CA2041260C - Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents - Google Patents
Ultrasonic contrast agents, processes for their preparation and the use thereof as diagnostic and therapeutic agents Download PDFInfo
- Publication number
- CA2041260C CA2041260C CA002041260A CA2041260A CA2041260C CA 2041260 C CA2041260 C CA 2041260C CA 002041260 A CA002041260 A CA 002041260A CA 2041260 A CA2041260 A CA 2041260A CA 2041260 C CA2041260 C CA 2041260C
- Authority
- CA
- Canada
- Prior art keywords
- ultrasonic contrast
- contrast agent
- formula
- solvent
- derivatives
- 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.)
- Expired - Lifetime
Links
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- 230000007717 exclusion Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229930182830 galactose Natural products 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 150000004676 glycans Chemical class 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
- 229940050526 hydroxyethylstarch Drugs 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000002163 immunogen Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000012442 inert solvent Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 229910052743 krypton Inorganic materials 0.000 description 1
- DNNSSWSSYDEUBZ-UHFFFAOYSA-N krypton atom Chemical compound [Kr] DNNSSWSSYDEUBZ-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 230000036244 malformation Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 125000001624 naphthyl group Chemical group 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
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- VFXVAXFIFHSGNR-UHFFFAOYSA-N octyl carbonochloridate Chemical compound CCCCCCCCOC(Cl)=O VFXVAXFIFHSGNR-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 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
- 239000004014 plasticizer Substances 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001993 poloxamer 188 Polymers 0.000 description 1
- 108010064470 polyaspartate Proteins 0.000 description 1
- 238000006068 polycondensation reaction Methods 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002643 polyglutamic acid Polymers 0.000 description 1
- 229920001721 polyimide Polymers 0.000 description 1
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 210000001147 pulmonary artery Anatomy 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 210000005245 right atrium Anatomy 0.000 description 1
- 210000005241 right ventricle Anatomy 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 description 1
- 235000015500 sitosterol Nutrition 0.000 description 1
- 229950005143 sitosterol Drugs 0.000 description 1
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 description 1
- 229940032091 stigmasterol Drugs 0.000 description 1
- 235000016831 stigmasterol Nutrition 0.000 description 1
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 125000003107 substituted aryl group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960002317 succinimide Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 210000000626 ureter Anatomy 0.000 description 1
- 210000003932 urinary bladder Anatomy 0.000 description 1
- 210000004291 uterus Anatomy 0.000 description 1
- 210000001215 vagina Anatomy 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 238000010792 warming Methods 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Abstract
The invention relates to ultrasonic contrast agents composed of microparticles which contain a gas and polyamino-dicarboxylic acid-co-imide derivatives, to processes for their preparation and to their use as diagnostic and therapeutic agents.
Description
HOECHST AKTIEIdGESELLSCHAF'T HOE 90/F 127 Dx. Tl~i/Le Description Ultrasonic contrast agents. processes for their preparation and the use thereof as dia~ctnostic and therapeutic a eg nts The invention relates to ultrasonic contrast agents composed of microparticles which contain a gas and polyamino-dicarboxylic acid-co-imide derivatives, pro cesses for their preparation and their use as diagnostic t0 and therapeutic agents.
Ultrasonic diagnosis has become very widely used in medicine because it is complication-free and straight-forward to perform. Ultrasonic waves are reflected at interfaces of different types of tissue. The echo signals i5 produced thereby are electronically amplified and displayed.
Visualization of blood vessels and internal organs by ultrasound does not in general allow visualization of the blood flow present therein. Liquids, especially blood, 20 provide ultrasonic eontrast only when there are density differences with respect to the surroundings. Used as contrast agents in medical ultrasonic diagnosis are, for example, substances which contain gases or produce gases, because the difference in ianpedance between gas and 25 surrounding blood is considerably greater than that between liquids or solids and blood (Levine R.A., J Am Coll Cardiol 3: 28, 1989; Machi I.J CU 11: 3, 1983).
