CA2077383A1 - Echogenic particles, a process for their production and their use - Google Patents
Echogenic particles, a process for their production and their useInfo
- Publication number
- CA2077383A1 CA2077383A1 CA002077383A CA2077383A CA2077383A1 CA 2077383 A1 CA2077383 A1 CA 2077383A1 CA 002077383 A CA002077383 A CA 002077383A CA 2077383 A CA2077383 A CA 2077383A CA 2077383 A1 CA2077383 A1 CA 2077383A1
- Authority
- CA
- Canada
- Prior art keywords
- echogenic
- particle
- particles
- acid
- substance
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
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- 238000001816 cooling Methods 0.000 description 1
- PYRZPBDTPRQYKG-UHFFFAOYSA-N cyclopentene-1-carboxylic acid Chemical compound OC(=O)C1=CCCC1 PYRZPBDTPRQYKG-UHFFFAOYSA-N 0.000 description 1
- 229940119744 dextran 40 Drugs 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 150000001991 dicarboxylic acids Chemical class 0.000 description 1
- XEBCWEDRGPSHQH-UHFFFAOYSA-N diisopropyl tartrate Chemical compound CC(C)OC(=O)C(O)C(O)C(=O)OC(C)C XEBCWEDRGPSHQH-UHFFFAOYSA-N 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- BMBDJILYIZBBMQ-UHFFFAOYSA-N furan-2,3-dicarbonyl chloride Chemical class ClC(=O)C=1C=COC=1C(Cl)=O BMBDJILYIZBBMQ-UHFFFAOYSA-N 0.000 description 1
- DNXDYHALMANNEJ-UHFFFAOYSA-N furan-2,3-dicarboxylic acid Chemical compound OC(=O)C=1C=COC=1C(O)=O DNXDYHALMANNEJ-UHFFFAOYSA-N 0.000 description 1
- ZZUFCTLCJUWOSV-UHFFFAOYSA-N furosemide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC(C(O)=O)=C1NCC1=CC=CO1 ZZUFCTLCJUWOSV-UHFFFAOYSA-N 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 239000001307 helium Substances 0.000 description 1
- 229910052734 helium Inorganic materials 0.000 description 1
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- DNZMDASEFMLYBU-RNBXVSKKSA-N hydroxyethyl starch Chemical compound OC[C@H]1O[C@H](O)[C@H](O)[C@@H](O)[C@@H]1O.OCCOC[C@H]1O[C@H](OCCO)[C@H](OCCO)[C@@H](OCCO)[C@@H]1OCCO DNZMDASEFMLYBU-RNBXVSKKSA-N 0.000 description 1
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 238000010191 image analysis Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 239000012280 lithium aluminium hydride Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 150000002739 metals Chemical class 0.000 description 1
- 239000000693 micelle Substances 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 210000004165 myocardium Anatomy 0.000 description 1
- VGGNVBNNVSIGKG-UHFFFAOYSA-N n,n,2-trimethylaziridine-1-carboxamide Chemical compound CC1CN1C(=O)N(C)C VGGNVBNNVSIGKG-UHFFFAOYSA-N 0.000 description 1
- 229940075566 naphthalene Drugs 0.000 description 1
- KQSABULTKYLFEV-UHFFFAOYSA-N naphthalene-1,5-diamine Chemical compound C1=CC=C2C(N)=CC=CC2=C1N KQSABULTKYLFEV-UHFFFAOYSA-N 0.000 description 1
- GOGZBMRXLADNEV-UHFFFAOYSA-N naphthalene-2,6-diamine Chemical compound C1=C(N)C=CC2=CC(N)=CC=C21 GOGZBMRXLADNEV-UHFFFAOYSA-N 0.000 description 1
- 229910052754 neon Inorganic materials 0.000 description 1
- GKAOGPIIYCISHV-UHFFFAOYSA-N neon atom Chemical compound [Ne] GKAOGPIIYCISHV-UHFFFAOYSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- YVOFTMXWTWHRBH-UHFFFAOYSA-N pentanedioyl dichloride Chemical compound ClC(=O)CCCC(Cl)=O YVOFTMXWTWHRBH-UHFFFAOYSA-N 0.000 description 1
- HCTVWSOKIJULET-LQDWTQKMSA-M phenoxymethylpenicillin potassium Chemical compound [K+].N([C@H]1[C@H]2SC([C@@H](N2C1=O)C([O-])=O)(C)C)C(=O)COC1=CC=CC=C1 HCTVWSOKIJULET-LQDWTQKMSA-M 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 125000003170 phenylsulfonyl group Chemical group C1(=CC=CC=C1)S(=O)(=O)* 0.000 description 1
- UHZYTMXLRWXGPK-UHFFFAOYSA-N phosphorus pentachloride Chemical compound ClP(Cl)(Cl)(Cl)Cl UHZYTMXLRWXGPK-UHFFFAOYSA-N 0.000 description 1
- FAIAAWCVCHQXDN-UHFFFAOYSA-N phosphorus trichloride Chemical compound ClP(Cl)Cl FAIAAWCVCHQXDN-UHFFFAOYSA-N 0.000 description 1
- 239000003058 plasma substitute Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229920000729 poly(L-lysine) polymer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000001878 scanning electron micrograph Methods 0.000 description 1
- 210000003491 skin Anatomy 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000000935 solvent evaporation Methods 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- SEEPANYCNGTZFQ-UHFFFAOYSA-N sulfadiazine Chemical compound C1=CC(N)=CC=C1S(=O)(=O)NC1=NC=CC=N1 SEEPANYCNGTZFQ-UHFFFAOYSA-N 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229940086542 triethylamine Drugs 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 238000009834 vaporization Methods 0.000 description 1
- 230000008016 vaporization Effects 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 230000002861 ventricular Effects 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
- 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
- A61K49/00—Preparations for testing in vivo
-
- 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
Abstract
Abstract of the disclosure HOE 91/F 277JK
Echogenic particles, a process for their production and their use The present invention describes echogenic particles having a smooth surface and/or echogenic particles having 1 to 10 concave surface segments, their production by spray drying and their use as an ultrasonic diagnostic agent.
Echogenic particles, a process for their production and their use The present invention describes echogenic particles having a smooth surface and/or echogenic particles having 1 to 10 concave surface segments, their production by spray drying and their use as an ultrasonic diagnostic agent.
Description
2~73~
HOECHST AKTIEMGESELLSCHAFT HOE 91/~ 277 JK Dr.TH/PL
Description Echogenic particles, a process for theix production and their use The invention relates to echogenic particles which comprise a gas and a shaping substance, wherein the surface of the particles is essentially smooth and the shape comprises no or 1 to 10 conca~e ~urface segments, or the surface is not smooth and the shape comprises 1 to 10 concave surface segmen~s, and which can pass through the lung in the blood circula~ion, a spray process for their preparation and their use, in particular a3 diag-nostic agents and therapeutic agents.
: Because it is easy to handle and has no complications, ultrasonic diagnosis has found wide use in medicine.
Ultrasonic waves are reflected at the boundarie~ of different types of tissue. The resulting echo 3ignal8 are amplified and visualized electronically.
The visualization of blood vessels and internal organs by ultrasound generally does not allow visualization of the ~: blood flow present therein. Fluids, especially blood, produce an ultrasonic contrast only if there are density : differences with respect ~o the environment. Contras~
media which are used in medical ultrasonic diagnosis are, for example, substances which comprise gases or produce gases, since the difference in impedance between the gas and ~urrounding blood is considerably ~reater than that between fluids or solids and blood (Le~ine R.A.f J. Am.
Coll. Cardiol 3: ~8, 1989; and Machi, i.J. CU 11: 3, 30 1983~.
Several methods for the preparation and stabilization of gas bubbles are known in the literature.
2 o ~ rl ~ ~ 3 -- 2 ~
U.S. Patent 4,276,885 describes the prepara~ion of gas bubbles of defined size, which are surrounded by a gelatin shell which protects the ga~ bubbles from merging. The finished gas bubbles can ~e stored only in the frozen state, and ~he gas bubbles have ko be brought to body temperature again before use.
EP-A2-0,123,235 and 0,122,624 describe gas-containing ultrasonic contrast media which comprise mixtures of surface-active substances with a solid in a liquid carrier. The ultrasonic contras$ media are prepared by an expensive grinding process with an air jet mill. The particles thus produced have only a short u6eful life, because they guickly lose the gases included.
EP-A2-0,224,934 describes ultrasonic contrast media in the form of gas-filled hollow bodies of gelatin or albumin. However, the use of proteins forei~n to the body or denatured endogenous proteins i~ a disadvantage, because of the associated allergenic risk.
The present invention is based on the object of discovering echogenic particles which refle t, absorb, diffract or scatter ultrasonic waves and in this way produce a significant contrast to the surro~nding tissue, which are so small and stable that, after intravenous administration, they reach the left ventricle without substantial 105s of gas and essentially guantitatively, and which can be produced quickly and easily.
It has been found that the quality of echogenic particles depends in particular on the shape and surface of ~hese particles. It i~ found that echogenic particles having concave surface segments can pass through the lung in the blood circulation considerably better and effect a higher contrast in ultrasound. These echogenic parti~les com-prise an air/water boundary, the scattering cross-section of which in ultrasonic examinations i8 very high.
~` .
2~7~3~3 Echogenic particl~s having an essentially smooth surface can pass through the lungs of vertebrate~ in the blood circulation without the particles being filtered ou~ to a great extent.
The invention thus relates to echogenic particles which comprise a gas and a shaping subs~ance or a substance mixture, which is biologically degradable and/or excret-able, and which can pa~s through the lung of vertebrates in the blood circulation, wherein the ~urface of the echogenic particle i~ essentially smooth and the shape of the Pchogenic particle comprises no or 1 to 10 concave surface segments, or the surface of the echogenic par-ticle is no~ smooth and the ~hape of ~he echogenic particle comprises 1 to 10 concave surface segments.
~chogenic par~icles are particle~ ha~ing a diameter which : ranges from 0.1 ~m to 20 ~m, preferably 0.2 ~m to 7 ~m, in particular from 0,5 ~m to 3 ~,m, in 90% of the par-~ ticles. These paxticles furthermore ar~ capable of ; reflecting, absorbing, diffracting or ~cattering sound waves.
Concave surface segment of an echogenic particle means a particle which has at least one surface curved inwards.
The particles according to the invention include, for example, particles in which the maximum curve inwards, that is to say the depth of the conca~e surface segment, is more than 10% of the smallest cross-sec~ion of the particle, the curve inwards particularly preferably being 30 to 90%, in particular 50 to gO~0 This thus essentially means particles which look cup~, hat- or pot-shaped.
The number of concave ~urface ~e~ments ranges from 1 to 10, preferably 1 to 5, in particular 1 ~o 3.
The paxticle~ can also have a smooth surface. An essen-tially smooth surface of an echogenic particle means - 4 - ~ ~7~3 surface~ which reveal no structural differences at all on the surface under lO,OOO fold magnification, i.e. distur-bances on the surface of these particles, such as eleva-tions or depressions, are essentially at a distance of less than 100 nm from the average fiurface of the particle, in par~icular 90 to 50 nm, preferably 60 to 80 ~m. The average par~icle surface i8 obtained from the average of the elevations and depressions of the surface.
Disturbances in the ~urface include changes in the homogeneous surface which, in an electron microscopy photograph, look like elevations, fractures, distortions, a ladder-, step-, scale or layer-like build up of the surface and holes, depressions or pores in the surfaGe.
The property of the particles according to the invention of being able to pass through the lung of vertebrates in the blood circulation is determined, for example, by injecting the echogenic particles into a peripheral vein of a test animal under s~erile conditions. An ultrasonic head of an ultrasonic unit is held on the thorax of th~
test animal, so that a typical cross-section through the right and left ventricle i6 obtained. As soon as the ul~rasonic contrast medium reaches the right ventricle, it can be seen on the monitor of the ultrasonic unit how the blood labeled by the contrast medium reaches the right auricle and then leaves the right ventricle and then ~he heart again via the pulmonary axtery. After passage through the lung, a significant increase in contrast due to the contrast medium is detectable in the left ventricle.
The echogenic particles compris~ gas, for example air, nitrogen, a noble gas such as helium, neon, argon or kryptonJ hydrogen, carbon dioxide, oxygen, or mi~ures thereof. The echogenic particle~ are charged with a ga~
by, for example, storing the particles in an appropriate gas atmosphere or obtaining the particles directly by spray drying during production in an appropriate 2~77~83 gas atmosphere.
