NO842731L - Ultrasonic contrast agent and method of preparation thereof - Google Patents
Ultrasonic contrast agent and method of preparation thereofInfo
- Publication number
- NO842731L NO842731L NO842731A NO842731A NO842731L NO 842731 L NO842731 L NO 842731L NO 842731 A NO842731 A NO 842731A NO 842731 A NO842731 A NO 842731A NO 842731 L NO842731 L NO 842731L
- Authority
- NO
- Norway
- Prior art keywords
- solution
- galactose
- lactose
- contrast agent
- dextrose
- Prior art date
Links
- 239000002961 echo contrast media Substances 0.000 title claims description 12
- 238000002360 preparation method Methods 0.000 title description 9
- 238000000034 method Methods 0.000 title description 8
- 239000000243 solution Substances 0.000 claims description 25
- 229930182830 galactose Natural products 0.000 claims description 20
- 239000011859 microparticle Substances 0.000 claims description 18
- 239000007788 liquid Substances 0.000 claims description 17
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 15
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 15
- 239000008101 lactose Substances 0.000 claims description 15
- WQZGKKKJIJFFOK-PHYPRBDBSA-N alpha-D-galactose Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@H]1O WQZGKKKJIJFFOK-PHYPRBDBSA-N 0.000 claims description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 13
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 12
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims description 12
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 12
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 12
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 12
- 239000008121 dextrose Substances 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 12
- 239000007864 aqueous solution Substances 0.000 claims description 11
- 239000011780 sodium chloride Substances 0.000 claims description 7
- 239000008151 electrolyte solution Substances 0.000 claims description 5
- 229960003082 galactose Drugs 0.000 claims 9
- 239000012891 Ringer solution Substances 0.000 claims 3
- 229940021013 electrolyte solution Drugs 0.000 claims 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 21
- 239000002872 contrast media Substances 0.000 description 9
- 238000002604 ultrasonography Methods 0.000 description 8
- 239000003708 ampul Substances 0.000 description 6
- 239000008280 blood Substances 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000007924 injection Substances 0.000 description 5
- 238000002592 echocardiography Methods 0.000 description 4
- 239000002245 particle Substances 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 238000003860 storage Methods 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010186 staining Methods 0.000 description 2
- 210000003462 vein Anatomy 0.000 description 2
- 239000008215 water for injection Substances 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000036760 body temperature Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 230000004856 capillary permeability Effects 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 238000002405 diagnostic procedure Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- -1 for example Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 229960005150 glycerol Drugs 0.000 description 1
- 230000036512 infertility Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940068886 polyethylene glycol 300 Drugs 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
Classifications
-
- 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
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
-
- 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
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B17/00—Surgical instruments, devices or methods, e.g. tourniquets
- A61B17/22—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for
- A61B2017/22082—Implements for squeezing-off ulcers or the like on the inside of inner organs of the body; Implements for scraping-out cavities of body organs, e.g. bones; Calculus removers; Calculus smashing apparatus; Apparatus for removing obstructions in blood vessels, not otherwise provided for after introduction of a substance
- A61B2017/22089—Gas-bubbles
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
Description
Denne oppfinnelse angår de i kravene angitte gjenstander. Undersøkelse av organer med ultralyd (sonografi) er en diagnostisk metode som har vært praktisert i noen år og er blitt/^godt kjent. Ultralydbølger i mega-hertz-området (over 2 mega-hertz med bølgelengder mellom 1 og 0,2 mm) reflekteres ved grense-flater mellom forskjellige vevsarter. De ekkoer som derved opp-står, forsterkes og gjøres synlige. Av spesiell betydning er hjerteundersøkelser med denne metode, som kalles ekkokardiografi (Haft, J.I. et al.; Clinical echocardiography, Futura, Mount Kisco, New York 1978; Kohler, E. Klinische Echokardiographie, Enke, Stuttgart 1979; Stefan, G. el al.: Echokardiographie, Thieme, Stuttgart-New York 1981; G. Biamino, L. Lange: This invention relates to the objects specified in the claims. Examination of organs with ultrasound (sonography) is a diagnostic method that has been practiced for some years and has become/^well known. Ultrasound waves in the mega-hertz range (over 2 mega-hertz with wavelengths between 1 and 0.2 mm) are reflected at interfaces between different types of tissue. The echoes that arise are amplified and made visible. Of particular importance are heart examinations with this method, which is called echocardiography (Haft, J.I. et al.; Clinical echocardiography, Futura, Mount Kisco, New York 1978; Kohler, E. Klinische Echokardiographie, Enke, Stuttgart 1979; Stefan, G. el al .: Echokardiographie, Thieme, Stuttgart-New York 1981; G. Biamino, L. Lange:
Echokardiographie, Hoechst AG, 19 83).Echocardiography, Hoechst AG, 1983).