Several methods for preparing and stabilizing gas bubbles are disclosed in the literature. Ua Patent 4,276,885 30 describes the preparation of small gas bubbles of defined size which are enclosed by a gelatin casing which pre-vents coalescence of the gas bubbles. The prepared small gas bubbles can be stored only in the frozen state, and A 2 - ~°~~~:~~~~
'the small gas bubbles must be returned to body tempera-ture for use.
EP-A2 0,123,235 and 0,122,624 describe ultrasonic con-trast agents which contain gases and are composed of mixtures of surface-active substances with a solid in a liquid vehicle. The ultrasonic contrast agents are prepared by an elaborate milling process with an air-jet mill. The particles prepared in this way have only a short duration of use because they rapidly lose the entrapped gases.
EP-A2 0,224,934 describes ultrasonic contrast agents in the form of gas-filled gelatin or albumin hollow bodies.
However, the disadvantage is the use o~ exogenous or denatured endogenous proteins because of the allergenic risk associated therewith.
EP-A1 0,327,490 describes microparticles which are composed of amyloses or synthetic, biodegradable polymers and of a gas andlor a liquid with a boiling point below 60°C. The disadvantages of these polymers are their sticky consistency in water or blood, their poor bio-degradability, their toxicity or the production of toxic degradation products.
It has already been proposed (German Patent Application P 40 02 736.8) to employ polyamino-dicarboxylic acid-co-imide derivatives as biodegradable depot formulations of pharmaceuticals with controlled release of active substance.
The object of the present invention was to develop ultrasonic contrast agents based on microparticles, which provide a distinct contrast from the surrounding tissue, which axe so small and stable that they reach, without considerable loss of gas and essentially quantitatively, the left half of the heart after intravenous administra-tion, are well tolerated without an allergenic potential, do not form aggregates in water or blood, and can be prepared rapidly and straightforwardly.
Microparticles which are, surprisingly, outstandingly suitable as ultrasonic contrast agents have been prepared from polyamino-dicarboxylic acid-co-imide derivatives (polydicarboxylic acid-co-AHADA derivatives). In particu-lar, the amenability of the prepared microparticles to be suspended in water is outstanding owing to the incorpora-tion of unopened imide rings (AHA1~A rings ) . The micro-IO particles do not have a sticky, greasy consistency in water-containing liquids and form scarcely any agglomer-ates. The polymers form a pharmacologically inert matrix in which the gas is entrapped. In vivo, these polymers are metabolized to non-toxic, non-allergenic and non-I5 immunogenic compounds and are excreted. It was possible to show in animal experiments that the microparticles essentially pass through the lungs without significant loss of gas and result in an ultrasonic contrast of equal intensity in both halves of the heart. The echocardio-20 grams recorded therewith show no wall-movement disturb-ances whatever during and up to 60 min after adminis-tration of the contrast agent. Furthermore, it was not possible to find any changes whatever in a six-channel ECG or in the contractility determined using a tip 25 manometer.
The ultrasonic contrast agents according to the invention bring about an improved increase in echogenicity in the myocardium and permit improved visualization of the endocardium. Tt is furthermore possible, for example, to 30 assess the following parameters better:
ventricle size, wall-movement disturbances, stroke volume, ejection fraction or intracavitary masses, for example thrombi or tumors. Furthermore, the ultrasanic contrast agents according to the invention make it 35 possible to evaluate flow patterns in cases of valvular insufficiency of the left and of the right half of the heart, intracardiac shunts, and improved visualization of the large vessels in cases of congenital malformation. A
massive enhancement of the Doppler signal has also been observed.
