WO1996025954A1 - Verwendung von methylenmalondiesterderivaten zur herstellung von gashaltigen mikropartikeln für die ultraschalldiagnostik, sowie diese partikel enthaltende mittel - Google Patents
Verwendung von methylenmalondiesterderivaten zur herstellung von gashaltigen mikropartikeln für die ultraschalldiagnostik, sowie diese partikel enthaltende mittel Download PDFInfo
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- WO1996025954A1 WO1996025954A1 PCT/EP1996/000538 EP9600538W WO9625954A1 WO 1996025954 A1 WO1996025954 A1 WO 1996025954A1 EP 9600538 W EP9600538 W EP 9600538W WO 9625954 A1 WO9625954 A1 WO 9625954A1
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- Prior art keywords
- particles
- gas
- methylene
- ultrasound
- ultrasound diagnostics
- Prior art date
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- 239000002245 particle Substances 0.000 title claims abstract description 46
- 238000002604 ultrasonography Methods 0.000 title claims abstract description 18
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 9
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 title claims abstract description 8
- 150000005690 diesters Chemical class 0.000 title claims abstract description 6
- 239000011859 microparticle Substances 0.000 title description 6
- 239000007789 gas Substances 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 18
- -1 propinyl Chemical group 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 7
- 239000007853 buffer solution Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 5
- 229920006395 saturated elastomer Polymers 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 3
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 2
- 125000001033 ether group Chemical group 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000005448 ethoxyethyl group Chemical group [H]C([H])([H])C([H])([H])OC([H])([H])C([H])([H])* 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000004184 methoxymethyl group Chemical group [H]C([H])([H])OC([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 239000002961 echo contrast media Substances 0.000 abstract description 6
- 239000000243 solution Substances 0.000 description 14
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 8
- 229930195725 Mannitol Natural products 0.000 description 8
- 239000000594 mannitol Substances 0.000 description 8
- 235000010355 mannitol Nutrition 0.000 description 8
- 229920000136 polysorbate Polymers 0.000 description 7
- 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 description 6
- 239000008103 glucose Substances 0.000 description 6
- 239000002872 contrast media Substances 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000008363 phosphate buffer Substances 0.000 description 5
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 229940039231 contrast media Drugs 0.000 description 3
- 210000004185 liver Anatomy 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 210000000952 spleen Anatomy 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 150000005846 sugar alcohols Chemical class 0.000 description 3
- 210000001519 tissue Anatomy 0.000 description 3
- 229960003853 ultrasound contrast media Drugs 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 239000013543 active substance Substances 0.000 description 2
- 150000005215 alkyl ethers Chemical class 0.000 description 2
- 230000002009 allergenic effect Effects 0.000 description 2
- 239000001569 carbon dioxide Substances 0.000 description 2
- 229910002092 carbon dioxide Inorganic materials 0.000 description 2
- 210000002216 heart Anatomy 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 210000004072 lung Anatomy 0.000 description 2
- 229920000191 poly(N-vinyl pyrrolidone) Polymers 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229940068965 polysorbates Drugs 0.000 description 2
- 238000011002 quantification Methods 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 1
- SXAMGRAIZSSWIH-UHFFFAOYSA-N 2-[3-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,2,4-oxadiazol-5-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NOC(=N1)CC(=O)N1CC2=C(CC1)NN=N2 SXAMGRAIZSSWIH-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 238000012404 In vitro experiment Methods 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003570 air Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 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 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004581 coalescence Methods 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 238000004925 denaturation Methods 0.000 description 1
- 230000036425 denaturation Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 229940021013 electrolyte solution Drugs 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 238000005188 flotation Methods 0.000 description 1
- 238000004108 freeze drying Methods 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000178 monomer Substances 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 229910052756 noble gas Inorganic materials 0.000 description 1
- 150000002835 noble gases Chemical class 0.000 description 1
- 230000010355 oscillation Effects 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 229920002994 synthetic fiber Polymers 0.000 description 1
- 210000001835 viscera Anatomy 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
-
- 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
- A61K49/225—Microparticles, microcapsules
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J13/00—Colloid chemistry, e.g. the production of colloidal materials or their solutions, not otherwise provided for; Making microcapsules or microballoons
- B01J13/02—Making microcapsules or microballoons
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S977/00—Nanotechnology
- Y10S977/902—Specified use of nanostructure
- Y10S977/904—Specified use of nanostructure for medical, immunological, body treatment, or diagnosis
- Y10S977/927—Diagnostic contrast agent
- Y10S977/929—Ultrasound contrast agent
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
Definitions
- Methylenmalondiesterderivaten for the production of gas-containing microparticles for the
- the invention relates to the subject matter characterized in the claims, that is to say the use of asymmetrical or symmetrical methylene maloniester derivatives for the production of gas-containing microparticles and contrast media containing these particles for ultrasound diagnostics.