Shaping ~ubs~ances or sub~tance mixtures are understood as meaning all compounds with which particles ~an be pr~duced O
These include, for example~ naturally occurring polymers or polymers which can be prepared by synthesis, lipids which form micelles in agueous solutions, or low mole~
cular weight amino acids, fats, or carbohydrates.
Biologically degradable and/or excretable shaping sub-stance or substance mixtur~ is und~rstood as meaning substances which are converted into non~toxic degradation products in th~ body of anLmals, humans or plants, or are excreted. The degradation can take place enzymaticallyJ
hydrolytically or by partial or complete solution of the substances or disintegration of the particles into smaller sub-units in water. The degradation product~ are excreted via the kidneys, skin, lungs or in~estine. If the su~stances dissolve completely or partly in water or arP not degraded, for ex~mple in the ca~e of low mole-cular weight carbohydrates, they are excreted via thekidneys without degradation.
Shaping substances or substance mixture~ which are biologically degradable a~d/or excretable are chosen from the following groups:
25 polyesters of an ~ or ~-hydroxycarbo~ylic acid, for example poly-~-caprolactone, polyhydroxybutyric acid, polylactic acid or polyhydroxyvaleric acid, copolymers of the abovementioned polyester% with one another or with polyglycolic acid, polycondeDsate~ which comprise 2,3-O-alkylidenetartaric acid, 2,3-O-alkylidene-L~threitol, furo-[2,5] group~ or terephthalates, 2~77~3 polyaminodicarboxylic acid co-imides, such a8 polysuccin-Lmide-co~ -(butoxycarbonylpropion ethyl)-D,~-aspartamide, polyamino acid6, such a~ polyglutamic acid, poly~spartic ; S acid or polylysine, which give a basic or acid reac~ion in aqueous solution~ and derivatives thereof, polyamide~ t for axample polylysine mathyl ester-fumaric acid-co glutar~mide or poly~
hydroxyethylaspartamide, `: polyortho esters, polyanhydride~ for example those which are compo~ed of ; sebacic acid and bis(p-carboxyphenoxy)-propane, 15 gelatin, for example hydrophobically modified gelatin, albumins, for example bovine ~erum albumin, poly~accharide~, for example dextrans, starch or basic or :~ acid deriva~ives thereof, polymethylene malonate, : ~ugars, for example glucose, galactose, lacto~e or Bucrose ~
fatty acids having 8 to 20 carbon ~toms, amino acid~, ~uch as proteinogenic amino acids ~nd hydrophobic derivatives thereof, alcohols having 12 to 20 carbon atoms and lipids, such as phospholipids.
The echoyenic particles according to the invention particularly preferably compri~e biologically degradable ~ 30 andJor excretable polymers from the following group:
: polyamides, polycondensates, polyh~droxybutyric acid and ~ poly~minodicarboxylic acid co-imides.
: ~.
The abovementioned shaping substances or substance mixture~ can be prepared by processe~ which are known 35 from the litarature (EP-0,327,490; EP-0,398,935;
~ .
, 2~773~3 EP-0,458,079; EP-0,123,235; EP-0,~24,934; EP-0,245,8~0, M. Bornschein et al., Die Pharmazie, 49, Volume 9, 1989, page 585ff.; J.W. Freytag, J. Microencapsulation~ 2, Volume 1, 1985, pages 31-38, Y. Kawashima et al. 7 J. Phanmaceutical Sciences, 81, Volume 2, lg92, page 135ff., EP OtO77,752 and EP 0,131,540).
The abovementioned polycondensates essentially contain at least 95 mol% of recurring structural units of the fo~mula I
O O
[-C-R'-C-X-R2 X-] (I~
in which Rl is : a) a compound of the formula II
--C--C--0 \ / 0 (II) R5 R~
in which Rs and R6 zre inert radicals, b) straight-chain or branched alkyl, alkenyl, ~` cycloalkyl or cycloalkenyl, which can be substituted b~ one or more inert radicals, c) aryl which is mono- or polynuclear and mono- or polysubstituted by inert radicals, d) compounds of the formula V
~o~ (V) ~' .
- 8 20773~3 or e) a heterocyclic radical; which can be mono- or polynu~lear and c~n be mono- or polysubstituted by inert radicals, 1 5 in which ~ is a) O-, b) -NH-- or c ) --S--, :
in which R2 iS
a) a compound of the formula III
\ / ~III) in which R5 and R6 have the abovementioned meaning, b) straight-chain or branched alkyl, alkenyl, cycloalkyl or cycloalkenyl, which can be substituted by one or more inert radicals, c) mono- or polynuclaar aryl, which i8 mono- or polysubstituted by inert radical6, d) a heterocyclic radical, which can be mono- or polynuclear and can be mono- or polysubstituted by inert radicals, or ~3 a compound of the formula VI
H H
--C - C--o = c c o (YI~
~ I I
o o ~: 1 5 1 6 20~73~
_ 9 _ in which Rs and R6 have ~he abovementioned meaning, wi~h the proviso ~hat ~he polycondensa~e of the formula I con~ains more than 5 mol% of the radicals R1 andior R2, S in which Rl is a compound of the formula II and/or R2 i8 a compound of the formula III, or that the polycondensate of the formula I comprises more than S mol% of the radicals R1 and ~2, in which a) R1 i5 a compound of the formula ~ and R2 is a compound of ~he formula VI, or b) R1 is phenyltl,2], phenylll,3] or phenyl[1,4]
and R2 is a compound of the formula VI.
The term "inert radicals~ is understood as meaning substances which do not react with one another or are prevented from reacting with one another by protective groups under the preparation and processing conditions for the polycondensates according to the invention. Inert radicals can be, for example, inorganic radicals, such as halogen, or organic radicals, ~uch as alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy or dialkylaminoalkyl.
:
Functional groups which are prevented from reaction by protective groups ara, for example, amino or hydroxyl.
Xnown protective groups are, for example, the benzyloxy or phenylsulfonyl group.
Heterocyclic radicals can be mono- or polynuclear and contain, in particular, one or two oxygen, nitrogen or sulfur atoms in the nucleus.
Aryl is an aromatic carbon ring. Polynuclear aryl radicals can ba fused to one another or bonded to one another linearly via C-C bon~s or via bridge groups, such as, for axample, -O-, -COO-, -CH2-, -CO-NH-, -S~, -CO- or 2~738~
an -SO~- group.
Examples of polynuclear aromatic aryl radicals are 4~4'-biphenyl, 1,5- or 2,6-naphthalene gxoups or 1,8-naph-thalene groups.
To prepare ~he abovementioned polycondensates, a dicar-bo~lic acid dichloride of the formula X
ClOC - R1- COCl (X) is reacted with one or more of the diols, di~min~s, dithio co~pounds or diazines of the formulae XI, XII, XIII or XIV
HO - R2 _ OH (XI) H2N - R2 _ NH2 ~S - R2 _ SH (XIII) I
/ CH2 - CH \
HN NH (XIV) IB
in which Rl, R2, R7 and R~ have the abovementioned meaning.
The dicarbo~ylic acid dichloride of the ~ormula X and the individual diol, diamine, dithio or diazine types of the formulae XI, XII, ~III or ~IV can also be employed in the form of mixtures with one another.
It is obvious to the expert that the 8um of all the structural units derived from the dicarboxylic acid~ (A) 7 3 ~ 3 and the sum of all the structural units derived from the diols, di~hio compounds, diamines and diazines (B) are essentially the same, i.e. they di~er by not more than about 1~, preferably by not more than 0.2%, and in parti.cular are the same in the context of practical measurement and metering possibilitie~.
The molecular weight of ~he polyamides fo~med can be controlled, inter alia, ~ia the choice of the proportions of ~ to B. These choice criteria are known to the expert in the field of polycondensation.
Examples of suitable dicarboxylic acids from which the dicarboxylic acid dichlorides of the formula ~ are derived are 2,3-0-isopropylidene-L-tartaric acid, 2-chloroterephthalic acid, furandicarboxylic acid, 2-bromoterephthalic acid, 2-methylterephthalic acid and in particular 2,3-0-isopropylidene-L-tartaric acid.
Examples of suitable diamines of the formula XII are lysine methyl ester, naphthalene-1,4~diamiDe, naph-thalene 1,5-diamine and naphthalene 2,6-diamine, and in particular lysine methyl ester or diazines.
Examples of suitable diols of the formula XI are diethyl tartrate, 2,3-0-isopropylidene-L threitol and diisopropyl tartrate.
The condensation of the components described above is in general carried out in solution.
For this, the monomeric compounds to be r~acted with one another are as a rule dissolved in an organic solvent.
The organic solvent here preferably comprises at least one solvent, such as, for example, N-methyl-2-pyrrol-idone, ~,N dimethylacetamide, pyridine, tetramethylurea,N-methyl-2-piperidone, methylene chloride, N,N~-dimethyl-ethyleneurea, N methylcaprolactam, N-acetylpyrrolidine 2~7~3 and N,N dimethylpropyleneurea. The preferred organic solvents pyridine, methylene chloridet furan or a mixtuxe of these compounds are of importance for the process according to the invention.
S In a pxeferred form of carrying out the solution polymer-i~ation, the monomeric 2,3-O-isopropylidene-L-tartaric acid dichlorides and diethyl tartrate are mlxed in a mixture of pyridine and methylene chloride, while stirring vi~orously.
The polycondensation temperatures usually ran~e from -20C to +120C, preferably from +10C to +100C, during the solution polymerizakion. Particularly good results are achieved at reaction temperatures of ~10C to +80C.
The 8Um of th~ concentrations of the monomeric compounds in the polymerization mixture solu-tion can be ad~usted taking into account the desired degree of polymerization, the desired viscosity of the polymeri~ation mixture, the nature of the monomeric compounds used, the nature of the solvent used and the desired polymeri~ation temperature.
~O The most favorable sum of the concentra~ions can be determined for the course of the polymerization on the - basis of a series of prelLminary experiments.
~he polycondensation reactions are preferably carried out such that, after the reaction, 2 to 15, preferably 5 to 15% by weight of polycondensate is pre ent in the 501u-tion. Particularly good results are achieved at concen-trations of 5.0 to 10% by weight.
In the course of the polycondensation, the molecular weight of the pol~mer and therefore also the viscosity of the reaction mixture increases. Molecular weights of 500 to 1,000,000, preferably 3000 to 100,000, are achieved.
Viscosities of more than 0.1 dl.g~l (Staudinger index, dimethylformamide, 25C) are achieved as a rule.
13 2~73~3 -~hen the polymex ~olution has reached the viscosity required for further proc0ssing, the polyconden~ation can be stopped in the customary manner by addition of mono-functional compounds, such as, or example, acetyl chloxide. The hydrogen chloxide formed, which is loo~ely bonded to the amide solvent, can then he neutralized by addition of basic substances. Substance~ which are suitable for this are, for example, pyridine, triethyl-amine and morpholine, bu~ in particular pyridine.
ln The 2,3~0-alkylidene-L-tartaric acid dichlorides which can be employed as the ~tarting ~ubstance are obtained, for example, by reaction of tartaric acid alkyl esters with 2,2-dLmethoxypropane to give the corresponding tartaric acid dialkyl ester-acetone ketals by a reaction analogous to tho~e described by M. Carmack et al. (J.
Org. Chem. 33, 1968, pages 2171 - 2173). These tartaric acid dialkyl ester-acetone ketals are converted into the corresponding salts using alkali metal hydroxides, and finally into the corresponding L-tartaric acid ~ichloride derivatives by reac~ion with phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
The 2,3-0-alkylidene-L-threitol is prepared, for example, by reaction of the tartaric acid dialkyl e~ter-acetone ketal with LiAlH4 to give the corresponding 2,3-0 alkyl-idene-2-threitol (P.W. Feit, J. Med. Chem. 7, 1964, pages 14 - 17).
Furandicarboxylic acid dichlorides are obtainabl~, for example, by the process described by Moore and Xelley 30 (American Chemical Societyy 11, No. 3, 1978, page~ 568 -573).
;` .
The invention furthermore relate~ to a process for the production of the echogenic particles according to the invention, which comprise5 di~olving the shaping 14- 2~77383 substance or sub8 tance mixture in a ~uitable solvent or solvent mixture ancl suhjecting the solution to spray dryîn~ .