Da ingen væsker, heller ikke blodet, gir noe ekko, ble det søkt etter muligheter for å gjøre blodet og dettes strøm-ning "synlig" for ultralyd-undersøkelser, hvilket også er mulig ved tilsetning av meget fine gassblærer. As no liquids, not even the blood, give any echo, a search was made for possibilities to make the blood and its flow "visible" for ultrasound examinations, which is also possible by adding very fine gas bubbles.
Fra litteraturen er. det kjent flere fremgangsmåter til fremstilling av de små gassblærer. Eksempelvis kan de fremstilles før injiseringen i blodstrømmen ved kraftig rystning eller om-røring av oppløsninger så som saltoppløsninger, fargestoffopp-løsninger eller av tidligere uttatt blod. Riktignok oppnås derved en ultralyd-kontrastvirkning, men disse metoder er forbundet med tungtveiende ulemper som ytrer seg ved dårlig reproduserbarhet, sterkt varierende størrelse på gassblærene og - betinget av en andel av synlige store blærer - en viss emboli-risiko. Disse ulemper ble delvis eliminert ved andre fremstillingsmåter, eksempelvis som angitt i U.S. patent 3 640 271, hvor små blærer med reproduserbar størrelse oppnås ved filtrering eller ved anvendelse av en elektrodeinnretning som fører likestrøm. Som motvekt mot den fordel som ligger i muligheten for å kunne fremstille små gassblærer med reproduserbar størrelse, står ulempene med den be-tydelige tekniske innsats/kostnad. From the literature is. Several methods are known for producing the small gas bubbles. For example, they can be prepared before the injection into the bloodstream by vigorous shaking or stirring of solutions such as salt solutions, dye solutions or of previously withdrawn blood. Admittedly, an ultrasound contrast effect is thereby achieved, but these methods are associated with significant disadvantages which manifest themselves in poor reproducibility, greatly varying size of the gas bubbles and - conditional on a proportion of visible large bubbles - a certain risk of embolism. These disadvantages were partially eliminated by other manufacturing methods, for example as indicated in U.S. Pat. patent 3,640,271, where small blisters of reproducible size are obtained by filtration or by the use of an electrode device which conducts direct current. As a counterweight to the advantage that lies in the possibility of being able to produce small gas bubbles with a reproducible size, there are the disadvantages of the considerable technical effort/cost.
I U.S. patent 4 276 885 beskrives fremstilling av små gassblærer med definert størrelse, hvilke er omgitt av et gelatin-overtrekk til beskyttelse mot sammenflyting. Oppbevaringen av de ferdige gassblærer kan bare skje i "innfrosset" tilstand, eksempelvis ved oppbevaring ved kjøleskaptemperatur, slik at de må gjen-oppvarmes til kroppstemperatur ved anvendelsen. In the U.S. patent 4 276 885 describes the production of small gas bubbles of defined size, which are surrounded by a gelatin coating to protect against coalescence. The storage of the finished gas bladders can only take place in a "frozen" state, for example by storage at refrigerator temperature, so that they must be re-heated to body temperature during use.