The invention thus relates to ultrasonic contrast agents composed of microparticles which contain a gas and a polyamino-dicarboxylic acid-co-amide derivative of the formula I, "">~-NH ,,.-C00H
(CH2)" (CH2>"- (CH ) C-R ~ ~'w=COOH
H2N ~ .0 0 x d in which n is 1 or 2 x is 1 to 500 y is Z to 500, where x + y is 2 to 1000, and R is 0-R1 or NH-R2, in. which I5 R2 is H, ( CHZ ) m-ORl, ( CH2 ) m-0-C ( o ) -Rl or ( CH2 ) m ~-C ( 0 ) -OR1, and m is 2 to 6, and R1 is H, aryl, aralkyl, arylalkenyl, alkyl or C3-C8-cycloalkyl or a biologically inactive steroid alcohol or an amino acid, where aryl is unsubstituted or is substituted by C1-C4-alkyl, CZ-C4-alkenyl, C1-C4-alkylcarbonyloxy, C1-C4-alkoxy-Carbonyl, Cl-CH-alkoxy or hydroxyl, where the alkyl radicals specified for R1 have i-22 - ~ - ~~~3~~~'~
carbon atoms and the alkenyl radicals have 2-22 caxbon atoms, which are not interrupted or are interrupted by a carbonyloxy or oxycarbonyl group, where the repeating units placed in square brackets are distributed randomly and/or in blocks in the polymer, and where both the repeating units labeled with x and those labeled with y are identical or different and where the amino acids are a- andlor ~-linked.
Hy aryl are meant aromatic hydrocarbons such as phenyl and naphthyl, especially phenyl. In the substituted aryl radicals indicated, 1 to all replaceable hydrogen atoms are replaced by identical or different substituents. The aryl radicals are preferably mono- or disubstituted.
The said alkyl and alkenyl radicals can be both straight-chain and branched.
The biologically inactive steroid alcohols are preferably linked via their OH group. A preferred steroid alcohol is cholesterol.
In the case of the amino acids specified for R1, they are preferably naturally occurring amina acids such as Tyr, Ala, Ser or Cys, particularly preferably Tyr and Ala.
They can be linked both via their hTHZ and via their C~OH
group.
The invention also relates to processes for the prepara-tion of gas-containing microparticles which are composed -of the abovementioned polymers or contain these, and to their use, also mixed with other, biocompatible andlor biodegradable polymers or physiologically acceptable 30' auxiliaries, for diagnostic or therapeutic procedures.
The invention further relates to diagnostic or thera peutic agents composed of at least one ultrasonic con trast agent as claa.med in one or more of claims 1 to 4 or of at least one ultrasonic contrast agent prepared by process 5.
-The invention additionally relates to processes for the preparation of diagnostic or therapeutic agents, which comprise converting the abovementioned ultrasonic con-trast agents with a physiological vehicle and, where appropriate, further additives and/or auxiliaries into a suitable administration form.
The invention is described in detail hereinafter.
Aspartic acid and/or glutamic acid are employed as amino dicarboxylic acids which react in a polycondensation reaction to give the corresponding polyimides (poly-anhydro-amino-dicarboxylic acids, formula II). Partial reaction with one or more compounds of the formulae ITI
and/or IV and/or NH3 HO-R1 (III) I S HZN- ( CHZ ) m OH ( I V ) r in which m and Rl are defined as above for formula I, results in an a, p-poly-D,L-amino acid ester-co-imide of the formula VIIT
0 ~'3 (C~ 2>~~COOH
Z 0 HEN i~ (CH2 )~ ( I I ) + H~-R1 ( I I I ) "''~COOH
x~.y HzN- ( OHa ) ro-OH ( I V ) ---~ f CHI ) NH CCH2 )" ( CH ) COON ('VII I ) HEN ~-R- ~ ~''~COOH
0 x 0 H .