Other proce~ses, for example emlllsion processe~ or precipitation processes, furthermore can al~o be employed for the production of the particle~ according to the invention (M. Bornschein et al~, ~ie Pharmazie, 44, Volume 9, 1989, page 585 ff.; and Y. KawashLma et al,, 3. Pharm. Sciences, &1, Yolume 2, 1g92J page 135 f).
The spray drying is carried out, for e~ample/ in accordance with the principle of ~et atomizativn in co-current, i.e. the direction of the solution to be sprayed and the dry ai.r run in the same direction.
The following adjustments of the essen~ial setting parameters on a spray dryer (Buchi 190; Buchi GmbH, Eislingen) have proved to be suita~le for production of the echogenic particles according to the invention. The int~ke temperature is 15C to 200C, in particular 20C
to 100C. HoweYer, the temperature can also vary within wide lLmit~, and essentially depends on the solvent used and the polymer.
The intake temperature is to be understood as meaning the temperature of the dryin~ air, which is sucked through the apparatu~ with the aid of the aspirator. Instead of air, it is of course also possible to employ another gas, if thP work to be carried out requires thi~.
During spray dryin~ of a solution, all or some of the solvent is removed, and the liquid ~olution droplets are thereby converted into particle~. So that the ~olvent evaporates during the contact time available when the goods to be dried are sprayed in a 6tream of air, the temperature of the stream of air must be above or clo~e to the boiling point of the solvent7 ~77~83 -- 1$ --That temperature of the stream of aix, which entrains the solid particles, before entry into the cyclone is the starting temperature. The starti.ng temperature results from the combination of intake temperature, ~spirator S setting, pump setting and concentration of the goods to be sprayed, and last bu~ not least also dep~nds on the heat o vaporization of the solvent.
The drying air is sucked through the apparatus with the aspirator, and at the same time a reduced pressure is generated. By regulating the aspirator output, on the one hand the amount of heated drying air i8 increased or reduced, and on the other hand the reduced pressure prevailing in the apparatus is regulated. A pressure which is in the range from 10 to 100 mbar below the pressure outside the apparatus, in particular from 30 to 70 mbar, is preferred.
The object of the delivery pump is to feed the spray solu~ion into the ~pparatus, and pump output~ of 100-500 ml/hour have proved appropria~eO
The spray flow is understood as meaning the amount o compressed air needed for atomization of the solution, emulsion or di~persion. Instead of compressed air; it i9 of course also possible to employ another gas.
The spray flow can be ~et on th~ appaxatu6 in ~he range ~5 from 100 to 800 Nl/hour (Nl = normal liter), in parti~
cular 600 to 800 Nl~hour.
Suitable solvents or solYent mixtures arer for example, water, tetrahydrofuran, methylene chloride, furan, DMSO
(dimethyl sulfo~ide), dioxane or acetone.
If the spray product doe~ not have a smooth ~urface after a trial spraying, smooth surfaces can be produced by addition of polymer pla~ticizers, such as DMSO or ~ 16 glycerol, to the solvent.
If the spray product shows smooth surfaces and circular particles after a trial spr~ying, concave surface curves inwards can be produced by addition of precipitating agents and/or temperature changes.
The shape of the particles according to the invention essentially results from the production pxocess and the choice of tha parameters, The particles according to the invention having concave surface segments are derived, for example, from circular particles having A constant diameter or hollow bodies. Shapes which look like cups, hats, cigars or cylinders also occur. The particles can be monolithic or in the form of hollow bodies, for example as hollow hemispheres curved inwar~s. Monolithic particles are tho~e which are essen~ially filled by the shaping substance; hollow bodies have a ~reater or smaller gas-filled interior. Hollow hemispherical par ticles curved inwards can be formed by greater or lesser invaginations of the hollow spheres. Spindle-shaped forms with two invagination~ of a circular particle furthermore have proved favorable. All the shape~ mentioned have proved to be suitable echogenic particles.
The distribution of the shapes in a batch produced by spray drying can vary within wide limits. Batches in which at least 5%, preferably 5 to 90~, in particular 10 to 60%, particularly preferably 30 to 40~ of the par-ticles have at least one concave surface segment have proved to bP favorable. Echogenic particles of which at least 5% have only one concave surface segment are parti-cularly preferred. The distribution of the shapes can be determined by computer a~sisted image analysis of the scanning electron microscope Lmage~ of tha particles, or with the aid of a cytophotometer.
- 17 - 2~773~3 The echogenic particles according to the invention can also have a smooth ~urface. This feature c~n be deter-mined, for example, by electron microscopy ~tudies, in particular by scanning electron microscopy (SEM3. For this, the particles are prepared and contrasted by the standard methods of electron microscopy. Vapor-deposited metals/ for example gold, have proved to be suitable contrast media for SEM image3. Smooth surface of par-ticles appear on the SEM image as homogeneous areas with a largely constant gray shade. Disturbances in the surface are recognized by different gray shades. Di tur-bances have a distanc~ from the average ~urface of the particles of more than 100 nm.
The particles according to the invention having a smooth surface are not completely ~ree from disturbances of the surface. The number of disturbances per ~m2 ranges from 0 to 4, preferably 0.5 to 3, in particular from 1 to 3. The quality of the ~mooth ~urface can be determined, for example, by selecting s~uare areas having an edge length of 0.5 ~m on the SEM Lmages of the particles according to the invention having a smooth surface, and determining the number of disturbances of the surface. The charac-teristic feature of a smooth surface is that, in a random selection of 10 ~quare areas, 0 to 10 disturbances of the surface are found, preferably on average 1 ~o 7.5~ in particular 2. 5 to 7 . 5 .
The distribution of the particles aecording to the i~ven~ion having a smooth surface in a batch produced by spray drying can vary within wide limits. Batches in which at least lO~, preferably 10 to 90%, in particular 20 to 60~, particularly preferably 30 ~o 40~ o~ the particles have a smooth surface have proved to be favorable.
The shaping substances can be employed by themselve or as a mixture in the proce~s described. These shaping :
2~77383 substances can al~o be employed as a mixture wi~h o~her biologically degradable and/or biologically compatible polymers, ~or example dex~ran~, polyethylene glycol~, hydroxyethyl-starch and other degradable or excretable polysaccharide3, or ph~siologically acceptable auxili-aries (for example D~SO, glycerol or other polymer plasticizers).
The invention furthe~more relates ~o diagnostic ag0nt~
and therapeutic agents, which can compri~e the ~chogenic particles according to the invention, in addition to pharmaceutically suitable and physiologically tolerated excipients, additives and/or auxiliaries.
Before administration, the echogenic particles according to the invention are conver~ed into a suitable diagnostic or therapeutic pres~nta~ion form by addition of one or more pharmaceutically suitable and physiologically acceptable excipients and if appropriate other additives and/or au~iliaries. For example, before administration, the echogenic particles are suspended by addition of water and mixi~g.
The physiological isotonicity of the particle suspen~ion can be established by addition of substances having an osmotic action, for example sodium chloride, galactose, glucose or fructose. Suspension auxiliaries, such as dextrans, or additives, such as colloidal infusion solutions or plasma substitution furthermore can be admixed to the particle suspensions.
In the processes described for the production of the echogenic particles according to the i~vention, particle sizes can be achieved in which 90% of the particles have : a diameter of 0.1 ~m to 50 ~m, and particle size distri-butions in which 90~ of the particles are less than 3 ~m are achieved in particular. Larger particles are siaved out with a sieve fabric which hae a mesh width of 1 ~m 19 2~7738~
to 50 ~m, in parkicular 3 ~m to 15 ~m. Particle ~izes o~
0.1 ~m to 7 ~m have pro~ed to be suitable for use of these echogenic particles as ultrasonic contrast media for diagnosis of cardiovascular diseases, and particle sizes of 0.1 ~m to 3 ~m are advantageously employed. The echogenic par~icles are injected, for example, into the bloodstream. 0.1 mg to 1000 mg of echogenic particles, preferably 1 mg to 100 mg, are employed per in~ection.
However, the echogenic particles can also be administered orally, in order to render the gastrointestinal tract accessible to ultrasonic examination.
The echogenic particles according to the invention can be used both for diagnostic and for therapeutic methods. The use of the echogenic particles according to the inYention is not limited merely to visualization of the blood-stream in the right ventricular portion of the blood circulation following venous administration. The echo-genic particles can be used with excellent success for ex~mination of the left side of the heart and of the myocardium. Furthermore, it i~ also possible to visualize other organs supplied with blood, such as the liver, spleen, kidneys or brain, using these echogenic particles.
However, the echogenic particles according to the inven-tion are also suitable for visualization of hollow cavities in humans, anLmal~ or plants, for example the urinary bladder, ureter, womb, vagina, ~ylem or phloem~
The invention is described in d~tail in the following e~amples. Percentage data relate to the weight, unless ~tated o~herwise.
., s~77~83 Example 1 Determination of the shape and lung accessibility of the echo~enic particles The average size, the shape and the na~ure of the ~urface are characteri~ed by means of scanning electron micro-scope images.
For this, the echogenic particles are ~prinkled onto conductive double-sided adhesive ~ape, and gold is vapor-deposited on in a sputtering unit - coating thickness about 1.8 nm, pressure ~bout 1 x 10-2 n~ar (sputtering unit type 07 120B, Balzerz Union). ~he SEM Lmages are produced with a Camscan ~canning electron microscope, type series 4; tilt angle 15; high voltage 20 kV, working distance 24 mm; secondary electrons, worXing lS vacuum abou~ 2 10-6 mbar.
In each case 30 mg of particles are dispersed in 2 ml of suspension auxiliary comprising 200 mg of dextran 40 (Roth, Germany), 10 mg of polysorbate and 16 mg of NaCl in distilled wa$er, and are then filtered with sieve fabrics (15 ~m and 3 ~m mesh width) and lyophili~ed.
The lung accessibility of the particles is tested in vivo. 30 mg of the filtered particles are resuspended in 1. 5 ml of distilled water with the ai-l of a gla~s rod.
This suspension is injected into a peripheral veLn with an injection syringe. An ultrasonic head of an ultrasonic unit (Toshiba, FSH 160a, Japan) is held against the thorax of the test animal, 50 that a typical cross-section through the right and left ventricle i8 obtained.
As soon as the ultrasonic contra~t medium re~ches the 30 right ventricle, it can be ~een on the monitor of the ultrasonic unit how the blood labeled by the contrast medium reaches the right auricle, and then leave~ the right Jentricle and sub~equently the heart via the - 21 - 2~7~3 pulmonary artery. ~fter passage through the lung, the contrast in th~ left ventricle is dis~inctly incrPa~ed by the contrast medium.
Example 2 S PreparationofpolysuccinLmide-co~ (hydroxyethyl)-D,L-aspartamide t70:30) 10 g (103 mmol) o polyanhydroaspartic acid are dissolved in about 40 ml of N,N-dLmethylformamide (DMF), if approp-riate with cautiou~ ~arming. 1.83 g (30 mmol) of freshly distilled 2-aminoethanol are added dropwise to this solution, and the mixture is stirred overnight at room temperature. The reaction mixture is precipitated in butanol and the product is washed several times with dried acetone. Drying is carried out in vacuo at elevated temperature. The white, wa~er-soluble product is formed to the extent of approximately 100~, and is tested for residues of DNF and butanol by NMR spectxoscopy. The molar ratio of polyanhydroaspartic acid to aminoethanol ~mployed approximately corresponds to th~ copolymer composition.
Example 3 Preparationofpolysuccinimide-co~ (nonyl carbonyloxy-ethyl)-D,L-aspartamide (50:50) 6 g of a polysuccinimide-co-~ (hydroxyethyl)-D,~-aspartamide (50:50) (= 24 mmol of hydro~yethyl groups), which was prepared analogously to Example 4 from poly-anhydroaspartic acid tmolecular weight = 14,000~ and 2-aminoethanol (molar ratio 2:1), are dissolved in 100 ml of dry DNF, 8 g (100 mmol) of dry pyridi~e are added and the mixture is cooled to 0C. 9.6 g of distilled decanoyl chloride are slowly added dropwise.
22 2~7~
The mixture i~ ~tirred overn.igh~ and precipitated in 0.5 l o ether. The product which has precipita~ed is filtered off with suction and washed with ethex, acetone, water t acetone and ether.