I U.S. patent 4 265 251 beskrives fremstilling og anvendelse av små gassblærer med et fast overtrekk av sakkarider, hvilke kan være fylt med en gass som står under trykk. Hvis de står under normaltrykk, så kan de anvendes som ultralyd-kontrastmiddel; ved anvendelse med forhøyet indre trykk anvendes de til måling av blodtrykket. Skjønt oppbevaringen av de faste gassblærer ikke frembyr noe problem, er den tekniske innsats ved fremstillingen en betydelig kostnadsfaktor. In the U.S. patent 4 265 251 describes the production and use of small gas bladders with a fixed coating of saccharides, which can be filled with a gas that is under pressure. If they are under normal pressure, they can be used as an ultrasound contrast agent; when used with elevated internal pressure, they are used to measure blood pressure. Although the storage of the solid gas bladders does not present any problem, the technical effort involved in manufacturing is a significant cost factor.
Risikoen med de kontrastmidler som står til forføyningThe risk with the contrast agents available
i henhold til teknikkens stand, skyldes to faktorer: størrelsen og antallet av faststoffpartikler såvel som gassblærer. according to the state of the art, is due to two factors: the size and number of solid particles as well as gas bubbles.
Den hittil beskrevne teknikkens stand muliggjør fremstilling av ultralyd-kontrastmidler som alltid oppviser bare noen av de påkrevede egenskaper: 1. ) Utkobling av emboli-risikoen - Gassblærer (størrelse og antall) The state of the art described so far enables the production of ultrasound contrast agents which always exhibit only some of the required properties: 1. ) Eliminating the embolism risk - Gas bladders (size and number)
- Faststoffpartikler (størrelse og antall)- Solid particles (size and number)
2. ) Reproduserbarhet2. ) Reproducibility
3. ) Tilstrekkelig langvarig stabilitet3. ) Sufficient long-term stability
4. ) Lunge-gjennomløpningsevne, f.eks. når det gjelder oppnåelse av ultralyd-kontrastvirkning i venstre halvdel av hjertet 4. ) Lung permeability, e.g. when it comes to achieving ultrasound contrast effect in the left half of the heart
5. ) Kapillar-gjennomløpningsevne5. ) Capillary permeability
6. ) Sterilitet og pyrogenfrihet av preparatet6. ) Sterility and pyrogen-freeness of the preparation
7. ) Lett å fremstille med forsvarlige kostnader7. ) Easy to manufacture with reasonable costs
8. ) og problemfri lagring.8. ) and problem-free storage.
I den europeiske patentsøknad med offentliggjørelses-nummeret 52575 beskrives fremstillingen av gassblærer som skal ha disse påkrevede egenskaper. For fremstillingen blir mikropartikler av en fast krystallinsk substans, eksempelvis galaktose, suspendert i en bærervæske, hvorved gassen, som adsorberes på partikkeloverflaten, er innesluttet i hulrom mellom partiklene eller i interkrystallinske hulrom som danner gassblærer. Den således fremstilte suspensjon av gassblærer og mikropartikler kan injiseres innenfor et tidsrom på 10 minutter. Den flytende bærer transporterer og dispergerer mikropartiklene og gassblærene og må være fysiologisk forlikelig. In the European patent application with publication number 52575, the production of gas bladders which must have these required properties is described. For the preparation, microparticles of a solid crystalline substance, for example galactose, are suspended in a carrier liquid, whereby the gas, which is adsorbed on the particle surface, is enclosed in cavities between the particles or in intercrystalline cavities that form gas bubbles. The thus prepared suspension of gas bubbles and microparticles can be injected within a period of 10 minutes. The liquid carrier transports and disperses the microparticles and gas bubbles and must be physiologically compatible.
I den europeiske patentsøknad nr. 52575 beskrives vandige oppløsninger som særlig godt egnede bæreroppløsninger, da deres forlikelighet er uproblematisk. Tilsetninger som øker viskosi-teten av oppløsningen er imidlertid påkrevet. Glyserol, propylenglykol, polyetylenglykol 300 og 400, polyvinylpyrrolidon og andre med vann blandbare eller i vann dispergerbare polymerer angis som særlig godt egnet for dette formål, forutsatt at de er tilstrekkelig forlikelige. Som spesielt foretrukket er det i eksempel 4 i denne søknad beskrevet en flytende bærer som består av en vandig 5%ig dekstrose-oppløsning som dessuten inneholder 10% propylenglykol. In the European patent application no. 52575, aqueous solutions are described as particularly suitable carrier solutions, as their compatibility is unproblematic. However, additives that increase the viscosity of the solution are required. Glycerol, propylene glycol, polyethylene glycol 300 and 400, polyvinylpyrrolidone and other water-miscible or water-dispersible polymers are indicated as particularly suitable for this purpose, provided they are sufficiently compatible. As particularly preferred, example 4 of this application describes a liquid carrier which consists of an aqueous 5% dextrose solution which also contains 10% propylene glycol.