R' = O-Rl, HN- ( CH2 ) ~ OH, NH2 It is essential that in this reaction the polyanhydro-n, a amino-dicaxboxylic acid (II) is only partially converted into the open-chain derivatives. The proportion of unopened anhydro-amino-dicarboxylic acid units is 0.1 to 99,9, preferably 10 to 90~ (the percentages relate to the total number of repeating units in the total poly-mer). Depending on the side on which the imide ring is opened in the reaction described above, «- or p-linked amino acids are obtained. Compounds of the formulae III
and IV which are preferably employed are: 2-aminoethanol, I0 3-aminopropanol, 2-aminopropanol, alcohols with 1-18 carbon atoms, especially methanol, ethanol, isoamyl alcohol and isopropyl alcohol, A process for the preparation of «,p-poly-(2-hydroxy-ethyl)-DL-aspartimide (PHEA) (formula I; y = 0;
R = NH-CHz-CHZ-QH) is described by P. Neri, G. Antoni, F. Benvenuti, F. Cocola, G. Gazzei, in J. Med. Chem.
Vol. 16, 893 ( 1913) . A general procedure for the prepara-tion of PHEA is to be found in P. Neri, G. Antoni, Macromol. Synth. Vol. 8, 25. Express reference is made to this citation at this point. The reaction takes place in high yield to give a product of high purity. It is possible to prepare in the same way, by less than stoichiometric use of NH3 and/or compounds of the formulae III and/or IV, the analogous poly-aspartic acid derivative-co-succinimide compaunds of the formula VIII
(n = 1).
A different, more elaborate process as is described in US Patent 4,356,166 must be used to prepare pure poly-(hydroxyalkyl)-L-glutamine. This entails initially the y-COON group of the L-glutamic acid being Protected by esterification with benzyl alcohol. This y-benzyl gluta-mate is subsequently reacted with phosgene to give an N-carboxylic anhydride which then polymerizes after addition of triethylamine in an inert solvent to result in poly-y-(benzyl)-L-glutamate. The protective group is eliminated either by adding an HC1/I~Br mixture to give the free poly-«-L-glutamic acid or else in the presence -of hydroxyalkylamines to give the analogous poly-a-(hydroxyalkyl)-h-glutamines. A general procedure for 'the preparation of poly-a-(hydroxypropyl)-h-glutamine is to be found in US Patent 4,355,166, to which express refer-s ence is made at this point. It is also possible in the same way, by using NH;~ and/or compounds of the formula ITT
and/or IV, to prepare the analogous compounds of the formula VIII (n = 2).
Compared with the elaborate preparation of pure poly-glutamic acid and its derivatives, it is possible to incorporate glutamic acid i.n up to high proportions on simple condensation of aspartic acid using phosphoric acid to give polyanhydroaspartic said-co-glutamic acid.
The polyamino-amide-co-imides of the formula VIIT
(R'= HN- (CHZ)m 0H) can now, if necessary, be reacted in the following reaction step with one or more different biologically inactive compounds of the formula V and/or VI and/or VIT
X-R1 (V) X-C-R~ (VI) X-C-OR1 (VII) 2 0 ~I II
to give further polyamino-dicarboxylic acid-co-AHADA
derivatives. In this case, X is a leaving group which allows mild esterification of the polymer alcohol group.
Chlorine, bromine, iodine, ianidazolides, anhydrides or hydroxyl, especially chlorine, are preferred.
The reaction with the compounds of the formula V, VI or VII type can be carried out both with a single compound of this type and with any desired combinations of these compounds, or else with compounds which have different radicals Rl, for example differing in the nature of their branching, in particular in their chain length.
The last-mentioned alkylation or acylation on the polymer is carried out by known processes of organic chemistry.
It takes place selectively on the hydroxyl group ( formula VI I I , F~' = HIS- ( C~i~ ) ~-OH ) to give ethers , esters , or carbonates without attacking other groups on the initial polymer. Particularly suitable is the Einhorn variant of the Schotten-Baumann acylation in the presence of gyridine. In this case, very high levels of. derivitiza tion (greater than 70~) axe achieved under mild condi tions.
The molecular weight of the polymers is 200 to 100,000, preferably 3,000 to 70,000.
Compounds of the formula V type can be bought or, if not, synthesized in a straightforward manner by processes known from the literature.
