethanol Chemical compound OCCOC(C)COCCO OQNWUUGFAWNUME-UHFFFAOYSA-N 0.000 description 1
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 1
- 239000004971 Cross linker Substances 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- IAYPIBMASNFSPL-UHFFFAOYSA-N Ethylene oxide Chemical compound C1CO1 IAYPIBMASNFSPL-UHFFFAOYSA-N 0.000 description 1
- 229920001612 Hydroxyethyl starch Polymers 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108020004511 Recombinant DNA Proteins 0.000 description 1
- 102000007562 Serum Albumin Human genes 0.000 description 1
- 108010071390 Serum Albumin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 239000001099 ammonium carbonate Substances 0.000 description 1
- 235000012501 ammonium carbonate Nutrition 0.000 description 1
- 229920001400 block copolymer Polymers 0.000 description 1
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000010382 chemical cross-linking Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000000536 complexating effect Effects 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000010924 continuous production Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000012024 dehydrating agents Substances 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- WBZKQQHYRPRKNJ-UHFFFAOYSA-L disulfite Chemical compound [O-]S(=O)S([O-])(=O)=O WBZKQQHYRPRKNJ-UHFFFAOYSA-L 0.000 description 1
- SNRUBQQJIBEYMU-UHFFFAOYSA-N dodecane Chemical compound CCCCCCCCCCCC SNRUBQQJIBEYMU-UHFFFAOYSA-N 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000000635 electron micrograph Methods 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 238000011067 equilibration Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940094933 n-dodecane Drugs 0.000 description 1
- SNMVRZFUUCLYTO-UHFFFAOYSA-N n-propyl chloride Chemical compound CCCCl SNMVRZFUUCLYTO-UHFFFAOYSA-N 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000012053 oil suspension Substances 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000003973 paint Substances 0.000 description 1
- UWEYRJFJVCLAGH-UHFFFAOYSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)C2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C21F UWEYRJFJVCLAGH-UHFFFAOYSA-N 0.000 description 1
- LGUZHRODIJCVOC-UHFFFAOYSA-N perfluoroheptane Chemical compound FC(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F LGUZHRODIJCVOC-UHFFFAOYSA-N 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229940044519 poloxamer 188 Drugs 0.000 description 1
- 229920002959 polymer blend Polymers 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000002310 reflectometry Methods 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 238000004513 sizing Methods 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- RBWSWDPRDBEWCR-RKJRWTFHSA-N sodium;(2r)-2-[(2r)-3,4-dihydroxy-5-oxo-2h-furan-2-yl]-2-hydroxyethanolate Chemical compound [Na+].[O-]C[C@@H](O)[C@H]1OC(=O)C(O)=C1O RBWSWDPRDBEWCR-RKJRWTFHSA-N 0.000 description 1
- 235000011069 sorbitan monooleate Nutrition 0.000 description 1
- 239000001593 sorbitan monooleate Substances 0.000 description 1
- 229940035049 sorbitan monooleate Drugs 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 239000008227 sterile water for injection Substances 0.000 description 1
- 238000004659 sterilization and disinfection Methods 0.000 description 1
- 238000000859 sublimation Methods 0.000 description 1
- 230000008022 sublimation Effects 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- NBRKLOOSMBRFMH-UHFFFAOYSA-N tert-butyl chloride Chemical compound CC(C)(C)Cl NBRKLOOSMBRFMH-UHFFFAOYSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
- A61B8/48—Diagnostic techniques
- A61B8/481—Diagnostic techniques involving the use of contrast agent, e.g. microbubbles introduced into the bloodstream
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/22—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations
- A61K49/222—Echographic preparations; Ultrasound imaging preparations ; Optoacoustic imaging preparations characterised by a special physical form, e.g. emulsions, liposomes
- A61K49/223—Microbubbles, hollow microspheres, free gas bubbles, gas microspheres
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
Definitions
- the present invention relates to diagnostic aids and, more particularly, to echogenic materials for echocardiography and other purposes.
- air-filled albumin microbubbles of about 1-10. ⁇ m can be injected into the bloodstream and will reflect ultrasonic radiation in such a way as to yield diagnostically-useful images of the heart and other internal organs.
- These microbubbles are formed by sonicating viscous aqueous albumin solutions at 5000 - 30,000 Hz. The resulting microbubbles are heat-denatured to make the albumin water- insoluble.
- One aspect of the invention provides a process for preparing gas-containing microcapsules comprising ' forming water- dispersible (preferably proteinaceous) microcapsules having a liquid or solid core and removing at least some of the said liquid or solid to create a microcapsule containing a gas.
- Forming non-proteinaceous microcapsules in this way ha previously been proposed in GB-A-1 288 " 583 for use in paints
- the polymers used in GB-A-1 288 583 were insoluble polymers lik polystyrene.