Anvendelsen av propylenglykol ved de undersøkelser som utføres med disse ultralyd-kontrastmidler, er imidlertid ikke uproblematisk når man tar i betraktning at diagnostiske under-søkelser av hjertet i første rekke utføres når det gjelder risikopasienter, hvor ethvert problembeheftet stoff såvidt mulig skal unngås. Ifølge de undersøkelser som er utført av P.P. Singh et al., Arzneimittel-Forschung/Drug Research 32. (II) Nr. 1 1/1982, s. 1443 ff, har det vist seg at propylenglykol i høyere konsen-trasjonsområder fremkaller forskjellige nevropsykofarmakologiske virkninger hos mus og rotter. Andre forskere beretter innvirkning på blodtrykket (Budden, R. et al., Arzneim.-Forschung 28/9: 1586 The use of propylene glycol in the examinations carried out with these ultrasound contrast agents is, however, not unproblematic when one takes into account that diagnostic examinations of the heart are primarily carried out in the case of patients at risk, where any problematic substance should be avoided as far as possible. According to the research carried out by P.P. Singh et al., Arzneimittel-Forschung/Drug Research 32. (II) No. 1 1/1982, p. 1443 ff, it has been shown that propylene glycol in higher concentration ranges induces different neuropsychopharmacological effects in mice and rats. Other researchers report effects on blood pressure (Budden, R. et al., Arzneim.-Forschung 28/9: 1586
(1978) . (1978).
I betraktning av atConsidering that
1. ) Ultralydundersøkelse med kontrastmidler ofte kan være påkrevet med korte mellomrom, og at 2. ) de anvendte ultralyd-kontrastmidler utføres som bolus-injeksjon for såvidt mulig å motvirke for-tynningseffekten av det strømmende blod, 1. ) Ultrasound examination with contrast agents may often be required at short intervals, and that 2. ) the ultrasound contrast agents used are performed as a bolus injection to counteract the dilution effect of the flowing blood as far as possible,
kan det ikke utelukkes at de proplylenglykol-konsentrasjoner som når hjernen, ikke er ufarlige, særlig når det gjelder risikopasienter . it cannot be ruled out that the propylene glycol concentrations that reach the brain are not harmless, particularly when it comes to patients at risk.
Det forelå derfor den oppgave å finne frem til et ultralyd-kontrastmiddel som ved minst like høy effektivitet med hensyn til fargning av blodet i de undersøkte organer også kan anvendes uten propylenglykol. There was therefore the task of finding an ultrasound contrast agent which, with at least as high efficiency in terms of staining the blood in the examined organs, could also be used without propylene glycol.
Det ble overraskende funnet at det ved anvendelse av en flytende bærer som er vann, en fysiologisk elektrolyttoppløsning så som 0,9%ig vandig natriumkloridoppløsning, Ringer-oppløsning eller Tyrode-oppløsning eller en vandig oppløsning av maltose, dekstrose, laktose eller galaktose, uten tilsetning av viskosi-tetsforhøyende stoffer, så som eksempelvis propylenglykol, It was surprisingly found that by using a liquid carrier which is water, a physiological electrolyte solution such as 0.9% aqueous sodium chloride solution, Ringer's solution or Tyrode's solution or an aqueous solution of maltose, dextrose, lactose or galactose, without addition of viscosity-increasing substances, such as, for example, propylene glycol,
kan oppnås en like god eller bedre fargningskvalitet ved ultralyd-opptak av blodgjennomstrømmede organer (hjertet, årer). an equally good or better staining quality can be achieved by ultrasound recording of blood-perfused organs (heart, veins).