- Ultrasound diagnostics have found widespread use in medicine because of the simple, uncomplicated handling. Ultrasonic waves are reflected at interfaces from different types of tissue. The resulting echo signals are electronically amplified and made visible.
- the representation of blood vessels and internal organs by means of ultrasound generally does not allow the representation of the blood flow contained therein. Liquids, especially blood, only provide ultrasound contrast if there are differences in density and compressibility to the environment.
- As a contrast medium in medical ultrasound diagnostics e.g. Gas-containing or gas-producing substances are used, since the impedance difference between gas and surrounding blood is considerably greater than that between liquids or solid bodies and blood (Levme RA, J. Am. Coll. Cardiol 3: 28, 1 989, Machi IJ CU 1 1: 3, 1 983).
- cardiac echo contrasts can be achieved by peripheral injections of solutions containing fine gas bubbles (Roelandt J, Ultrasound Med. Biol. 8: 471-492, 1 982).
- These gas bubbles are in physiologically contractual solutions e.g. obtained by rubble, other agitation or by adding carbon dioxide.
- They are not standardized in number and size and can only be reproduced inadequately. They are also usually not stabilized, so that their lifespan is short.
- Their mean diameters are usually larger than erythrocytes, so that no lung capillary passage with subsequent contrasting of organs such as the left heart, liver, kidney or spleen is possible
- EP 0 1 31 540 describes the stabilization of the gas bubbles by sugar. Although this improves the reproducibility and homogeneity of the contrast effect, these bubbles do not survive passage through the lungs.
- EP 0 1 22 624 and 0 1 23 235 describe that the gas bubble-stabilizing effect of sugars, sugar alcohols and salts is improved by the addition of surface-active substances.
- the contrast effect is limited to the vessel lumen, since the vesicles are not absorbed by the tissue cells.
- Encapsulation of gases such as air as an ultrasound contrast medium, is described in EP 0 224 934.
- the wall material used here consists of protein, in particular human serum albumin with the known allergenic properties, to which cytotoxic effects can be added by denaturation.
- EP 0 327 490 and EP 0 458 745 describe gas-containing microparticles for ultrasound diagnostics based on biodegradable, synthetic materials. These agents have a sufficient in vivo lifespan and are enriched intravenously during intracellular administration in the reticuloendothehal system and thus also in the liver or spleen
- the object of the present invention was to provide contrast media for ultrasound diagnostics which have the disadvantages of the prior art overcome, ie to develop ultrasound contrast media based on microparticles that
- gas-filled particles consisting of polymerized asymmetrical or symmetrical methylene malonic esters of the general formula I
- radicals R ⁇ and R ⁇ may be the same or different and represent saturated or unsaturated groups containing 1 to 8 carbon atoms, which may contain oxygen atoms (ether groups) and carboxyl groups (esters), are outstandingly suitable as contrast agents for ultrasound diagnostics
- the preferred methylene malonic ester is ⁇ 2 -
- the gases contained in the particles are air, nitrogen, oxygen, noble gases, carbon dioxide and fluorocarbons.
- the particles have an average size in the range from 500 nm to 7 ⁇ m.
- the wall thickness can be influenced by the manufacturing processes, it is possible to produce particles whose oscillation modes can be excited by the sound field, so that a further additional component is involved in the contrasting
- Another aspect of the invention relates to methods for producing the particles according to the invention.