The chloroformic esters (foranula VxI) are obtained by reacting phosgene with the appropriate biologically inactive, physiologically acceptable, aromatic, araliphatic, aliphatic or cycloaliphatic, especially unbranched alcohols. The alcohols which are particularly preferably employed are those which have an even number of carbon atoms. The chloroformylated steroids are also obtained in this way. Thus, in principle, all bio-logically inactive steroids having reactive hydroxyl groups can be obtained. Examples which may be mentioned here are: cholesterol, cholestanoi, coprostanol, ergosterol, sitosterol or stigmasterol.
The acid chlorides (formula VI) which can likewise be employed are obtained, for example, from the correspond-ing carboxylic acids by reaction with phosphorus tri-chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
Compounds of the formula V, VI or VII type in which an alkyl chain is interrupted by an oxycarbonyl or carbonyloxy group are prepared, for example, by reaction of cyclic dicarboxylic acid anhydrides with alcohols. The dicarboxylic monoesters obtained in this way are then reacted in analogy to the carboxylic acids described above, for example with oxalyl chloride, to give the corresponding acid chlorides.
An advantageaus process for the preparation of the ultrasonic contrast agents comprises dissolving one or more of the polyamino-dicarboxylic acid-co-imide deriva-tines of the formula I in a solvent or solvent mixture with high melting point, or mixing these derivatives with one or more other polymers and/or physiologically accept-able auxiliaries, and dissolving in a solvent or solvent mixture with high melting point, and adding dropwise to a condensed cold gas, for example liquid nitrogen. This results, owing to the Leidenfrost phenomenon, in absolutely round particles. examples of solvents which can be employed are alcohols, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, dioxane, acetonitrile or mixtures with alcohols. The high-melting and water-miscible solvent is dissolved out, for example by transferring the microparticles into water, and the polymer is precipitated thereby, with retention of the spherical shape of the microparticles.
If the organic solvent which is used not only has a high melting point but also has a low boiling point, this dropwise addition process can be further simplified by the possibility of removing the solvent, far example tart-butanol, directly and under mild conditions by freeze-drying.
Another process for the preparation of the ultrasonic contrast agents comprises one or more of the polyamino-dicarboxylic acid-co-imide derivatives of the formula I
being dissolved in a solvent or solvent mixture and, where appropriate after addition of another solvent and/or of one or more further polymers, being - 1 7. - e.rl ~~
precipitated or dispersed in water. Examples of other polymers which are suitable are polyvinyl alcohol (~Mowiol 28-99) ar polyoxyethylene-polyoxypropylene (~pluronic ~' 127 ) . Ethers, for example, can be used as further solvents. 7Microparticles with a diameter of 0.5 to 15 ~cm are obtained by vigorous stirring, far example with a mixer (25,000 rpm). The solvents are subsequently removed, for example by lyophilization.
A particularly advantageous process comprises obtaining the microparticles by spray-drying. For this, one or more polyamino-dicarboxylic acid-co-imide derivatives of the formula T are dissolved, or these derivatives are mixed with one or more other polymers and/or physiologically acceptable auxiliaries and dissolved. Examples of suit-able solvents or solvent mixtures are alcohol, dimethyl-formamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, dioxane or acetonitrile. The solution is then sprayed to give microparticles in a spray drier.
The polymers of the formula I can be used alone or else as mixture of various polymers of the formula I in the described process . These polymers can also be employed in mixtures with other biodegradable and/or biocompatible polymers (far example ~Pluronic F68, PHEA, dextrans, polyethylene glycols, hydroxyethyl starch and other degradable or excretable polysaccharides) or physio-logically acceptable auxiliaries (for example polymer plasticizers).
The microparticles contain gas, for example air, nitro-gen, noble gases such as helium, neon, argon or krypton, hydrogen, carbon dioxide, oxygen or mixtures thereof. The microparticles are charged with a gas by, for example, the microparticles being stored in an appropriate gas atmosphere after the lyophilization or, in the case of spray-drying, are obtained directly on preparation in an appropriate gas atmosphere.