About 8 g of a white, completely substituted polymer ~NNR
control), which is soluble, for example, in methylene chloride and tetrahydrofuran, in each ca~e with a trace of DMSO, or in methanol/methylene chloride mixtures, are obtained.
Example 4 PreparationofpolysuccinLmide-co-~fl (nonyl-carbo~yloxy-ethyl)-D,L-aspaxtamide Various poly~uccinLmide-co~ -(hydro~yethyl)-D,L-aspart-amides, inter alia having the composition 70:30, 50:50 and 30:70, are prepared from polyanhydroaspartic acids of different molecular weight (molecular weight - 7000;
about 13,000, 30,000) analogously to ~xa~ple 2 and are reacted with decanoyl chloride, as described in Example 5, to give the corresponding poly~uccinLmide-co-~,~-(nonylcarbo~yloxyethyl~-D,L-aspartamides.
a) - PolysuccinLmide-co~ (nonylcarbonyloxy-ethyl)-D,L-aspartamide (70:30) ~rom polyanhydroaspartic acid (molecular weight = 7000); characterized by NMR.
b) - PolysuccinLmide-co-~ t ~- (nonylcarbonyloxy-ethyl)~
D,L-aspartamide (70:30) from polyanhydroaspaxtic acid (molecular weight = 14,000); characteri~ed by NMR.
c) - PolysuccinLmide-co~ -(nonylcarbonyloxy-ethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (molecular weigh~ = 30,000), characterized ~77.~3 - 2.~ -by NMR.
Ex~mple 5 20 g of polyanhydroaspartic acid-co~ (nonylcarbonyl-oxyethyl)-D,L-a~partamide 70:30 (prepared as in Example 6b) are dissolved in 400 ml of methylene chloride and the solution is sprayed to paxticles under the following conditions in a spray dryer (~ini Spray Dryer Buchi 190, Buchi GmbH, EislingPn):
Spraying conditions 10 Intake temperature: 60C
Outlet temperature: 40C
Scale divisions heating: 1.5 Pump settingl ~
Aspirator: 12 15 Spray flow jet air: 700 Nl/h Pressure in the filter: 55 mbar Cooling jet: 20C
Yield: about 8 g After spray drying, the methylene chloride concentration in the particles is less ~han 0~05%. The average size and shape and the nature of the surface are characterixed by means of scanning electxon mi~roscopy image~; the lung accessibility of the particles is determined as in Example 1.
~5 100 mg of the particles produced are suspended in a 1%
strength ~Haemaccel solution (Behring Werke ~&, ~arburg, Germany) and filtered throuyh sieve fabric (10 ym)~ The filtrate is then lyophilized and used to determined the lung accessibility.
2~77~3 Under the scanning electron microscope, the particles produced have an average particle ~iæe of 2 ~m and a smooth surface. Furthermore, the~e particle8 have access to the lungs.
About 15~ of the particles are circular hollow spheres and 50% of the particles are hollow spheres which have a spheric~l invagination, so ~hat a hemispherical hollow sphere is formed. The shell thickness of these hemi-spherical hollow spheres at the maximum invagination can be described by the equation rm - ri = 2 d (d = shell thickness, r~ - radius of the outer hemisphere, r1 =
radius of the inner concave hemisphere. If the hemi-sph~rical shape is not ideal, the radius is to be deter-mined from the relative central point of the invaginated hollow sphere.
About 25~ of the particles are hollow spheres having 2 ~o 5 invaginations of different size.
Example 6 Particles are produced from polyhydro~ybutyric acid type 159PHB (ICI Biological Products Ltd) in accordance with instructions by J.R. Embleton, B.J. ~ighe (J.
Microencapsulation, 1992, ~olume 9, ~o. 1, 73-87) by the so-called "double emulsion solvent evaporation proce~s".
The evaporation is carried out at room temperature. The particles are fractionated by centrifugation and filtra-tion through a 10 ~m sieve fabric. A particle content of 35~ having concave surface segments i6 then determined in thè filtrate by scanning electron microscopy.
The evaporation is also carried out at 40C and the particles are then fractionated. For comparison, fraction with a particle content of only 5~ having concave surface 8e~ments is determined in thi~ manner ~y scanning electron microscopy.
~77383 EY.amP1 e 7 ( LMP G 5 0 / 5 0 ) Preparation of poly(L-lysine methyl ester-fumaric acid/-L-lysine methyl ester-glutaramide ) Copolymer 5 0 : 5 0 ~ LMFG 5 0: 5 0 ) 0.7 g of glutaric acid dichloride and 0.84 g of fumaric acid dichloride are dissolved in 170 ml of CH2Cl2. ~his solution is added ~o a solution of 2.91 g of L-ly~ine methyl ester ~nd 3.0 g of Na2C03 in 120 ml of H20 at room temperature, while tirring vigoxously. The polyconden-sation, which starts suddenly, is interrupted after15 minutes by addition of 150 ml of lN agueou~ HCl. The me~hylene chloride is then driven off by passing in steam. The hot aqueous mixture is filtered and the solid product is washed ~everal tLmes with water~
Yield: 1.3 g (60% of theory) after vacuum drying (20 hours) Exampls 8 2 g of polymer from Example 7 are dissolved in 100 ml of DNS0 and the solution is ~prayed to particles at an intake temperature of about 200C in a Mini Spray Dryer Buchi 190. The average size and the nature of the surface are characteriz~d by means of scanning electron micro-scopy images tsee Table 1). In each case 50 mg of par-ticles ar~ suspended in 2 ml of suspension auxiliary l1%
of ~Haemaccel in isotonic water) and subsequently filtered with sieve fabric (15 ~m and 3 ~m mesh width) and lyophilized.
Example 9 2 g of polyhydroxybutyric acid type 159 PHB (ICI
Biological ~roducts ~td) are dissolved in 100 ml of a - 26 - 2~773~3 furan/methylene chloride (9:1~ mixture, the solution is sprayed to particles at about 45C in a Bushi Mini Spxay Dryer, and the particles are further processed analogously to Example 8.
Example 10 A solution of 2 g of polyhydroxybutyric acid type 159 PHB
(ICI Biological Products Ltd) in 100 ml of methylene chloride/MeOH (1:2) is sprayed to particles at about 45C
in a Buchi Mini Spray Dryer, and the particles are further processed analogously to Example 8.
Example 11 2 g of poly_e-caprolactone (Polysciences 19561~ are dissolved in methylene chloride to give a 2% strength solution, the solution is sprayed to particles at room temperature in a BUchi Mini Spray Dryer, and the par-ticles are further processed analogously to Example 8.
The lung accessibility of the particles from Examples 8 to 11 is tested in vivo and determined as in Example 1.
The following table shows the resultsO
- 27 2~7~
Table 1 PolymerSolvent ~verage Surf ace Lung according particle access-to size ibility . Example ~ _ 8 DMSO 3 ~m smooth yes 9 furan/ 3 ~m smooth yes methylene . ~ l~lori~ _ _ t0 CH2Cl2/ 2 ~m rough no MeOH 1:2 .
11 CH2Cl2 3 ~m smooth yes
HOECHST AKTIEMGESELLSCHAFT HOE 91/~ 277 JK Dr.TH/PL
Description Echogenic particles, a process for theix production and their use The invention relates to echogenic particles which comprise a gas and a shaping substance, wherein the surface of the particles is essentially smooth and the shape comprises no or 1 to 10 conca~e ~urface segments, or the surface is not smooth and the shape comprises 1 to 10 concave surface segmen~s, and which can pass through the lung in the blood circula~ion, a spray process for their preparation and their use, in particular a3 diag-nostic agents and therapeutic agents.
: Because it is easy to handle and has no complications, ultrasonic diagnosis has found wide use in medicine.
Ultrasonic waves are reflected at the boundarie~ of different types of tissue. The resulting echo 3ignal8 are amplified and visualized electronically.
The visualization of blood vessels and internal organs by ultrasound generally does not allow visualization of the ~: blood flow present therein. Fluids, especially blood, produce an ultrasonic contrast only if there are density : differences with respect ~o the environment. Contras~
media which are used in medical ultrasonic diagnosis are, for example, substances which comprise gases or produce gases, since the difference in impedance between the gas and ~urrounding blood is considerably ~reater than that between fluids or solids and blood (Le~ine R.A.f J. Am.
Coll. Cardiol 3: ~8, 1989; and Machi, i.J. CU 11: 3, 30 1983~.
Several methods for the preparation and stabilization of gas bubbles are known in the literature.
2 o ~ rl ~ ~ 3 -- 2 ~
U.S. Patent 4,276,885 describes the prepara~ion of gas bubbles of defined size, which are surrounded by a gelatin shell which protects the ga~ bubbles from merging. The finished gas bubbles can ~e stored only in the frozen state, and ~he gas bubbles have ko be brought to body temperature again before use.
EP-A2-0,123,235 and 0,122,624 describe gas-containing ultrasonic contrast media which comprise mixtures of surface-active substances with a solid in a liquid carrier. The ultrasonic contras$ media are prepared by an expensive grinding process with an air jet mill. The particles thus produced have only a short u6eful life, because they guickly lose the gases included.
EP-A2-0,224,934 describes ultrasonic contrast media in the form of gas-filled hollow bodies of gelatin or albumin. However, the use of proteins forei~n to the body or denatured endogenous proteins i~ a disadvantage, because of the associated allergenic risk.
The present invention is based on the object of discovering echogenic particles which refle t, absorb, diffract or scatter ultrasonic waves and in this way produce a significant contrast to the surro~nding tissue, which are so small and stable that, after intravenous administration, they reach the left ventricle without substantial 105s of gas and essentially guantitatively, and which can be produced quickly and easily.
It has been found that the quality of echogenic particles depends in particular on the shape and surface of ~hese particles. It i~ found that echogenic particles having concave surface segments can pass through the lung in the blood circulation considerably better and effect a higher contrast in ultrasound. These echogenic parti~les com-prise an air/water boundary, the scattering cross-section of which in ultrasonic examinations i8 very high.
~` .
2~7~3~3 Echogenic particl~s having an essentially smooth surface can pass through the lungs of vertebrate~ in the blood circulation without the particles being filtered ou~ to a great extent.
The invention thus relates to echogenic particles which comprise a gas and a shaping subs~ance or a substance mixture, which is biologically degradable and/or excret-able, and which can pa~s through the lung of vertebrates in the blood circulation, wherein the ~urface of the echogenic particle i~ essentially smooth and the shape of the Pchogenic particle comprises no or 1 to 10 concave surface segments, or the surface of the echogenic par-ticle is no~ smooth and the ~hape of ~he echogenic particle comprises 1 to 10 concave surface segments.
~chogenic par~icles are particle~ ha~ing a diameter which : ranges from 0.1 ~m to 20 ~m, preferably 0.2 ~m to 7 ~m, in particular from 0,5 ~m to 3 ~,m, in 90% of the par-~ ticles. These paxticles furthermore ar~ capable of ; reflecting, absorbing, diffracting or ~cattering sound waves.
Concave surface segment of an echogenic particle means a particle which has at least one surface curved inwards.
The particles according to the invention include, for example, particles in which the maximum curve inwards, that is to say the depth of the conca~e surface segment, is more than 10% of the smallest cross-sec~ion of the particle, the curve inwards particularly preferably being 30 to 90%, in particular 50 to gO~0 This thus essentially means particles which look cup~, hat- or pot-shaped.
The number of concave ~urface ~e~ments ranges from 1 to 10, preferably 1 to 5, in particular 1 ~o 3.
The paxticle~ can also have a smooth surface. An essen-tially smooth surface of an echogenic particle means - 4 - ~ ~7~3 surface~ which reveal no structural differences at all on the surface under lO,OOO fold magnification, i.e. distur-bances on the surface of these particles, such as eleva-tions or depressions, are essentially at a distance of less than 100 nm from the average fiurface of the particle, in par~icular 90 to 50 nm, preferably 60 to 80 ~m. The average par~icle surface i8 obtained from the average of the elevations and depressions of the surface.
Disturbances in the ~urface include changes in the homogeneous surface which, in an electron microscopy photograph, look like elevations, fractures, distortions, a ladder-, step-, scale or layer-like build up of the surface and holes, depressions or pores in the surfaGe.