- the particles according to the invention are prepared on the basis of asymmetrical or symmetrical methylene malonic esters by dispersing the desired monomeric methylene malonic ester in an aqueous gas-saturated buffer solution, which optionally contains one or more surface-active substance (s), with a Ruhrer after the polymerization has taken place (about 2 - 6 hours) the particles obtained, optionally washed with water, then taken up in a pharmaceutically acceptable suspension medium and freeze-dried.
- aqueous gas-saturated buffer solution which optionally contains one or more surface-active substance (s)
- s surface-active substance
- Possible surface-active substances optionally added to the reaction process are substances (s) from the group of the Poloxamere®, Polysaccha ⁇ de, Polysorbate, sucrose mono or diester, polyethylene glycol alkyl ether and mixtures thereof
- the pH of the aqueous gas-saturated buffer solution is preferably between 5 and 8.
- the particles are separated off by flotation
- the separated particles are then washed, resuspended in a suspension medium and lyophilized.
- Water is suitable as a suspension medium for injection purposes, if appropriate with the addition of sodium chloride and / or glucose and / or mannitol and / or lactose optionally additionally contains a surface-active substance, such as, for example, polysaccharides, polysorbates, Poloxamere®, sucrose mono- or diester or polyethylene glycol alkyl ethers and mixtures thereof.
- the ready-to-use, injectable ultrasound scanning agents are prepared from the freeze-dried particles by resuspending the lyophilisate in a pharmaceutically acceptable suspension medium such as e.g. Water p.i., aqueous solutions of one or more inorganic salts such as physiological electrolyte solutions and buffer solutions such as e.g. Tyrode, aqueous solutions of mono- or disacchants such as glucose or lactose, sugar alcohols such as mannitol, which may also contain a surface-active substance, e.g.
- a pharmaceutically acceptable suspension medium such as e.g. Water p.i., aqueous solutions of one or more inorganic salts such as physiological electrolyte solutions and buffer solutions such as e.g. Tyrode, aqueous solutions of mono- or disacchants such as glucose or lactose, sugar alcohols such as mannitol, which may also contain a surface-active substance, e.g.
- the preferred suspension medium is water suitable for injection purposes.
- the total concentration of any dissolved substances is 0 - 1 5 percent by weight.
- An alternative process for the production of the ready-to-use, injectable preparations consists in that in a process according to the invention - for the production of the particles - the final freeze-drying is dispensed with.
- the suspension can be filtered immediately before injection.
- Methylene malonic ester derivatives are known from the literature and are described, for example, in DE-PS 27 34 082; U.S. Patent 4,931,584, J. Org. Chem. __, 3603 (1,983) and in Macromulecular Chemistry 1QZ, 4-5 (1,967).
- example 1 Methylene malonic ester derivatives are known from the literature and are described, for example, in DE-PS 27 34 082; U.S. Patent 4,931,584, J. Org. Chem. __, 3603 (1,983) and in Macromulecular Chemistry 1QZ, 4-5 (1,967). example 1
- 1 ml of diethyl methylidene emalonate is mixed in 100 ml of 0.01 m phosphate buffer pH 7.4, which contains 1% Dextran-8 (Serva, Fembiochemica GmbH & Co.), with a stirrer (Dispermat-FT, VMA-Getzmann GmbH) at 20 ° C, Dispersed at 10,000 rpm for 60 minutes.
- the reaction mixture is then transferred to a flask equipped with a stirrer and further polymerized for 6 hours at room temperature with stirring (300 rpm).
- the ultrasound-active, gas-filled nano- or microparticles are separated by floatation, washed several times with water or 0.9% NaCl solution and taken up in 200 ml of an aqueous solution of 1% dextran-8.
- the particles have an average size of 800 nm and show excellent ultrasound activities.
- Example (1) The procedure is as in Example (1), the buffer system having a pH of 8.0 and dextren-8 being replaced by dextran-10.
- the particles have an average size of 700 nm.
- the particles are taken up in 1,50 ml, 5% mannitol solution, which contains OJ% dextran.