- the compositions o the present invention at least when used for such a purpose are biocompatible, biodegradable and non-immunogenic.
- EP-A-0 327 490 discloses the use of synthetic polymer to surround gas bubbles in a liquid medium and subsequently for microcapsules for echocardiography. This is a different proces from that of the present invention and the prior specificatio does not mention using proteins.
- the core in the process of the present invention is preferably a water-immiscible oil and is preferably also relatively volatile so that it can be evaporated after the microcapsules have been formed, in other words during or after the hardening of the wall. This is what we mean by "relatively volatile”. More specifically, any inert oil, preferably a perfluoro compound, having a boiling point of 20-100°C, preferably 40-90°C and more preferably 50-80°C is generally suitable.
- the process for the production of hollow microcapsules may be any of those generally known as simple coacervation, complex coacervation, MSIEP (minimisation of solubility at isoelectric point) and double emulsion, but is preferably the latter.
- Interfacial polymerisation may be used for some wall-forming materials, although not for proteinaceous materials. Any suitable wall-forming material may be used which is (i) dispersible (preferably soluble) in water, (ii) capable of bein rendered water-insoluble once the microcapsules are made an (iii) physiologically non-toxic and non-immunogenic, at least i the conditions of use. Materials which are biodegradable in the patient following administration are preferred. Proteinaceous materials are preferred and serum albumin is generally suitable.
- HSA human serum albumin
- Other materials include gelatin, hydroxyethyl starch, starch and dextran.
- the properties of some materials may be modified by the presence of an added non-ionic surfactant, such as is described by Omotosho et al as interfacial complexation (1986 J. Pharm. Pharmacol . 38, 865-870).
- the materials are chemically or thermally denatured, to render them insoluble, after the microcapsules have been formed.
- the (preferably proteinaceous) material can be made water- insoluble by chemical cross-linking, denaturation (for example with heat), chelating or grafting.
- microcapsules of the invention are filled with a gas or vapour, which may be air or any other true gas but is often a mixture of air and the vapour from the volatile oil.
- a gas or vapour which may be air or any other true gas but is often a mixture of air and the vapour from the volatile oil.
- air-filled is loosely used to cover pure air, any other gas, any vapour or mixtures thereof.
- the microcapsules which are formed are preferably from 0.1 to 500 ⁇ m in diameter.
- a range of 1.0 to 10 ⁇ m or 2.0 to 8 ⁇ m is especially suitable.
- Such sizes may be achieved by appropriately selecting the process parameters and/or by separating out, for example by wet micro-sieving or air elutriation, the desired size from the resulting microcapsules. Since a range of sizes will usually result, the figures in this specification refer to 90% of the population by weight.
- the size range can be measured with a light microscope or by using known apparatus such as the Coulter Counter and known methods such as those disclosed in Morris & Warburton, J. Pharm. Pharmacol . 36, 73-76 (1984).
- a multi- chamber microcapsule results, resembling a honeycomb or the type of confectionery sold in the UK under the registered trademark "Malteser” . This is a preferred product.
- the final product is typically obtained in the form of suspension which may be washed, sterilised and used.
- the microcapsules can be freeze-drie without collapsing and stored as a free-flowing powder fo future use.
- the air-filled microcapsules may be used in echocardiography an other ultrasonic imaging techniques in ways known in the ar (see, for example, EP-A-0 324 938, US-A-4 276 885 and US-A-4 572 203, all incorporated by reference), in nasal and lung deliver systems for drugs (when prepared as powder, rather than suspensions) and as opacifiers or reflectivity enhancers in cosmetics.
- the air-filled microcapsules themselves (especially the multi- chamber capsules) and their uses, particularly as echogenic materials in diagnostic procedures, form f rther aspects of the invention.
- Figures 1 and 2 are views from above and one side of respective stirring paddles
- Figure 3 is a vertical section of a mixing vessel in which the paddles operate.
- Figures 4 and 5 are respective scanning electron micrographs of microcapsules prepared in accordance with the invention using the double emulsion method.
- a dehydrating agent (isopropanol (6 ml) or a salt eg 6 ml of 20% sodium sulphate can be used) was then added over 10 mins, to induce coacervation, or concentration of the albumin around the droplets of volatile oil, and the product was stirred for 1 hour at 1233 rpm.
- a surfactant (Span 80 (sorbitan mono-oleate) ; 0.2 ml; was added after coacervation and before cross-linking to preve agglomeration of the microcapsules following cross-linking.
- T albumin was cross-linked using glutaraldehyde (0.2 ml) a excess reagent was inactivated with sodium metabisulphite (0.
- the suspension of microcapsules obtained was stored i a desiccator at 5°C.