The property of the particles according to the invention of being able to pass through the lung of vertebrates in the blood circulation is determined, for example, by injecting the echogenic particles into a peripheral vein of a test animal under s~erile conditions. An ultrasonic head of an ultrasonic unit is held on the thorax of th~
test animal, so that a typical cross-section through the right and left ventricle i6 obtained. As soon as the ul~rasonic contrast medium reaches the right ventricle, it can be seen on the monitor of the ultrasonic unit how the blood labeled by the contrast medium reaches the right auricle and then leaves the right ventricle and then ~he heart again via the pulmonary axtery. After passage through the lung, a significant increase in contrast due to the contrast medium is detectable in the left ventricle.
The echogenic particles compris~ gas, for example air, nitrogen, a noble gas such as helium, neon, argon or kryptonJ hydrogen, carbon dioxide, oxygen, or mi~ures thereof. The echogenic particle~ are charged with a ga~
by, for example, storing the particles in an appropriate gas atmosphere or obtaining the particles directly by spray drying during production in an appropriate 2~77~83 gas atmosphere.
Shaping ~ubs~ances or sub~tance mixtures are understood as meaning all compounds with which particles ~an be pr~duced O
These include, for example~ naturally occurring polymers or polymers which can be prepared by synthesis, lipids which form micelles in agueous solutions, or low mole~
cular weight amino acids, fats, or carbohydrates.
Biologically degradable and/or excretable shaping sub-stance or substance mixtur~ is und~rstood as meaning substances which are converted into non~toxic degradation products in th~ body of anLmals, humans or plants, or are excreted. The degradation can take place enzymaticallyJ
hydrolytically or by partial or complete solution of the substances or disintegration of the particles into smaller sub-units in water. The degradation product~ are excreted via the kidneys, skin, lungs or in~estine. If the su~stances dissolve completely or partly in water or arP not degraded, for ex~mple in the ca~e of low mole-cular weight carbohydrates, they are excreted via thekidneys without degradation.
Shaping substances or substance mixture~ which are biologically degradable a~d/or excretable are chosen from the following groups:
25 polyesters of an ~ or ~-hydroxycarbo~ylic acid, for example poly-~-caprolactone, polyhydroxybutyric acid, polylactic acid or polyhydroxyvaleric acid, copolymers of the abovementioned polyester% with one another or with polyglycolic acid, polycondeDsate~ which comprise 2,3-O-alkylidenetartaric acid, 2,3-O-alkylidene-L~threitol, furo-[2,5] group~ or terephthalates, 2~77~3 polyaminodicarboxylic acid co-imides, such a8 polysuccin-Lmide-co~ -(butoxycarbonylpropion ethyl)-D,~-aspartamide, polyamino acid6, such a~ polyglutamic acid, poly~spartic ; S acid or polylysine, which give a basic or acid reac~ion in aqueous solution~ and derivatives thereof, polyamide~ t for axample polylysine mathyl ester-fumaric acid-co glutar~mide or poly~
hydroxyethylaspartamide, `: polyortho esters, polyanhydride~ for example those which are compo~ed of ; sebacic acid and bis(p-carboxyphenoxy)-propane, 15 gelatin, for example hydrophobically modified gelatin, albumins, for example bovine ~erum albumin, poly~accharide~, for example dextrans, starch or basic or :~ acid deriva~ives thereof, polymethylene malonate, : ~ugars, for example glucose, galactose, lacto~e or Bucrose ~
fatty acids having 8 to 20 carbon ~toms, amino acid~, ~uch as proteinogenic amino acids ~nd hydrophobic derivatives thereof, alcohols having 12 to 20 carbon atoms and lipids, such as phospholipids.
The echoyenic particles according to the invention particularly preferably compri~e biologically degradable ~ 30 andJor excretable polymers from the following group:
: polyamides, polycondensates, polyh~droxybutyric acid and ~ poly~minodicarboxylic acid co-imides.
: ~.
The abovementioned shaping substances or substance mixture~ can be prepared by processe~ which are known 35 from the litarature (EP-0,327,490; EP-0,398,935;
~ .
, 2~773~3 EP-0,458,079; EP-0,123,235; EP-0,~24,934; EP-0,245,8~0, M. Bornschein et al., Die Pharmazie, 49, Volume 9, 1989, page 585ff.; J.W. Freytag, J. Microencapsulation~ 2, Volume 1, 1985, pages 31-38, Y. Kawashima et al. 7 J. Phanmaceutical Sciences, 81, Volume 2, lg92, page 135ff., EP OtO77,752 and EP 0,131,540).
The abovementioned polycondensates essentially contain at least 95 mol% of recurring structural units of the fo~mula I
O O
[-C-R'-C-X-R2 X-] (I~
in which Rl is : a) a compound of the formula II
--C--C--0 \ / 0 (II) R5 R~
in which Rs and R6 zre inert radicals, b) straight-chain or branched alkyl, alkenyl, ~` cycloalkyl or cycloalkenyl, which can be substituted b~ one or more inert radicals, c) aryl which is mono- or polynuclear and mono- or polysubstituted by inert radicals, d) compounds of the formula V
~o~ (V) ~' .
- 8 20773~3 or e) a heterocyclic radical; which can be mono- or polynu~lear and c~n be mono- or polysubstituted by inert radicals, 1 5 in which ~ is a) O-, b) -NH-- or c ) --S--, :
in which R2 iS
a) a compound of the formula III
\ / ~III) in which R5 and R6 have the abovementioned meaning, b) straight-chain or branched alkyl, alkenyl, cycloalkyl or cycloalkenyl, which can be substituted by one or more inert radicals, c) mono- or polynuclaar aryl, which i8 mono- or polysubstituted by inert radical6, d) a heterocyclic radical, which can be mono- or polynuclear and can be mono- or polysubstituted by inert radicals, or ~3 a compound of the formula VI
H H
--C - C--o = c c o (YI~
~ I I
o o ~: 1 5 1 6 20~73~
_ 9 _ in which Rs and R6 have ~he abovementioned meaning, wi~h the proviso ~hat ~he polycondensa~e of the formula I con~ains more than 5 mol% of the radicals R1 andior R2, S in which Rl is a compound of the formula II and/or R2 i8 a compound of the formula III, or that the polycondensate of the formula I comprises more than S mol% of the radicals R1 and ~2, in which a) R1 i5 a compound of the formula ~ and R2 is a compound of ~he formula VI, or b) R1 is phenyltl,2], phenylll,3] or phenyl[1,4]
and R2 is a compound of the formula VI.
The term "inert radicals~ is understood as meaning substances which do not react with one another or are prevented from reacting with one another by protective groups under the preparation and processing conditions for the polycondensates according to the invention. Inert radicals can be, for example, inorganic radicals, such as halogen, or organic radicals, ~uch as alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy or dialkylaminoalkyl.
:
Functional groups which are prevented from reaction by protective groups ara, for example, amino or hydroxyl.
Xnown protective groups are, for example, the benzyloxy or phenylsulfonyl group.
Heterocyclic radicals can be mono- or polynuclear and contain, in particular, one or two oxygen, nitrogen or sulfur atoms in the nucleus.
Aryl is an aromatic carbon ring. Polynuclear aryl radicals can ba fused to one another or bonded to one another linearly via C-C bon~s or via bridge groups, such as, for axample, -O-, -COO-, -CH2-, -CO-NH-, -S~, -CO- or 2~738~
an -SO~- group.
Examples of polynuclear aromatic aryl radicals are 4~4'-biphenyl, 1,5- or 2,6-naphthalene gxoups or 1,8-naph-thalene groups.
To prepare ~he abovementioned polycondensates, a dicar-bo~lic acid dichloride of the formula X
ClOC - R1- COCl (X) is reacted with one or more of the diols, di~min~s, dithio co~pounds or diazines of the formulae XI, XII, XIII or XIV
HO - R2 _ OH (XI) H2N - R2 _ NH2 ~S - R2 _ SH (XIII) I
/ CH2 - CH \
HN NH (XIV) IB
in which Rl, R2, R7 and R~ have the abovementioned meaning.
The dicarbo~ylic acid dichloride of the ~ormula X and the individual diol, diamine, dithio or diazine types of the formulae XI, XII, ~III or ~IV can also be employed in the form of mixtures with one another.
It is obvious to the expert that the 8um of all the structural units derived from the dicarboxylic acid~ (A) 7 3 ~ 3 and the sum of all the structural units derived from the diols, di~hio compounds, diamines and diazines (B) are essentially the same, i.e. they di~er by not more than about 1~, preferably by not more than 0.2%, and in parti.cular are the same in the context of practical measurement and metering possibilitie~.
The molecular weight of ~he polyamides fo~med can be controlled, inter alia, ~ia the choice of the proportions of ~ to B. These choice criteria are known to the expert in the field of polycondensation.
Examples of suitable dicarboxylic acids from which the dicarboxylic acid dichlorides of the formula ~ are derived are 2,3-0-isopropylidene-L-tartaric acid, 2-chloroterephthalic acid, furandicarboxylic acid, 2-bromoterephthalic acid, 2-methylterephthalic acid and in particular 2,3-0-isopropylidene-L-tartaric acid.
Examples of suitable diamines of the formula XII are lysine methyl ester, naphthalene-1,4~diamiDe, naph-thalene 1,5-diamine and naphthalene 2,6-diamine, and in particular lysine methyl ester or diazines.
Examples of suitable diols of the formula XI are diethyl tartrate, 2,3-0-isopropylidene-L threitol and diisopropyl tartrate.
The condensation of the components described above is in general carried out in solution.
For this, the monomeric compounds to be r~acted with one another are as a rule dissolved in an organic solvent.
The organic solvent here preferably comprises at least one solvent, such as, for example, N-methyl-2-pyrrol-idone, ~,N dimethylacetamide, pyridine, tetramethylurea,N-methyl-2-piperidone, methylene chloride, N,N~-dimethyl-ethyleneurea, N methylcaprolactam, N-acetylpyrrolidine 2~7~3 and N,N dimethylpropyleneurea. The preferred organic solvents pyridine, methylene chloridet furan or a mixtuxe of these compounds are of importance for the process according to the invention.
S In a pxeferred form of carrying out the solution polymer-i~ation, the monomeric 2,3-O-isopropylidene-L-tartaric acid dichlorides and diethyl tartrate are mlxed in a mixture of pyridine and methylene chloride, while stirring vi~orously.
The polycondensation temperatures usually ran~e from -20C to +120C, preferably from +10C to +100C, during the solution polymerizakion. Particularly good results are achieved at reaction temperatures of ~10C to +80C.
The 8Um of th~ concentrations of the monomeric compounds in the polymerization mixture solu-tion can be ad~usted taking into account the desired degree of polymerization, the desired viscosity of the polymeri~ation mixture, the nature of the monomeric compounds used, the nature of the solvent used and the desired polymeri~ation temperature.
~O The most favorable sum of the concentra~ions can be determined for the course of the polymerization on the - basis of a series of prelLminary experiments.
~he polycondensation reactions are preferably carried out such that, after the reaction, 2 to 15, preferably 5 to 15% by weight of polycondensate is pre ent in the 501u-tion. Particularly good results are achieved at concen-trations of 5.0 to 10% by weight.
In the course of the polycondensation, the molecular weight of the pol~mer and therefore also the viscosity of the reaction mixture increases. Molecular weights of 500 to 1,000,000, preferably 3000 to 100,000, are achieved.
Viscosities of more than 0.1 dl.g~l (Staudinger index, dimethylformamide, 25C) are achieved as a rule.
13 2~73~3 -~hen the polymex ~olution has reached the viscosity required for further proc0ssing, the polyconden~ation can be stopped in the customary manner by addition of mono-functional compounds, such as, or example, acetyl chloxide. The hydrogen chloxide formed, which is loo~ely bonded to the amide solvent, can then he neutralized by addition of basic substances. Substance~ which are suitable for this are, for example, pyridine, triethyl-amine and morpholine, bu~ in particular pyridine.
ln The 2,3~0-alkylidene-L-tartaric acid dichlorides which can be employed as the ~tarting ~ubstance are obtained, for example, by reaction of tartaric acid alkyl esters with 2,2-dLmethoxypropane to give the corresponding tartaric acid dialkyl ester-acetone ketals by a reaction analogous to tho~e described by M. Carmack et al. (J.