- Example (1) Procedure is as in Example (1), wherein the buffer system having a pH of 7.4 and Dextren-8 is replaced by Polyvinylpyro don Kol don ® PF-1. 7
- the particles have an average size of 1.3 ⁇ m. The particles are taken up in 1 50 ml. 5% glucose solution containing OJ% Kollidon ® PF-1 7.
- Example 4 The procedure is as in Example (1), with dextran-8 being replaced by Br ⁇ j * -35.
- the particles have an average size of 2.0 ⁇ m.
- the particles are taken up in 1 50 ml, 0.5% glucose solution containing 1% Br ⁇ j ® -35.
- Example 6 The procedure is as in Example (1), with dextran-8 being replaced by Br ⁇ j ⁇ -96.
- the particles have an average size of 2.0 ⁇ m.
- the particles are taken up in 1 50 ml, OJ% ⁇ ger Br ⁇ j ⁇ -96 solution.
- Example (1) The procedure is as in Example (1), with dextran-8 being replaced by the 2% Tween * -20.
- the particles are taken up in 1 50 ml, 5% mannitol solution containing OJ% Tween ⁇ -20.
- the particles have an average size of 1.0 ⁇ m.
- Example 7 1 ml of monomer "1-ethoxycarbonyl, 1-ethoxycarbonylmethylene oxycarbonylethane" are dissolved in 100 ml of aqueous phosphate buffer (KH 2 P0 4 / Na 2 HP0 4 , 0.066 N, pH 5, 5), the 1% dextran-8 (Serva, Feinbiochemica GmbH & Co.) contains, with a stirrer (Disperment FT, Getzmann GmbH), dispersed at 20 ° C for 60 minutes at 8000 rpm. The reaction mixture is then transferred to a flask equipped with a stirrer and further polymerized for 6 hours at room temperature with stirring (300 rpm).
- aqueous phosphate buffer KH 2 P0 4 / Na 2 HP0 4 , 0.066 N, pH 5, 5
- the 1% dextran-8 contains, with a stirrer (Disperment FT, Getzmann GmbH), dispersed at 20 ° C for 60 minutes at 8000 rpm
- the ultrasound-active or gas-filled nano or particles are either separated by floatation or centrifugation, washed several times with water and taken up in 200 ml, 5% mannitol solution, which contains OJ% dextran-8.
- the particles have an average size of 1.5 ⁇ m and show excellent ultrasound activities.
- Example (7) The procedure is as in Example (7), the phosphate buffer having a pH of 6.0.
- the particles have an average size of 1.0 ⁇ m.
- Example 9 The procedure is as in Example (7), the phosphate buffer having a pH of 6.5.
- the particles have an average size of 1.2 ⁇ m.
- Example 1 The procedure is as in Example (7), the phosphate buffer being replaced by the citric acid (OJ m) / Na 2 HP0 4 (0.2 m) buffer of pH 5.5.
- the particles have an average size of 1.0 ⁇ m.
- Example (7) The procedure is as in Example (7), with dextran-8 being replaced by dextran-10.
- the particles have an average size of 0.8 ⁇ m.
- the particles are taken up in 200 ml, 5% glucose solution containing 5% dextran-10.
- Example (7) The procedure is as in Example (7), with dextran-8 being replaced by 3% polyvinylpyrolidone PF-1 7.
- the particles have an average size of 1.5 ⁇ m.
- the particles are taken up in 200 ml, 5% mannitol solution, the 0.5% Kollidon ® PF-1 7.
- Example (7) The procedure is as in Example (7), the dextran-8 being replaced by the 3% Tween * - 80.
- the particles have an average size of 1.2 ⁇ m.
- the particles are taken up in 200 ml, 5% glucose solution.
- Example (7) The procedure is as in Example (7), with dextran-8 being replaced by the 2% Tween * -40.