For fremstilling av midlet ifølge oppfinnelsen går man frem på den måte at man under sterile betingelser suspenderer de ifølge den fremgangsmåte som er beskrevet i den europeiske patentsøknad nr. 52 575 fremstilte mikropartikler av maltose, dekstrose, laktose eller galaktose, hvor galaktose foretrekkes, For the production of the agent according to the invention, one proceeds in such a way that, under sterile conditions, the microparticles of maltose, dextrose, lactose or galactose produced according to the method described in European patent application no. 52,575 are suspended, where galactose is preferred,
i en vandig oppløsning av maltose, dekstrose, laktose eller fortrinnsvis galaktose. in an aqueous solution of maltose, dextrose, lactose or preferably galactose.
Hvis den vandige oppløsning av maltose, dekstrose, laktose eller galaktose anvendes som flytende bærer, er konsentrasjonen opptil 30% (vekt%), hvorved konsentrasjonen avhenger av oppløseligheten av det anvendte sukker i vann. Eksempelvis anvendes det i tilfellet av laktose en vandig oppløsning med en konsentrasjon på opptil 25% (vekt%) og i tilfellet av galaktose en oppløsning med en konsentrasjon på opptil 30%, hvorved en 20%ig vandig oppløsning foretrekkes. If the aqueous solution of maltose, dextrose, lactose or galactose is used as liquid carrier, the concentration is up to 30% (wt%), whereby the concentration depends on the solubility of the sugar used in water. For example, in the case of lactose, an aqueous solution with a concentration of up to 25% (weight%) is used and in the case of galactose, a solution with a concentration of up to 30%, whereby a 20% aqueous solution is preferred.
En ytterligere fremgangsmåte for fremstillingen består i at mikropartiklene suspenderes i vann, i fysiologisk elektrolytt-oppløsning så som 0,9% vandig natriumkloridoppløsning, Ringer-oppløsning eller Tyrode-oppløsning, hvorved en del av mikropartiklene oppløses spontant, spesielt hurtig de mikropartikler som har de minste dimensjoner. A further method for the production consists in the microparticles being suspended in water, in a physiological electrolyte solution such as 0.9% aqueous sodium chloride solution, Ringer's solution or Tyrode's solution, whereby a part of the microparticles dissolves spontaneously, especially quickly the microparticles that have the smallest dimensions.
Sammenlignet med suspenderingen av mikropartiklene i en vandig oppløsning av maltose, dekstrose, laktose eller galaktose oppviser denne fremgangsmåte den fordel at man for fremstillingen av kontrastmidlet ifølge oppfinnelsen foruten mikropartiklene utelukkende behøver vann, hvilket kan oppbevares sterilt i lengre tid enn en vandig oppløsning av maltose, laktose, dekstrose eller galaktose. Compared to the suspension of the microparticles in an aqueous solution of maltose, dextrose, lactose or galactose, this method has the advantage that for the production of the contrast medium according to the invention, in addition to the microparticles, only water is needed, which can be kept sterile for a longer time than an aqueous solution of maltose, lactose, dextrose or galactose.
Anvendelsen av kontrastmidlet ifølge oppfinnelsen skjer etter den fremgangsmåte som er beskrevet i eksempel 7 i ovennevnte europeiske patentsøknad nr. 52 575. For å lette håndteringen under sterile betingelser er det hensiktsmessig at mikropartiklene og den flytende bærer holdes klar i adskilte sterile be-holdere (flasker, ampuller), og at den flytende bærer om nød-vendig uttas fra angjeldende beholder ved hjelp av injiserings-sprøyte og overføres til beholderen med mikropartiklene, blandingen rystes i ca. 5-10 sekunder, og den påkrevede mengde av suspensjonen uttas deretter og injiseres i en perifer vene, idet det anvendes 0,01 ml til 1 ml pr. kg legemsvekt. Straks etter kontrastmiddelinjiseringen følger injiseringen av 5 - 10 ml koksaltoppløsning for at kontrastmiddel-bolusen så langt det er mulig bibeholdes inntil hjertet er nådd. Ultralydmålingen og -undersøkelsen utføres som beskrevet i den europeiske patent-søknad . The use of the contrast agent according to the invention takes place according to the method described in example 7 in the above-mentioned European patent application no. 52 575. To facilitate handling under sterile conditions, it is appropriate that the microparticles and the liquid carrier are kept ready in separate sterile containers (bottles , ampoules), and that the liquid carrier is, if necessary, removed from the relevant container using an injection syringe and transferred to the container with the microparticles, the mixture is shaken for approx. 5-10 seconds, and the required amount of the suspension is then withdrawn and injected into a peripheral vein, using 0.01 ml to 1 ml per kg body weight. Immediately after the contrast agent injection, 5 - 10 ml of saline solution is injected so that the contrast agent bolus is maintained as far as possible until the heart is reached. The ultrasound measurement and examination is carried out as described in the European patent application.