Org. Chem. 33, 1968, pages 2171 - 2173). These tartaric acid dialkyl ester-acetone ketals are converted into the corresponding salts using alkali metal hydroxides, and finally into the corresponding L-tartaric acid ~ichloride derivatives by reac~ion with phosphorus trichloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
The 2,3-0-alkylidene-L-threitol is prepared, for example, by reaction of the tartaric acid dialkyl e~ter-acetone ketal with LiAlH4 to give the corresponding 2,3-0 alkyl-idene-2-threitol (P.W. Feit, J. Med. Chem. 7, 1964, pages 14 - 17).
Furandicarboxylic acid dichlorides are obtainabl~, for example, by the process described by Moore and Xelley 30 (American Chemical Societyy 11, No. 3, 1978, page~ 568 -573).
;` .
The invention furthermore relate~ to a process for the production of the echogenic particles according to the invention, which comprise5 di~olving the shaping 14- 2~77383 substance or sub8 tance mixture in a ~uitable solvent or solvent mixture ancl suhjecting the solution to spray dryîn~ .
Other proce~ses, for example emlllsion processe~ or precipitation processes, furthermore can al~o be employed for the production of the particle~ according to the invention (M. Bornschein et al~, ~ie Pharmazie, 44, Volume 9, 1989, page 585 ff.; and Y. KawashLma et al,, 3. Pharm. Sciences, &1, Yolume 2, 1g92J page 135 f).
The spray drying is carried out, for e~ample/ in accordance with the principle of ~et atomizativn in co-current, i.e. the direction of the solution to be sprayed and the dry ai.r run in the same direction.
The following adjustments of the essen~ial setting parameters on a spray dryer (Buchi 190; Buchi GmbH, Eislingen) have proved to be suita~le for production of the echogenic particles according to the invention. The int~ke temperature is 15C to 200C, in particular 20C
to 100C. HoweYer, the temperature can also vary within wide lLmit~, and essentially depends on the solvent used and the polymer.
The intake temperature is to be understood as meaning the temperature of the dryin~ air, which is sucked through the apparatu~ with the aid of the aspirator. Instead of air, it is of course also possible to employ another gas, if thP work to be carried out requires thi~.
During spray dryin~ of a solution, all or some of the solvent is removed, and the liquid ~olution droplets are thereby converted into particle~. So that the ~olvent evaporates during the contact time available when the goods to be dried are sprayed in a 6tream of air, the temperature of the stream of air must be above or clo~e to the boiling point of the solvent7 ~77~83 -- 1$ --That temperature of the stream of aix, which entrains the solid particles, before entry into the cyclone is the starting temperature. The starti.ng temperature results from the combination of intake temperature, ~spirator S setting, pump setting and concentration of the goods to be sprayed, and last bu~ not least also dep~nds on the heat o vaporization of the solvent.
The drying air is sucked through the apparatus with the aspirator, and at the same time a reduced pressure is generated. By regulating the aspirator output, on the one hand the amount of heated drying air i8 increased or reduced, and on the other hand the reduced pressure prevailing in the apparatus is regulated. A pressure which is in the range from 10 to 100 mbar below the pressure outside the apparatus, in particular from 30 to 70 mbar, is preferred.
The object of the delivery pump is to feed the spray solu~ion into the ~pparatus, and pump output~ of 100-500 ml/hour have proved appropria~eO
The spray flow is understood as meaning the amount o compressed air needed for atomization of the solution, emulsion or di~persion. Instead of compressed air; it i9 of course also possible to employ another gas.
The spray flow can be ~et on th~ appaxatu6 in ~he range ~5 from 100 to 800 Nl/hour (Nl = normal liter), in parti~
cular 600 to 800 Nl~hour.
Suitable solvents or solYent mixtures arer for example, water, tetrahydrofuran, methylene chloride, furan, DMSO
(dimethyl sulfo~ide), dioxane or acetone.
If the spray product doe~ not have a smooth ~urface after a trial spraying, smooth surfaces can be produced by addition of polymer pla~ticizers, such as DMSO or ~ 16 glycerol, to the solvent.
If the spray product shows smooth surfaces and circular particles after a trial spr~ying, concave surface curves inwards can be produced by addition of precipitating agents and/or temperature changes.
The shape of the particles according to the invention essentially results from the production pxocess and the choice of tha parameters, The particles according to the invention having concave surface segments are derived, for example, from circular particles having A constant diameter or hollow bodies. Shapes which look like cups, hats, cigars or cylinders also occur. The particles can be monolithic or in the form of hollow bodies, for example as hollow hemispheres curved inwar~s. Monolithic particles are tho~e which are essen~ially filled by the shaping substance; hollow bodies have a ~reater or smaller gas-filled interior. Hollow hemispherical par ticles curved inwards can be formed by greater or lesser invaginations of the hollow spheres. Spindle-shaped forms with two invagination~ of a circular particle furthermore have proved favorable. All the shape~ mentioned have proved to be suitable echogenic particles.
The distribution of the shapes in a batch produced by spray drying can vary within wide limits. Batches in which at least 5%, preferably 5 to 90~, in particular 10 to 60%, particularly preferably 30 to 40~ of the par-ticles have at least one concave surface segment have proved to bP favorable. Echogenic particles of which at least 5% have only one concave surface segment are parti-cularly preferred. The distribution of the shapes can be determined by computer a~sisted image analysis of the scanning electron microscope Lmage~ of tha particles, or with the aid of a cytophotometer.
- 17 - 2~773~3 The echogenic particles according to the invention can also have a smooth ~urface. This feature c~n be deter-mined, for example, by electron microscopy ~tudies, in particular by scanning electron microscopy (SEM3. For this, the particles are prepared and contrasted by the standard methods of electron microscopy. Vapor-deposited metals/ for example gold, have proved to be suitable contrast media for SEM image3. Smooth surface of par-ticles appear on the SEM image as homogeneous areas with a largely constant gray shade. Disturbances in the surface are recognized by different gray shades. Di tur-bances have a distanc~ from the average ~urface of the particles of more than 100 nm.
The particles according to the invention having a smooth surface are not completely ~ree from disturbances of the surface. The number of disturbances per ~m2 ranges from 0 to 4, preferably 0.5 to 3, in particular from 1 to 3. The quality of the ~mooth ~urface can be determined, for example, by selecting s~uare areas having an edge length of 0.5 ~m on the SEM Lmages of the particles according to the invention having a smooth surface, and determining the number of disturbances of the surface. The charac-teristic feature of a smooth surface is that, in a random selection of 10 ~quare areas, 0 to 10 disturbances of the surface are found, preferably on average 1 ~o 7.5~ in particular 2. 5 to 7 . 5 .
The distribution of the particles aecording to the i~ven~ion having a smooth surface in a batch produced by spray drying can vary within wide limits. Batches in which at least lO~, preferably 10 to 90%, in particular 20 to 60~, particularly preferably 30 ~o 40~ o~ the particles have a smooth surface have proved to be favorable.
The shaping substances can be employed by themselve or as a mixture in the proce~s described. These shaping :
2~77383 substances can al~o be employed as a mixture wi~h o~her biologically degradable and/or biologically compatible polymers, ~or example dex~ran~, polyethylene glycol~, hydroxyethyl-starch and other degradable or excretable polysaccharide3, or ph~siologically acceptable auxili-aries (for example D~SO, glycerol or other polymer plasticizers).
The invention furthe~more relates ~o diagnostic ag0nt~
and therapeutic agents, which can compri~e the ~chogenic particles according to the invention, in addition to pharmaceutically suitable and physiologically tolerated excipients, additives and/or auxiliaries.
Before administration, the echogenic particles according to the invention are conver~ed into a suitable diagnostic or therapeutic pres~nta~ion form by addition of one or more pharmaceutically suitable and physiologically acceptable excipients and if appropriate other additives and/or au~iliaries. For example, before administration, the echogenic particles are suspended by addition of water and mixi~g.
The physiological isotonicity of the particle suspen~ion can be established by addition of substances having an osmotic action, for example sodium chloride, galactose, glucose or fructose. Suspension auxiliaries, such as dextrans, or additives, such as colloidal infusion solutions or plasma substitution furthermore can be admixed to the particle suspensions.
In the processes described for the production of the echogenic particles according to the i~vention, particle sizes can be achieved in which 90% of the particles have : a diameter of 0.1 ~m to 50 ~m, and particle size distri-butions in which 90~ of the particles are less than 3 ~m are achieved in particular. Larger particles are siaved out with a sieve fabric which hae a mesh width of 1 ~m 19 2~7738~
to 50 ~m, in parkicular 3 ~m to 15 ~m. Particle ~izes o~
0.1 ~m to 7 ~m have pro~ed to be suitable for use of these echogenic particles as ultrasonic contrast media for diagnosis of cardiovascular diseases, and particle sizes of 0.1 ~m to 3 ~m are advantageously employed. The echogenic par~icles are injected, for example, into the bloodstream. 0.1 mg to 1000 mg of echogenic particles, preferably 1 mg to 100 mg, are employed per in~ection.
However, the echogenic particles can also be administered orally, in order to render the gastrointestinal tract accessible to ultrasonic examination.
The echogenic particles according to the invention can be used both for diagnostic and for therapeutic methods. The use of the echogenic particles according to the inYention is not limited merely to visualization of the blood-stream in the right ventricular portion of the blood circulation following venous administration. The echo-genic particles can be used with excellent success for ex~mination of the left side of the heart and of the myocardium. Furthermore, it i~ also possible to visualize other organs supplied with blood, such as the liver, spleen, kidneys or brain, using these echogenic particles.
However, the echogenic particles according to the inven-tion are also suitable for visualization of hollow cavities in humans, anLmal~ or plants, for example the urinary bladder, ureter, womb, vagina, ~ylem or phloem~
The invention is described in d~tail in the following e~amples. Percentage data relate to the weight, unless ~tated o~herwise.
., s~77~83 Example 1 Determination of the shape and lung accessibility of the echo~enic particles The average size, the shape and the na~ure of the ~urface are characteri~ed by means of scanning electron micro-scope images.
For this, the echogenic particles are ~prinkled onto conductive double-sided adhesive ~ape, and gold is vapor-deposited on in a sputtering unit - coating thickness about 1.8 nm, pressure ~bout 1 x 10-2 n~ar (sputtering unit type 07 120B, Balzerz Union). ~he SEM Lmages are produced with a Camscan ~canning electron microscope, type series 4; tilt angle 15; high voltage 20 kV, working distance 24 mm; secondary electrons, worXing lS vacuum abou~ 2 10-6 mbar.
In each case 30 mg of particles are dispersed in 2 ml of suspension auxiliary comprising 200 mg of dextran 40 (Roth, Germany), 10 mg of polysorbate and 16 mg of NaCl in distilled wa$er, and are then filtered with sieve fabrics (15 ~m and 3 ~m mesh width) and lyophili~ed.
The lung accessibility of the particles is tested in vivo. 30 mg of the filtered particles are resuspended in 1. 5 ml of distilled water with the ai-l of a gla~s rod.
This suspension is injected into a peripheral veLn with an injection syringe. An ultrasonic head of an ultrasonic unit (Toshiba, FSH 160a, Japan) is held against the thorax of the test animal, 50 that a typical cross-section through the right and left ventricle i8 obtained.
As soon as the ultrasonic contra~t medium re~ches the 30 right ventricle, it can be ~een on the monitor of the ultrasonic unit how the blood labeled by the contrast medium reaches the right auricle, and then leave~ the right Jentricle and sub~equently the heart via the - 21 - 2~7~3 pulmonary artery. ~fter passage through the lung, the contrast in th~ left ventricle is dis~inctly incrPa~ed by the contrast medium.
Example 2 S PreparationofpolysuccinLmide-co~ (hydroxyethyl)-D,L-aspartamide t70:30) 10 g (103 mmol) o polyanhydroaspartic acid are dissolved in about 40 ml of N,N-dLmethylformamide (DMF), if approp-riate with cautiou~ ~arming. 1.83 g (30 mmol) of freshly distilled 2-aminoethanol are added dropwise to this solution, and the mixture is stirred overnight at room temperature. The reaction mixture is precipitated in butanol and the product is washed several times with dried acetone. Drying is carried out in vacuo at elevated temperature. The white, wa~er-soluble product is formed to the extent of approximately 100~, and is tested for residues of DNF and butanol by NMR spectxoscopy. The molar ratio of polyanhydroaspartic acid to aminoethanol ~mployed approximately corresponds to th~ copolymer composition.