- the capsules were sized using a Malver 3600 particle sizer.
- microcapsules were produced. Most were muc smaller than 5 ⁇ m in diameter.
- the stirring spee from 1233 to 874 rpm, using perfluoro-1,2-dimethyl cyclohexan as volatile oil and Span 80 as surfactant, the yield o microcapsules in the size range 2 - 8 ⁇ m was increased but th range was also broader.
- the surfactant was changed t Pluronic F68, the proportion of microcapsules in the desire size range increased to 71.7%; however, the range was stil broad.
- Example 1 The basic method of Example 1 was followed. 1 ml of perfluorohexane was homogenised into 10 ml of a 10% aqueous albumin solution in 30 sec using a Silverson homogeniser at 6800 rpm, following by stirring at 1370 rpm for 15 mins, at room temperature. The isopropanol was added as before but this step was followed by stirring for 1.5 hours at 1370 rpm. Similarly, the additions of Span 80 and glutaraldehyde were each followed by 15 min of stirring at 1370 rpm instead of 1233 rpm. Excess glutaraldehyde was removed with ethanolamine (0.8 ml) and the final stirring was at 1370 rpm for 15 min. The product was obtained as a suspension of relatively uniform microcapsules in the desired range of 2 - 8 ⁇ m.
- a primary o/w emulsion was produced by homogenising a volatile oil (perfluoro-1,3 dimethyl cyclohexane) with a solution of HSA, as in Example 1. This emulsion was then re-emulsi ied into olive oil to produce an o/w/o emulsion, with the volatile oil as the inner oil phase. After addition of a surfactant, Pluronic F68, to prevent agglomeration of the particles, glutaraldehyde was added to cross-link the albumin. The excess glutaraldehyde was then inactivated using sodium metabisulphite. The resulting microcapsules were separated by centrifugation and washed with petroleum ether and acetone, to remove the olive oil. Afte drying overnight in a desiccator at " room temperature, th microcapsules were collected as a dry powder. Details of th method are as follows.
- 0.5 ml perfluoro-l,3-methylcyclohexane was homogenised into 1 m of 20% aqueous HSA solution over 5 min at 6800 rpm. This o/ emulsion was poured into 25 ml of previously stirred olive oi and stirred at room temperature for 15 min at 1233 rpm. 0.4 m of 10% Pluronic F68 was added and stirred for 15 min at 123 rpm. 0.2 ml of glutaraldehyde was added and stirred as before 0.4 ml of 12% aq. sodium metabisulphite added and stirred a before. The product was centrifuged at 3000 rpm for 20 min an washed etc as above.
- the mixture was allowed to cool to 25°C. Once this temperature had been reached, 20 ml of petroleum ether (May & Baker, UK) was added to the microsphere-soya oil suspension. This mixture was centrifuged at 3000 rpm for 20 minutes. The supernatant was decanted and the microspheres were washed with 40 ml of petroleum ether, centrifuged, decanted; washed again with petroleum ether and finally with ethanol.
- petroleum ether May & Baker, UK
- Differing conditions were tried, for example using a mechanical stirrer or a homogenizer for the o/w/o emulsion; 1, 2 or 3% o/w emulsion in the soya oil; olive instead of soya oil; 874, 1250 or 2000 rpm stirring speed; type of paddle; 16.7 or 33.3% volatile oil; non-volatile oil (n-dodecane) instead of volatile oil; 5, 10 or 20% HSA; and 0, 1 or 10% lecithin as a surfactant in the primary emulsion.
- Example 4 The method of Example 4 was adapted as follows to produce particularly satisfactory result. 10 ml of perfuorohexane w emulsified into 20 ml of 10% aq. HSA with Microfluidiser circulating the liquid three times at 60 - 90,000 kPa. 1 ml o o/w emulsion was poured into 50 ml soya oil and homogenised wit the Silverson blender for 5 min at 6800 rpm. The albumin wa cross-linked by heating to about 120°C in an oil bath (15 mi equilibration; 30 min heating) whilst paddle stirring at 200 rpm and then cooled to room temperature, followed by paddl stirring at 2000 rpm whilst adding 20 ml petroleum ether.
- Th product was paddle stirred at 2000 rpm for 2 min, centrifuged a 3000 rpm for 20 min, decanted, washed twice with ether (20 ml and once with ethanol (20 ml), shaken, centrifuged and decanted Finally, the product was freeze-dried.
- the MSIEP method uses elements of both complex coacervation and simple (o/w) emulsion techniques.
- the albumin coating can then be cross-linked by heat or a chemical method(s) as described above. If glutaraldehyde is used to cross-link the albumin (typically 1 ml of 25% solution) then excess glutaraldehyde can be removed with 2 ml of ethanolamine (free base) .