- 12 - ~.~ra~ ~.~ c'~~~
The ultrasonic contrast agents according to the invention are converted before administration into a suitable diag-nostic or therapeutic administration farm by addition of one or more physiologically acceptable vehicles and, where appropriate, further additives and/or auxiliaries.
The ultrasonic contrast agents are, for example, sus-pended before administration by addition of water and mixing.
Physiological isotanicity of the particle suspension can be set up by addition of substances with osmotic activ-ity, for example sodium chloride, galactose, glucose or fructose.
The described process for the preparation of the ultra-sonic contrast agents according to the invention can result in particle sizes in which 90~ of the particles are between 0.1 ~m and 15 ~sm. Using the spray-drying process it is possible to obtain particle size distribu-tions in which 90~ of the particles are smaller than 3 yam. Larger particles are removed by screening out, fox example with a 15 ~cm screen fabric and/or 3 ~m screen fabric. When these microparticles are used as ultrasonic contrast agents for the diagnosis of cardiovascular disorders, particle sizes of 0.1 ~m to 7 ~,m have proven suitable, and particle sizes of 0.1 gem to 3 yam are preferably employed. The ultrasonic contrast agents are injected, for example, into the blood circulation. Per injection, 0.1 mg to 1000 mg of the microparticles, preferably 1 mg to 100 mg, are employed.
The ultrasonic contrast agents described above can be used for both diagnostic and therapeutic procedures. The use of the ultrasonic contrast agents according to the invention is not confined just to the visualization of the blood flow in the right-ventricular part of the blood circulation after venous administration. The ultrasonic contrast agents can be used with exceptional success for investigating the left side of the heart and the myocardium. Furthermare, it is also possible to visualize other organs with a blood supply, such as the liver, spleen, kidney or brain, using these contrast agents.
The ultrasonic contrast agents according to the invention are, however, also suitable for the visualization of cavities in humans, animals or plants, for example the urinary bladder, ureter, uterus or vagina.
The invention is described in detail in the examples which follow. Unless otherwise indicated, percentages relate to weight.
Example 1 Preparation of polysuccinianide-co-«,p-(hydroxyethyl)-D,Z-aspartamide (70x30) 10 g (103 mmol) of polyanhydroaspartic acid are dissolved in about 40 ml of N,N-dimethylformamide (DMF'), if neces-sary warming gently. To this solution are added dropwise 1.~3 g (30 mmol) of freshly distilled 2-aminoethanol and stirred at room temperature overnight. The reaction mixture is precipitated in butanol and washed several times with dry acetone. The drying is carried out at elevated temperature in vacuo. The white, water-soluble product is obtained in approximately 100 yield and is examined by NMR spectroscopy for residues of DMF and butanol. The molar ratio of polyanhydroaspartic acid to aminoethanol employed corresponds approximately to the copolymer composition.
Example 2 Preparation of n-butyl 4-chloro-4-oxobutyrate Excess thionyl chloride and one drop of DMF are added to monobutyl succinate. The reaction takes place with evolution of gas. The mixture is left to stir with exclusion of moisture overnight and subsequently the excess thionyl chloride is removed by distillation under 14 °- s;
atmospheric pressure. The remaining crude product is fractionally distilled under 0.05 mbar, and the pure product is obtained at about 7U°C. The characterization of the product by IR spectroscopy shows bands at 1800 cm-1 (acid chloride) and 1740 cm 1 (ester) of equal intensity.
Example 3 Preparation of polysuccinimide-co-«,p-(butyloxycarbonyl-propionyloxyethyl)-D,L-aspartamide (70:30) 6 g of polysuccinimide-co-«,~-(hydroxyethyl)-D,L-aspart-amide (= 16 mmol of hydroxyethyl groups), prepared as described in Example 1, are dissolved in 100 ml of dry N,N-dimethylformamide (DMF). Addition of 4 g (50 mmol) of pyridine is followed by cooling to 0°C and addition, while stirring, of 4.8 g (25 mmol) of n-butyl 4-chloro-4-oxobutyrate (see Example 2) over the course of 15 minutes. The mixture is stirred overnight and precipi-tated in 0.5 1 of ether. The precipitate is filtered off with suction and washed with ether, acetone, water, acetone and ether. The result is about 8 g of a white polymer with an approximately 100$ degree of substitution (can be checked by NMR spectroscopy). The resulting polymer is sohable, for example, in acetonitrile with a trace of dimethyl sulfoxide (DMSO), in DMSO or DMF.