- the particles have an average size of 1.0 ⁇ m. These particles are taken up in 1,50 ml, 5% mannitol solution.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Radiology & Medical Imaging (AREA)
- Epidemiology (AREA)
- Physics & Mathematics (AREA)
- Organic Chemistry (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US08/894,593 US6106807A (en) | 1995-02-23 | 1996-02-09 | Use of methylenemalondiester derivatives for the production of gas-containing microparticles for ultrasound diagnosis, as well as media that contain said particles |
JP8525343A JPH11500435A (ja) | 1995-02-23 | 1996-02-09 | 超音波診断用のガス含有微小粒子を製造するためのメチレンマロン酸ジエステル誘導体の使用、及びこの粒子を含有する薬剤 |
EP96904032A EP0804250A1 (de) | 1995-02-23 | 1996-02-09 | Verwendung von methylenmalondiesterderivaten zur herstellung von gashaltigen mikropartikeln für die ultraschalldiagnostik, sowie diese partikel enthaltende mittel |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19508049A DE19508049C2 (de) | 1995-02-23 | 1995-02-23 | Verwendung von Methylenmalondiesterderivaten zur Herstellung von gasenthaltenden Mikropartikeln |
DE19508049.1 | 1995-02-23 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996025954A1 true WO1996025954A1 (de) | 1996-08-29 |
Family
ID=7755924
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/000538 WO1996025954A1 (de) | 1995-02-23 | 1996-02-09 | Verwendung von methylenmalondiesterderivaten zur herstellung von gashaltigen mikropartikeln für die ultraschalldiagnostik, sowie diese partikel enthaltende mittel |
Country Status (6)
Country | Link |
---|---|
US (1) | US6106807A (de) |
EP (1) | EP0804250A1 (de) |
JP (1) | JPH11500435A (de) |
CA (1) | CA2213615A1 (de) |
DE (1) | DE19508049C2 (de) |
WO (1) | WO1996025954A1 (de) |
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WO1999055309A1 (fr) * | 1998-04-29 | 1999-11-04 | Virsol | Nouvelles microspheres a base de poly(methylidene malonate), leur procede de preparation et compositions pharmaceutiques les contenant |
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- 1996-02-09 CA CA002213615A patent/CA2213615A1/en not_active Abandoned
- 1996-02-09 US US08/894,593 patent/US6106807A/en not_active Expired - Fee Related
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- 1996-02-09 JP JP8525343A patent/JPH11500435A/ja active Pending
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Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR2774096A1 (fr) * | 1998-01-29 | 1999-07-30 | Virsol | Nouveaux copolymeres tensioactifs a base de methylidene malonate |
WO1999038898A1 (fr) * | 1998-01-29 | 1999-08-05 | Virsol | Nouveaux copolymeres tensioactifs a base de methylidene malonate |
AU744995B2 (en) * | 1998-01-29 | 2002-03-07 | Virsol | Novel surfactant copolymers based on methylidene malonate |
CN1114633C (zh) * | 1998-01-29 | 2003-07-16 | 维赫索拉公司 | 基于1,1-亚甲基丙二酸酯的新型表面活性剂共聚物 |
US6750298B1 (en) | 1998-01-29 | 2004-06-15 | Virsol | Surfactant copolymers based on methylidene malonate |
WO1999055309A1 (fr) * | 1998-04-29 | 1999-11-04 | Virsol | Nouvelles microspheres a base de poly(methylidene malonate), leur procede de preparation et compositions pharmaceutiques les contenant |
FR2778100A1 (fr) * | 1998-04-29 | 1999-11-05 | Virsol | Nouvelles microspheres a base de poly(methylidene malonate), leur procede de preparation et compositions pharmaceutiques les contenant |
AU752644B2 (en) * | 1998-04-29 | 2002-09-26 | Virsol | Novel poly(methylidene malonate) microspheres, preparation method and pharmaceutical compositions containing them |
Also Published As
Publication number | Publication date |
---|---|
JPH11500435A (ja) | 1999-01-12 |
CA2213615A1 (en) | 1996-08-29 |
DE19508049C2 (de) | 1997-02-06 |
EP0804250A1 (de) | 1997-11-05 |
DE19508049A1 (de) | 1996-09-12 |
US6106807A (en) | 2000-08-22 |
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