De konsentrasjoner som er angitt i prosent, betyr alltid vekt/volum-prosent. The concentrations stated in percentage always mean weight/volume percentage.
EKSEMPEL 1EXAMPLE 1
a) Fremstilling av bærervæskena) Preparation of the carrier liquid
80 g galaktose oppløses i vann for injeksjonsformål og fylles 80 g of galactose is dissolved in water for injection purposes and filled
opp til et volum på 400 ml, presses gjennom et 0,2 ym filter, og 5 ml ampuller fylles med 5 ml av dette filtrat og steriliseres up to a volume of 400 ml, is pressed through a 0.2 µm filter, and 5 ml ampoules are filled with 5 ml of this filtrate and sterilized
1 20 minutter ved 120°C.1 20 minutes at 120°C.
b) Fremstilling av den bruksferdige kontrastmiddeloppløsning Innholdet i en ampulle med bærervæske (5 ml) tilsettes 2 g b) Preparation of the ready-to-use contrast medium solution Add 2 g to the contents of an ampoule of carrier liquid (5 ml)
galaktose-mikropartikler (fremstilt i henhold til europeisk patentsøknad 52575, eksempel 1), hvilke befinner seg i en 10 ml ampulle, og blandingen rystes i 5 - 10 sekunder. galactose microparticles (produced according to European patent application 52575, example 1), which are in a 10 ml ampoule, and the mixture is shaken for 5 - 10 seconds.
EKSEMPEL 2EXAMPLE 2
a) Fremstilling av bærervæskena) Preparation of the carrier liquid
Vann for injiseringsformål (5 ml) fylles på 5 ml ampuller og Water for injection purposes (5 ml) is filled into 5 ml ampoules and
steriliseres i 20 minutter ved 120°C.sterilized for 20 minutes at 120°C.
b) Fremstilling av den bruksferdige kontrastmiddeloppløsning Innholdet i en ampulle med bærervæske (vann, 5 ml) tilsettes 2 g galaktose-mikropartikler, hvilke befinner seg i en 10 ml ampulle, og rystes i 5 - 10 sekunder. b) Preparation of the ready-to-use contrast agent solution 2 g of galactose microparticles, which are in a 10 ml ampoule, are added to the contents of an ampoule of carrier liquid (water, 5 ml) and shaken for 5 - 10 seconds.
EKSEMPEL 3EXAMPLE 3
a) Fremstilling av bærervæskena) Preparation of the carrier liquid
For injiseringsformål oppløses 9 g natriumklorid i vann, opp-løsningen fylles opp til et volum på 1000 ml, presses gjennom et 0,2 ym filter, og 5 ml av dette filtrat fylles på 5 ml ampuller og steriliseres i 20 minutter ved 120°C. b) Fremstilling av den bruksferdige kontrastmiddeloppløsning Innholdet i en ampulle med bærervæske (5 ml 0,9%ig natrium-kloridoppløsning) tilsettes 2 g galaktose-mikropartikler som befinner seg i en 10 ml ampulle, og blandingen rystes i 5 - 10 sekunder. For injection purposes, 9 g of sodium chloride are dissolved in water, the solution is made up to a volume of 1000 ml, pressed through a 0.2 µm filter, and 5 ml of this filtrate is filled into 5 ml ampoules and sterilized for 20 minutes at 120°C . b) Preparation of the ready-to-use contrast agent solution The contents of an ampoule of carrier liquid (5 ml of 0.9% sodium chloride solution) are added to 2 g of galactose microparticles in a 10 ml ampoule, and the mixture is shaken for 5 - 10 seconds.