Example 3 Preparationofpolysuccinimide-co~ (nonyl carbonyloxy-ethyl)-D,L-aspartamide (50:50) 6 g of a polysuccinimide-co-~ (hydroxyethyl)-D,~-aspartamide (50:50) (= 24 mmol of hydro~yethyl groups), which was prepared analogously to Example 4 from poly-anhydroaspartic acid tmolecular weight = 14,000~ and 2-aminoethanol (molar ratio 2:1), are dissolved in 100 ml of dry DNF, 8 g (100 mmol) of dry pyridi~e are added and the mixture is cooled to 0C. 9.6 g of distilled decanoyl chloride are slowly added dropwise.
22 2~7~
The mixture i~ ~tirred overn.igh~ and precipitated in 0.5 l o ether. The product which has precipita~ed is filtered off with suction and washed with ethex, acetone, water t acetone and ether.
About 8 g of a white, completely substituted polymer ~NNR
control), which is soluble, for example, in methylene chloride and tetrahydrofuran, in each ca~e with a trace of DMSO, or in methanol/methylene chloride mixtures, are obtained.
Example 4 PreparationofpolysuccinLmide-co-~fl (nonyl-carbo~yloxy-ethyl)-D,L-aspaxtamide Various poly~uccinLmide-co~ -(hydro~yethyl)-D,L-aspart-amides, inter alia having the composition 70:30, 50:50 and 30:70, are prepared from polyanhydroaspartic acids of different molecular weight (molecular weight - 7000;
about 13,000, 30,000) analogously to ~xa~ple 2 and are reacted with decanoyl chloride, as described in Example 5, to give the corresponding poly~uccinLmide-co-~,~-(nonylcarbo~yloxyethyl~-D,L-aspartamides.
a) - PolysuccinLmide-co~ (nonylcarbonyloxy-ethyl)-D,L-aspartamide (70:30) ~rom polyanhydroaspartic acid (molecular weight = 7000); characterized by NMR.
b) - PolysuccinLmide-co-~ t ~- (nonylcarbonyloxy-ethyl)~
D,L-aspartamide (70:30) from polyanhydroaspaxtic acid (molecular weight = 14,000); characteri~ed by NMR.
c) - PolysuccinLmide-co~ -(nonylcarbonyloxy-ethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (molecular weigh~ = 30,000), characterized ~77.~3 - 2.~ -by NMR.
Ex~mple 5 20 g of polyanhydroaspartic acid-co~ (nonylcarbonyl-oxyethyl)-D,L-a~partamide 70:30 (prepared as in Example 6b) are dissolved in 400 ml of methylene chloride and the solution is sprayed to paxticles under the following conditions in a spray dryer (~ini Spray Dryer Buchi 190, Buchi GmbH, EislingPn):
Spraying conditions 10 Intake temperature: 60C
Outlet temperature: 40C
Scale divisions heating: 1.5 Pump settingl ~
Aspirator: 12 15 Spray flow jet air: 700 Nl/h Pressure in the filter: 55 mbar Cooling jet: 20C
Yield: about 8 g After spray drying, the methylene chloride concentration in the particles is less ~han 0~05%. The average size and shape and the nature of the surface are characterixed by means of scanning electxon mi~roscopy image~; the lung accessibility of the particles is determined as in Example 1.
~5 100 mg of the particles produced are suspended in a 1%
strength ~Haemaccel solution (Behring Werke ~&, ~arburg, Germany) and filtered throuyh sieve fabric (10 ym)~ The filtrate is then lyophilized and used to determined the lung accessibility.
2~77~3 Under the scanning electron microscope, the particles produced have an average particle ~iæe of 2 ~m and a smooth surface. Furthermore, the~e particle8 have access to the lungs.
About 15~ of the particles are circular hollow spheres and 50% of the particles are hollow spheres which have a spheric~l invagination, so ~hat a hemispherical hollow sphere is formed. The shell thickness of these hemi-spherical hollow spheres at the maximum invagination can be described by the equation rm - ri = 2 d (d = shell thickness, r~ - radius of the outer hemisphere, r1 =
radius of the inner concave hemisphere. If the hemi-sph~rical shape is not ideal, the radius is to be deter-mined from the relative central point of the invaginated hollow sphere.
About 25~ of the particles are hollow spheres having 2 ~o 5 invaginations of different size.
Example 6 Particles are produced from polyhydro~ybutyric acid type 159PHB (ICI Biological Products Ltd) in accordance with instructions by J.R. Embleton, B.J. ~ighe (J.
Microencapsulation, 1992, ~olume 9, ~o. 1, 73-87) by the so-called "double emulsion solvent evaporation proce~s".
The evaporation is carried out at room temperature. The particles are fractionated by centrifugation and filtra-tion through a 10 ~m sieve fabric. A particle content of 35~ having concave surface segments i6 then determined in thè filtrate by scanning electron microscopy.
The evaporation is also carried out at 40C and the particles are then fractionated. For comparison, fraction with a particle content of only 5~ having concave surface 8e~ments is determined in thi~ manner ~y scanning electron microscopy.
~77383 EY.amP1 e 7 ( LMP G 5 0 / 5 0 ) Preparation of poly(L-lysine methyl ester-fumaric acid/-L-lysine methyl ester-glutaramide ) Copolymer 5 0 : 5 0 ~ LMFG 5 0: 5 0 ) 0.7 g of glutaric acid dichloride and 0.84 g of fumaric acid dichloride are dissolved in 170 ml of CH2Cl2. ~his solution is added ~o a solution of 2.91 g of L-ly~ine methyl ester ~nd 3.0 g of Na2C03 in 120 ml of H20 at room temperature, while tirring vigoxously. The polyconden-sation, which starts suddenly, is interrupted after15 minutes by addition of 150 ml of lN agueou~ HCl. The me~hylene chloride is then driven off by passing in steam. The hot aqueous mixture is filtered and the solid product is washed ~everal tLmes with water~
Yield: 1.3 g (60% of theory) after vacuum drying (20 hours) Exampls 8 2 g of polymer from Example 7 are dissolved in 100 ml of DNS0 and the solution is ~prayed to particles at an intake temperature of about 200C in a Mini Spray Dryer Buchi 190. The average size and the nature of the surface are characteriz~d by means of scanning electron micro-scopy images tsee Table 1). In each case 50 mg of par-ticles ar~ suspended in 2 ml of suspension auxiliary l1%
of ~Haemaccel in isotonic water) and subsequently filtered with sieve fabric (15 ~m and 3 ~m mesh width) and lyophilized.
Example 9 2 g of polyhydroxybutyric acid type 159 PHB (ICI
Biological ~roducts ~td) are dissolved in 100 ml of a - 26 - 2~773~3 furan/methylene chloride (9:1~ mixture, the solution is sprayed to particles at about 45C in a Bushi Mini Spxay Dryer, and the particles are further processed analogously to Example 8.
Example 10 A solution of 2 g of polyhydroxybutyric acid type 159 PHB
(ICI Biological Products Ltd) in 100 ml of methylene chloride/MeOH (1:2) is sprayed to particles at about 45C
in a Buchi Mini Spray Dryer, and the particles are further processed analogously to Example 8.
Example 11 2 g of poly_e-caprolactone (Polysciences 19561~ are dissolved in methylene chloride to give a 2% strength solution, the solution is sprayed to particles at room temperature in a BUchi Mini Spray Dryer, and the par-ticles are further processed analogously to Example 8.
The lung accessibility of the particles from Examples 8 to 11 is tested in vivo and determined as in Example 1.
The following table shows the resultsO
- 27 2~7~
Table 1 PolymerSolvent ~verage Surf ace Lung according particle access-to size ibility . Example ~ _ 8 DMSO 3 ~m smooth yes 9 furan/ 3 ~m smooth yes methylene . ~ l~lori~ _ _ t0 CH2Cl2/ 2 ~m rough no MeOH 1:2 .
11 CH2Cl2 3 ~m smooth yes
Claims (18)
1. An echoganic particle which comprises a gas and a shaping substance or a substance mixture, which is biologically degradable and/or excretable, and can pass through the lungs of vertebrates in the blood circulation, wherein the surface of the echogenic particle is essentially smooth and the shape of the echogenic particle comprises no or 1 to 10 concave surface segments, or the surface of the echogenic particle is not smooth and the shape of the echogenic particle comprises 1 to 10 concave surface segments.
2. An echogenic particle as claimed in claim 1, which comprises, as the shaping substance, at least one polymer from the following group, polyesters of .alpha.-, .beta.-, .lambda.-, or .epsilon.-hydroxycarboxylic acids, copolymers of the polyesters with one another or with polyglycolic acid; polyamides; polyamino acids; polyorthoesters;
polycondensates which comprise 2,3-O-alkylidenetar-taric acid, 2,3-O-alkylidene-L-threitol, furo-[2,5]
groups or terephthalates; polyaminodicarboxylic acid; co-imides polyanhydrides; polymethylene malonate; gelatin; albumins and polysaccharides, or comprises at least one shaping substance from the group comprising sugars; fatty acids; amino acids;
alcohols having 12 to 20 carbon atoms and lipids.
polycondensates which comprise 2,3-O-alkylidenetar-taric acid, 2,3-O-alkylidene-L-threitol, furo-[2,5]
groups or terephthalates; polyaminodicarboxylic acid; co-imides polyanhydrides; polymethylene malonate; gelatin; albumins and polysaccharides, or comprises at least one shaping substance from the group comprising sugars; fatty acids; amino acids;
alcohols having 12 to 20 carbon atoms and lipids.
3. An echogenic particle as claimed in claim 1 or 2, which comprises, as the shaping substance, at least one polymer from the following groups poly-.epsilon.-capro-lactone; polyhydroxybutyric acid; polylactic acid;
polyhydroxyvaleric acid; polyglutamic acid; poly-aspartic acid; polylysine; polysuccinimide-co-.alpha.,.beta.-(butyl-oxycarbonyl-propionyloxyethyl)-D,L-aspart-amide; polyanhydrides of sebacic acid and bis(p-carboxyphenoxy)propane; polylysine methyl ester fumaric acid co-glutaramide; dextrans; starch; basic or acid derivatives of dextrans or starch; poly-hydroxyethylaspartamide; bovine serum albumin; and hydrophobically modified gelatin, and at least one shaping substance from the following group compris-ing glucose; galactose; lactose; sucrose; fatty acids having 8 to 20 carbon atoms; proteinogenic amino acids; hydrophobic derivatives of proteino-genic amino acids and phospholipids, or mixtures thereof.
polyhydroxyvaleric acid; polyglutamic acid; poly-aspartic acid; polylysine; polysuccinimide-co-.alpha.,.beta.-(butyl-oxycarbonyl-propionyloxyethyl)-D,L-aspart-amide; polyanhydrides of sebacic acid and bis(p-carboxyphenoxy)propane; polylysine methyl ester fumaric acid co-glutaramide; dextrans; starch; basic or acid derivatives of dextrans or starch; poly-hydroxyethylaspartamide; bovine serum albumin; and hydrophobically modified gelatin, and at least one shaping substance from the following group compris-ing glucose; galactose; lactose; sucrose; fatty acids having 8 to 20 carbon atoms; proteinogenic amino acids; hydrophobic derivatives of proteino-genic amino acids and phospholipids, or mixtures thereof.
4. An echogenic particle as claimed in one or more of claims 1 to 3, which comprises, as the shaping substance, at least one polymer from the following group: polyamides; polycondensates; polyhydroxy-butyric acid and polyaminodicarboxylic acid co-imides.
5. An echogenic particle as claimed in one or more of claims 1 to 4, wherein the maximum invagination of the concave surface segment is more than 10% of the smallest particle cross-section.
6. An echogenic particle as claimed in claim 5, wherein the invagination is 30% to 90%, in particular 50% to 90%.
7. An echogenic particle as claimed in one or more of claims 1 to 6, which comprises, as the gas, air, oxygen, a noble gas, hydrogen, carbon dioxide, oxygen or mixtures thereof.
8. An echogenic particle as claimed in one or more of claims 1 to 7, wherein the particle is monolithic or in the form of a hollow body.
9. An echogenic particle as claimed in claim 8, wherein the hollow body has 2 to 10 concave surface segments.
10. A mixture of echogenic particles as claimed in claim 8, wherein at least 5%, in particular 10 to 60% of the echogenic particles have at least one concave surface segment per particle.