Example 4 Preparation of polysuccinimide-co-«,~9-(nonylcarbonyloxy-ethyl)-D,L-aspartamide (50a50) 6 g of a polysuccinimide-co-«,~9-(hydroxyethyl)-D,L-aspartamide (50:50) (= 24 mmol of hydroxyethyl groups), which was prepared in analogy to Example 1 from poly-anhydroaspartic acid (MW = 14000) and 2-aminoethanol (molar ratio 2 > 1 ) , are dissolved in 100 rnl of dry DMA', and 8 g (100 mmol) of dry pyridine are added and cooled to 0°C. 9.6 g of distilled decanoyl chloride are slowly added dropwise, arid further operations are in analogy to Example 3. About 8 g of a white, completely substituted d,J z...~-15 _ polymer (~TI~IFt check) which is soluble, for example, in dichloromethane and T~F with, in each case, a trace of DMSO or in methanol/dichloromethane mixtures are obtained.
Example 5 Preparation of polysuccinimi.de-.co-«,p-(nonylcarbonyloxy-ethyl)-D,L-aspartamide of diverse copolymer composition and various molecular weights Tn analogy to Example 1, various polysuccinimide-co-«,p-(hydroxyethyl)-D,L-aspartamides of, inter alia, the compositions 70x30, 50s50 and 30:70 were prepared from polyanhydroaspartic acids of various molecular weights (MW = 7000; about 13000; 30000) and reacted with decanoyl chloride as described in Example 4 to give the corres-ponding polysuccinimide-co-«,p-(nonylcarbonyloxyethyl)-D,L-aspartamides.
a) - polysuccinimide-co-a,~-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW = 7000); characterized by 1~MR
b) - polysuccinimide-co-«,~9-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30] from polyanhydroaspartic acid (MW = 14000); characterized by ~TMR
c) - polysuccinimide-co-«,p-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (lbiWW = 30000); characterized by NMR
d) - polysuccinimide-co-«,p-(nonylcarbonyloxyethyl)-D,L-aspartamide (30:70) from polyanhydroaspartic acid (~T = 12000); characterized by ATMR
Example 6 Preparation of polysuccinimide-.co-a,p-{octyloxycarbonyl-oxyethyl)-D,L-aspartamide (70:30) 6 g of polysuccini.wide-co-a,,B-(hydroxyethyl)-D,L-aspart-amide {70:30) (= 16 mmol of hydroxyethyl groups), pre-pared as described in Example 1 from polyanhydroaspartic acid, (Mw = 37000) and aminoethanol, are reacted in analogy to Example 3 with 4.8 g (25 mmol) of octyl chloroformate and worked up correspondingly. About 8 g of a white, completely substituted polymer which is soluble in THF or methanol/dichloromethane mixtures are obtained.
Example 7 Preparation of polysuccinimide-co-a,~-(nonylcarbonyloxy-ethyl)-co-a,~-(hydroxyethyl)-D,L-aspartamide (60:20:20) 6 g of polysuccinimide-co-a "B-(hydroxyethyl)-D,L-aspart-amide (60:40) (= 20 mmol of hydroxyethyl groups), which was prepared in analogy to Example 1 from polyanhydro-aspartic acid and 2-aminoethanol (molar ratio 6:4), are reacted in analogy to Example 3 with 2.3 g of decanoyl chloride (= 12 mmol). Hecause reaction was incomplete (relatively low excess of acid chloride), only half the free OH groups are esterified. The result is about 7 g of a white polymer. Microparticles of this substance show a firm consistency in water and are easily suspendible.