- an oil-in-water emulsion was formed from 1 ml of 10% HSA (pH 6.3) and 1 ml perfluorohexane by Silverso blending for 5 mins at 6800 rpm, and then stirred at 638 rpm fo 10 mins at 45°C.
- 0.4 ml of Span 80 was added and the mixture wa stirred as before, following which 0.1 ml of 37% aqueou formaldehyde (cross-linker) was added and the mixture wa stirred as before.
- 0.2 ml of 12% w/v sodiu metabisulphite was added to quench the formaldehyde and the mixture was stirred as before.
- a " suspension of 2-50 ⁇ m microspheres was obtained.
- microcapsules may be filtered, washed and dried.
- HSA Human Serum Albumin
- HSA Human Serum Albumin
- Soya oil edible grade
- Petroleum ether Bpt 60-90C°(AR) Fisons, Loughborough, UK.
- Ethanol Absolute (AR) Fisons, Loughborough, UK.
- Acetone (AR) Fisons, Loughborough, UK.
- Fluorophore Filters 0.5 ⁇ m pore size), Millipore Filters.
- Secondary emulsion 15 ml primary emulsion, 500 ml Soya oil.
- the HSA and the volatil oil which was any of those listed above or a combination of tw in varying proportions, were mixed.
- the mixture was the emulsified using the microfluidiser or the Silversto homogeniser.
- the Microfluidiser was used at an operatin pressure of 5.5-9.7 x 10 7 N/m 2 (8000-14000 pounds per squar inch).
- the homogeniser - was operated at 5000-9000 revolution per minutes (rpm) .
- the emulsion was manufactured in th microfluidiser either with or without the cooling coil. It wa processed through 1-4 cycles.
- the volume of the formulation were scaled up by a factor of 4 to make u the minimum homogenisation volume.
- the emulsion was the homogenised for 1-4 minutes.
- the emulsion was used as soon a possible after manufacture or stored at 4°C for use after a fe hours.
- the size of the pores within the microcapsules depended on the volatile oil and the method of homogenisation used in the manufacture of the primary emulsion.
- Perfluorodecalin in conjunction with the Microfluidiser tended to produce microcapsules with an interior having a plurality of hollow spaces, resembling a "Malteser" sweet.
- Malteser is a registered trademark.
- Perfluorohexane emulsions made using the Microfluidiser tended to be solid while perfluorohexane emulsions made using the Silverson homogeniser were thin-walled microspheres with 5-10 pores per microcapsule. Flow charts for two methods are given in Tables 1 and 2 below.
- the microcapsules have been prepare as follows: 1° emulsion: 20 ml 10% HSA, 10 ml Perfluorodecalin, microfluidised at 9.7 x 10 7 N/m 2 (14000 psi), 4 cycles. 2° emulsion: 15 ml of the 1° emulsion was added to 500 ml soya oil and homogenised at 5500 rpm for 3 mins. The emulsion was stirred at 3000 rpm using a 6-blade stirrer head. The sample was freeze-dried before microscopy.
- Microspheres collect and weigh
- the whole process of the invention can advantageously be carried out aseptically, starting with raw materials filtered through 0.22 ⁇ m filters so that no subsequent sterilisation is needed.
- established methods such as the use of moist heat (autoclave), ethylene oxide or gamma irradiation may be used.
- the final product will preferably be prepared as a powder which will be reconstituted by the addition of sterile water for injection of sterile saline and then administered by intravenous injection.
- the powder may contain a suitable wetting agent such as Poloxamer 188 to aid redispersion, if needed.
Abstract
Description
Claims
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE1991905331 DE516732T1 (en) | 1990-02-20 | 1991-02-19 | DIAGNOSTIC TOOL. |
GB9214210A GB2256183B (en) | 1990-02-20 | 1992-07-03 | Double emulsion technique producing diagnostic aid microcapsules for pharmaceutical use |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB9003821.7 | 1990-02-20 | ||
GB909003821A GB9003821D0 (en) | 1990-02-20 | 1990-02-20 | Diagnostic aid |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1991012823A1 true WO1991012823A1 (en) | 1991-09-05 |
Family
ID=10671314
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/GB1991/000247 WO1991012823A1 (en) | 1990-02-20 | 1991-02-19 | Diagnostic aid |
Country Status (5)
Country | Link |
---|---|
EP (1) | EP0516732A1 (en) |
JP (1) | JPH05504573A (en) |
ES (1) | ES2032726T1 (en) |
GB (1) | GB9003821D0 (en) |
WO (1) | WO1991012823A1 (en) |
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ES2032726T1 (en) | 1993-03-01 |
GB9003821D0 (en) | 1990-04-18 |
JPH05504573A (en) | 1993-07-15 |
EP0516732A1 (en) | 1992-12-09 |
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