11. An echogenic particle as claimed in one or more of claims 1 to 10, wherein the surface has 0 to 4, in particular 1 to 3, disturbances per µm2.
12. A mixture of echogenic particles as claimed in claim 11, wherein at least 10%, in particular 20 to 60%, of the echogenic particles have 0 to 4, in parti-cular 1 to 3 disturbances per µm2.
13. A process for the production of echogenic particles as claimed in one or more of claims 1 to 12, which comprises dissolving the shaping substance or the substance mixture in a suitable solvent or solvent mixture and then subjecting the solution to spray drying.
14. A diagnostic agent or therapeutic agent comprising echogenic particles as claimed in one or more of claims 1 to 12 or produced by the process as claimed in claim 13, in addition to pharmaceutically suit-able and physiologically tolerated excipients and if appropriate other additives and/or auxiliaries.
15. A process for the preparation of a diagnostic agent or therapeutic agent as claimed in claim 14, which comprises bringing echogenic particles as claimed in one or more of claims 1 to 12 or produced as claimed in claim 13 into a suitable diagnostic or thera-peutic presentation form with a pharmaceutically suitable and physiologically tolerated excipient and if appropriate other additives and auxiliaries.
16. A process as claimed in claim 15, wherein the echogenic particles are filtered through a sieve fabric having a mesh width of 1 µm to 50 µm, in particular 3 µm to 15 µm.
17. The use of the echogenic particles as claimed in one or more of claims 1 to 12 or produced by the process as claimed in claim 13 for the preparation of diagnostic agents for visualization of the blood circulation or of organs supplied by blood.
18. The use of the echogenic particles as claimed in one or more of claims 1 to 12 for the preparation of a diagnostic agent for contrasting hollow cavities in humans, animals or plants.
Applications Claiming Priority (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE4129187 | 1991-09-03 | ||
DEP4129187.5 | 1991-09-03 | ||
DE4209487 | 1992-03-24 | ||
DE4209488A DE4209488A1 (en) | 1992-03-24 | 1992-03-24 | Ectogenic particles with smooth surface and/or concave segments |
DEP4209487.9 | 1992-03-24 | ||
DEP4209488.7 | 1992-03-24 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA2077383A1 true CA2077383A1 (en) | 1993-03-04 |
Family
ID=27202878
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA002077383A Abandoned CA2077383A1 (en) | 1991-09-03 | 1992-09-02 | Echogenic particles, a process for their production and their use |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0535387B2 (en) |
JP (1) | JPH05194276A (en) |
KR (1) | KR100267164B1 (en) |
AT (1) | ATE141518T1 (en) |
AU (1) | AU660039B2 (en) |
CA (1) | CA2077383A1 (en) |
DE (1) | DE59206943D1 (en) |
DK (1) | DK0535387T3 (en) |
ES (1) | ES2093160T5 (en) |
GR (1) | GR3021038T3 (en) |
NO (1) | NO305685B2 (en) |
NZ (1) | NZ244147A (en) |
TW (1) | TW222236B (en) |
Cited By (9)
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US6258339B1 (en) | 1993-07-30 | 2001-07-10 | Alliance Pharmaceutical Corp. | Osmotically stabilized microbubble preparations |
US6280705B1 (en) | 1993-07-30 | 2001-08-28 | Alliance Pharmaceutical Corp. | Kits & systems for ultrasonic imaging |
US6585955B1 (en) | 1990-04-02 | 2003-07-01 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US6881397B2 (en) | 1990-04-02 | 2005-04-19 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
US6896875B2 (en) | 1990-04-02 | 2005-05-24 | Bracco International B.V. | Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging |
US6989141B2 (en) | 1990-05-18 | 2006-01-24 | 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 |
US7083778B2 (en) | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
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DE4219723A1 (en) * | 1992-06-13 | 1993-12-16 | Schering Ag | Microparticles, processes for their production and their use in diagnostics |
US6333021B1 (en) | 1994-11-22 | 2001-12-25 | Bracco Research S.A. | Microcapsules, method of making and their use |
WO1996040277A2 (en) * | 1995-06-07 | 1996-12-19 | Brown University Research Foundation | Spray dried polymeric microparticles containing imaging agents |
PT904113E (en) * | 1996-03-05 | 2004-09-30 | Acusphere Inc | FLUORATED GASES MICROENCAPSULATED FOR USE AS IMAGE ACQUISITIVE AGENTS |
US5611344A (en) * | 1996-03-05 | 1997-03-18 | Acusphere, Inc. | Microencapsulated fluorinated gases for use as imaging agents |
US5837221A (en) | 1996-07-29 | 1998-11-17 | Acusphere, Inc. | Polymer-lipid microencapsulated gases for use as imaging agents |
US8012457B2 (en) | 2004-06-04 | 2011-09-06 | Acusphere, Inc. | Ultrasound contrast agent dosage formulation |
EP1824521B1 (en) * | 2004-11-19 | 2015-01-07 | Koninklijke Philips N.V. | Ultrasound contrast agents for molecular imaging |
EP1741968A1 (en) * | 2005-07-08 | 2007-01-10 | Uponor Innovation Ab | Clamping ring |
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US4107288A (en) † | 1974-09-18 | 1978-08-15 | Pharmaceutical Society Of Victoria | Injectable compositions, nanoparticles useful therein, and process of manufacturing same |
US4265251A (en) * | 1979-06-28 | 1981-05-05 | Rasor Associates, Inc. | Method of determining pressure within liquid containing vessel |
US4718433A (en) † | 1983-01-27 | 1988-01-12 | Feinstein Steven B | Contrast agents for ultrasonic imaging |
US4900540A (en) † | 1983-06-20 | 1990-02-13 | Trustees Of The University Of Massachusetts | Lipisomes containing gas for ultrasound detection |
SE8701479L (en) † | 1987-04-09 | 1988-10-10 | Carbomatrix Ab | METHOD FOR CONTAINING BIOLOGICALLY EFFECTIVE PREPARATIONS AND USE THEREOF |
IE61591B1 (en) † | 1987-12-29 | 1994-11-16 | Molecular Biosystems Inc | Concentrated stabilized microbubble-type ultrasonic imaging agent and method of production |
SE465910B (en) * | 1988-01-28 | 1991-11-18 | Jan Axel Svensson | DEVICE FOR CONNECTING CATHETRES IN A SKIN REVIEW |
IE66912B1 (en) * | 1988-02-05 | 1996-02-07 | Schering Ag | Ultrasonic contrast agents process for their preparation and their use as diagnostic and therapeutic agents |
US4957656A (en) † | 1988-09-14 | 1990-09-18 | Molecular Biosystems, Inc. | Continuous sonication method for preparing protein encapsulated microbubbles |
FR2660864A1 (en) † | 1990-04-13 | 1991-10-18 | Guerbet Sa | CONTRAST COMPOSITION, PROCESS FOR PREPARING THE SAME, AND IMAGING APPLICATION. |
US5137928A (en) * | 1990-04-26 | 1992-08-11 | Hoechst Aktiengesellschaft | Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents |
AU636481B2 (en) † | 1990-05-18 | 1993-04-29 | Bracco International B.V. | Polymeric gas or air filled microballoons usable as suspensions in liquid carriers for ultrasonic echography |
US5236693A (en) * | 1990-11-14 | 1993-08-17 | Brigham And Women's Hospital | Medical ultrasound contrast agent and method of using same |
DE4219723A1 (en) † | 1992-06-13 | 1993-12-16 | Schering Ag | Microparticles, processes for their production and their use in diagnostics |
-
1992
- 1992-08-31 NZ NZ244147A patent/NZ244147A/en unknown
- 1992-09-02 JP JP4234020A patent/JPH05194276A/en not_active Abandoned
- 1992-09-02 KR KR1019920015887A patent/KR100267164B1/en not_active IP Right Cessation
- 1992-09-02 DK DK92114981.1T patent/DK0535387T3/en active
- 1992-09-02 AU AU22039/92A patent/AU660039B2/en not_active Ceased
- 1992-09-02 CA CA002077383A patent/CA2077383A1/en not_active Abandoned
- 1992-09-02 AT AT92114981T patent/ATE141518T1/en not_active IP Right Cessation
- 1992-09-02 ES ES92114981T patent/ES2093160T5/en not_active Expired - Lifetime
- 1992-09-02 NO NO19923424A patent/NO305685B2/en not_active IP Right Cessation
- 1992-09-02 EP EP92114981A patent/EP0535387B2/en not_active Expired - Lifetime
- 1992-09-02 DE DE59206943T patent/DE59206943D1/en not_active Expired - Lifetime
- 1992-09-05 TW TW081107034A patent/TW222236B/zh active
-
1996
- 1996-09-13 GR GR960402397T patent/GR3021038T3/en unknown
Cited By (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US6585955B1 (en) | 1990-04-02 | 2003-07-01 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
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 |
US6896875B2 (en) | 1990-04-02 | 2005-05-24 | Bracco International B.V. | Mixable combination for generating a suspension of stable microbubbles for ultrasonic imaging |
US6881397B2 (en) | 1990-04-02 | 2005-04-19 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure-resistant gas-filled microvesicles and methods for the preparation thereof |
US6613306B1 (en) | 1990-04-02 | 2003-09-02 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US6989141B2 (en) | 1990-05-18 | 2006-01-24 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US6592846B1 (en) | 1991-05-03 | 2003-07-15 | Bracco International B.V. | Long-lasting aqueous dispersions or suspensions of pressure resistant gas-filled microvesicles and methods for thereof preparation thereof |
US7083778B2 (en) | 1991-05-03 | 2006-08-01 | Bracco International B.V. | Ultrasound contrast agents and methods of making and using them |
US6372195B1 (en) | 1993-07-30 | 2002-04-16 | Alliance Pharmaceutical Corp. | Mixed gas microbubble compositions |
US6287539B1 (en) | 1993-07-30 | 2001-09-11 | Alliance Pharmaceuticals Corp. | Methods of imaging using osmotically stabilized microbubble preparations |
US6280705B1 (en) | 1993-07-30 | 2001-08-28 | Alliance Pharmaceutical Corp. | Kits & systems for ultrasonic imaging |
US6939531B2 (en) | 1993-07-30 | 2005-09-06 | Imcor Pharmaceutical Company | Ultrasonic imaging system utilizing a long-persistence contrast agent |
US6953569B2 (en) | 1993-07-30 | 2005-10-11 | Imcor Pharmaceutical Company | Mixed gas microbubble compositions |
US6258339B1 (en) | 1993-07-30 | 2001-07-10 | Alliance Pharmaceutical Corp. | Osmotically stabilized microbubble preparations |
US7005120B2 (en) | 1993-07-30 | 2006-02-28 | Imcor Pharmaceutical Company | Osmotically stabilized microbubble preparations |
US6280704B1 (en) | 1993-07-30 | 2001-08-28 | Alliance Pharmaceutical Corp. | Ultrasonic imaging system utilizing a long-persistence contrast agent |
US7141235B2 (en) | 1993-07-30 | 2006-11-28 | Imcor Pharmaceutical Co. | Stabilized gas emulsion containing phospholipid for ultrasound contrast enhancement |
Also Published As
Publication number | Publication date |
---|---|
AU660039B2 (en) | 1995-06-08 |
KR100267164B1 (en) | 2000-10-16 |
NO923424D0 (en) | 1992-09-02 |
NO305685B1 (en) | 1999-07-12 |
NO923424L (en) | 1993-03-04 |
AU2203992A (en) | 1993-03-11 |
EP0535387B2 (en) | 2001-10-04 |
DK0535387T3 (en) | 1996-12-09 |
ES2093160T3 (en) | 1996-12-16 |
TW222236B (en) | 1994-04-11 |
JPH05194276A (en) | 1993-08-03 |
ES2093160T5 (en) | 2002-03-16 |
EP0535387A1 (en) | 1993-04-07 |
NO305685B2 (en) | 1999-07-12 |
ATE141518T1 (en) | 1996-09-15 |
KR930005618A (en) | 1993-04-20 |
DE59206943D1 (en) | 1996-09-26 |
EP0535387B1 (en) | 1996-08-21 |
GR3021038T3 (en) | 1996-12-31 |
NZ244147A (en) | 1994-09-27 |
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Legal Events
Date | Code | Title | Description |
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EEER | Examination request | ||
FZDE | Discontinued |