Claims (6)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833324754 DE3324754A1 (en) | 1983-07-06 | 1983-07-06 | ULTRASONIC CONTRASTING AGENTS AND THEIR PRODUCTION |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| NO842731L true NO842731L (en) | 1985-01-07 |
Family
ID=6203543
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO842731A NO842731L (en) | 1983-07-06 | 1984-07-05 | Ultrasonic contrast agent and method of preparation thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0131540A3 (en) |
| JP (1) | JPS6075437A (en) |
| DE (1) | DE3324754A1 (en) |
| NO (1) | NO842731L (en) |
Families Citing this family (45)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3637926C1 (en) * | 1986-11-05 | 1987-11-26 | Schering Ag | Ultrasonic manometry in a liquid using microbubbles |
| DE3741199A1 (en) * | 1987-12-02 | 1989-08-17 | Schering Ag | USE OF ULTRASONIC CONTRASTING AGENTS FOR ULTRASONIC LITHOTRIPSY |
| DE3741201A1 (en) * | 1987-12-02 | 1989-06-15 | Schering Ag | ULTRASONIC PROCESS AND METHOD FOR IMPLEMENTING IT |
| DE3803972A1 (en) * | 1988-02-05 | 1989-08-10 | Schering Ag | Ultrasound contrast media |
| IN172208B (en) * | 1990-04-02 | 1993-05-01 | Sint Sa | |
| US5578292A (en) | 1991-11-20 | 1996-11-26 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US5445813A (en) * | 1992-11-02 | 1995-08-29 | Bracco International B.V. | Stable microbubble suspensions as enhancement agents for ultrasound echography |
| US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| US7083778B2 (en) | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| USRE39146E1 (en) | 1990-04-02 | 2006-06-27 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
| US6989141B2 (en) | 1990-05-18 | 2006-01-24 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
| EP0531421B1 (en) * | 1990-06-01 | 1997-12-10 | Imarx Pharmaceutical Corp. | Contrast media for ultrasonic imaging |
| US5948387A (en) * | 1990-06-01 | 1999-09-07 | Imarx Pharmaceutical Corp. | Contrast media for ultrasonic imaging |
| US5420176A (en) * | 1990-06-01 | 1995-05-30 | Imarx Pharmaceutical Corp. | Contrast media for ultrasonic imaging |
| JP3247374B2 (en) * | 1990-10-05 | 2002-01-15 | ブラッコ インターナショナル ベスローテン フェンノートシャップ | A method for the production of stable suspensions of hollow gas-encapsulated microspheres suitable for ultrasound ecology |
| GB9107628D0 (en) * | 1991-04-10 | 1991-05-29 | Moonbrook Limited | Preparation of diagnostic agents |
| US5993805A (en) * | 1991-04-10 | 1999-11-30 | Quadrant Healthcare (Uk) Limited | Spray-dried microparticles and their use as therapeutic vehicles |
| GB9200391D0 (en) * | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
| GB9200387D0 (en) * | 1992-01-09 | 1992-02-26 | Nycomed As | Improvements in or relating to contrast agents |
| IL104084A (en) | 1992-01-24 | 1996-09-12 | Bracco Int Bv | Long-lasting aqueous suspensions of pressure-resistant gas-filled microvesicles their preparation and contrast agents consisting of them |
| US5302372A (en) * | 1992-07-27 | 1994-04-12 | National Science Council | Method to opacify left ventricle in echocardiography |
| GB9221329D0 (en) * | 1992-10-10 | 1992-11-25 | Delta Biotechnology Ltd | Preparation of further diagnostic agents |
| ES2068151B1 (en) | 1993-06-23 | 1995-11-16 | Cabrera Garrido Juan | INJECTABLE MICROS FOAM FOR SCLEROSIS. |
| US5798091A (en) | 1993-07-30 | 1998-08-25 | Alliance Pharmaceutical Corp. | Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement |
| DK0711179T3 (en) | 1993-07-30 | 2005-02-14 | Imcor Pharmaceutical Co | Stabilized ultrasound microbubble compositions |
| KR100295173B1 (en) | 1993-12-15 | 2001-09-17 | 엔. 토모브 | Gas Mixtures Useful as Ultrasonic Contrast Media |
| US5540909A (en) * | 1994-09-28 | 1996-07-30 | Alliance Pharmaceutical Corp. | Harmonic ultrasound imaging with microbubbles |
| GB9423419D0 (en) * | 1994-11-19 | 1995-01-11 | Andaris Ltd | Preparation of hollow microcapsules |
| DE19510690A1 (en) | 1995-03-14 | 1996-09-19 | Schering Ag | Polymeric nano- and / or microparticles, processes for their production, and use in medical diagnostics and therapy |
| US5804162A (en) | 1995-06-07 | 1998-09-08 | Alliance Pharmaceutical Corp. | Gas emulsions stabilized with fluorinated ethers having low Ostwald coefficients |
| US6017310A (en) * | 1996-09-07 | 2000-01-25 | Andaris Limited | Use of hollow microcapsules |
| US6068600A (en) * | 1996-12-06 | 2000-05-30 | Quadrant Healthcare (Uk) Limited | Use of hollow microcapsules |
| GB9800813D0 (en) | 1998-01-16 | 1998-03-11 | Andaris Ltd | Improved ultrasound contrast imaging method and apparatus |
| DE19813174A1 (en) * | 1998-03-25 | 1999-05-27 | Schering Ag | Gas-filled microparticles, used for administering biologically active substances |
| GB9912356D0 (en) | 1999-05-26 | 1999-07-28 | Btg Int Ltd | Generation of microfoam |
| US8512680B2 (en) | 2001-08-08 | 2013-08-20 | Btg International Ltd. | Injectables in foam, new pharmaceutical applications |
| EP1791519B1 (en) | 2003-11-17 | 2017-07-19 | BTG International Limited | Therapeutic foams with a sclerosant and a viscosity-improving agent, methods for its manufacturing |
| US8048439B2 (en) | 2003-11-17 | 2011-11-01 | Btg International Ltd. | Therapeutic foam |
| US9238127B2 (en) | 2004-02-25 | 2016-01-19 | Femasys Inc. | Methods and devices for delivering to conduit |
| US8052669B2 (en) | 2004-02-25 | 2011-11-08 | Femasys Inc. | Methods and devices for delivery of compositions to conduits |
| US8048101B2 (en) | 2004-02-25 | 2011-11-01 | Femasys Inc. | Methods and devices for conduit occlusion |
| US8048086B2 (en) | 2004-02-25 | 2011-11-01 | Femasys Inc. | Methods and devices for conduit occlusion |
| GB0509824D0 (en) | 2005-05-13 | 2005-06-22 | Btg Int Ltd | Therapeutic foam |
| US10070888B2 (en) | 2008-10-03 | 2018-09-11 | Femasys, Inc. | Methods and devices for sonographic imaging |
| US9554826B2 (en) | 2008-10-03 | 2017-01-31 | Femasys, Inc. | Contrast agent injection system for sonographic imaging |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4276885A (en) * | 1979-05-04 | 1981-07-07 | Rasor Associates, Inc | Ultrasonic image enhancement |
| US4265251A (en) * | 1979-06-28 | 1981-05-05 | Rasor Associates, Inc. | Method of determining pressure within liquid containing vessel |
| WO1982001642A1 (en) * | 1980-11-17 | 1982-05-27 | Med Inc Ultra | Microbubble precursors and methods for their production and use |
| DE3141641A1 (en) * | 1981-10-16 | 1983-04-28 | Schering Ag, 1000 Berlin Und 4619 Bergkamen | ULTRASONIC CONTRAST AGENTS AND THEIR PRODUCTION |
-
1983
- 1983-07-06 DE DE19833324754 patent/DE3324754A1/en not_active Withdrawn
-
1984
- 1984-07-02 JP JP59137865A patent/JPS6075437A/en active Pending
- 1984-07-05 NO NO842731A patent/NO842731L/en unknown
- 1984-07-05 EP EP84730075A patent/EP0131540A3/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| EP0131540A3 (en) | 1986-11-26 |
| JPS6075437A (en) | 1985-04-27 |
| DE3324754A1 (en) | 1985-01-17 |
| EP0131540A2 (en) | 1985-01-16 |
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