Example 8 Preparation of polysuccini.wide-co-a,~-(oleyloxyethyl)-D,L-aspartamide (10:90) 6 g of polysuccinimide-co-a,p-(hydroxyethyl)-D,L-aspart-amide (10:90) (= 40 mmol of hydroxyethyl groups), pre-pared in analogy to Example ~, with a 1:9 molar ratio of polyanhydroaspartic acid to 2-aminoethanol, are reacted with 20 g of distilled oleyl chloride in analogy to Example 3. The heterogeneous reaction mixture becomes homogeneous on addition of dichloromethane. Tt is ~a~~
precipitated twice in methanol which is cooled to -20°C.
The yellowish-colored polymer is thermoplastic, Example 9 a) Preparation of microparticles 40 mg of polysuccinimide-co-«,,e-(nonylcarbonyloxyethyl)-D,L-aspartamide (50050) from Example 4 are dissolved in 1 ml of methylene chloride/methanol (proportion 5011 by volume). The solution is introduced while stirring (800 rpm) into a beaker containing 60 m1 of 0.1~ by weight of aqueous polyvinyl alcohol solution (~Mowiol 28-99) which is saturated with 0.3 ml of methylene chloride/methanol (50/1). At the same time, the solution is finely dispersed with a mixer (25,000 rpm).
After 5 minutes, the contents axe poured into a beaker containing 200 ml of water and stirred for 30 minutes (200 rpm). The supernatant water is decanted off and the microparticles are lyophilized (diameter after lyophil-ization: 0.5 to 15 dam) .
Example 10 Preparation of microparticles 80 mg of polysuccini.wide-co-«,p-(octylcarbonyloxyethyl)-D,L-aspartamide (70:30) from Example 6 are dissolved at 50°C in 1 ml of dimethyl sulfoxide, and 20 mg of hydroxy-propylcellulose (~Klucel M.) are added. The solution of the two polymers is added dropwise, using a needle (disposable syringe, external diameter of needle 0.6 mm), to previously introduced liquid nitrogen (100 ml).
The resulting microparticles are transferred into 200 ml of water and extracted from remaining solvent for 2 hours. Excess water is decanted off, and the micrp-particles are lyophilized (diameter after lyophilization:
1-2 dam) .
~i _ 1g Example 11 Preparation of microparticles 4 g each of polysuccinimide-co-a,p-(octyloxycarbonyloxy ethyl)-D,L-aspartamide (A) (Example 6) and polysuccin imide-co-cz,,e-(nonylcarbonyloxyethyl}-D,L-aspartamide (B) (Example 5 d) are made into 2~ solutions in the solvents indicated in Table 1. The polymers are subsedu.ently sprayed to give microparticles in a spray drier (Biichi 190 mini spray drier supplied by Biichi, West Germany).
Table is Sub- Solvent Particle size stance 10~ smaller 50~ smaller90~ smaller than than than A THF 1.6 dam 3.6 ~sm 6.7 hem B CH2C12 2.4 ~sm 3.6 ~sm 6.7 ~m B CHZCIz/ 1.3 ~cm 1.9 ~m 3.0 yam methanol 3.6:1 (vol.) B CHzClz/ 1.2 ~cm 1.0 ~m 2.6 ~m methanol 2a3 (vol.) B THF/methanol 1.3 ~sm 1.9 ~m 2.7 ~m 3.6e1 (vol.) The size of the microparticleswas deter-distribution mined in a Cilas granulometer.
In each portions of the mic ropartieles case, mg prepared above are dispersed in 1.5 ml of suspension aid.
The suspension dextran aids 40 are composed of 150 mg o~
30 (supplied polysorbate by Roth, West Germany), 7.5 mg o~
- 1~
and 13.5 mg of T~aCI in 1.5 ml of distilled water. The suspensions are filtered using screen fabrics (15 ~sm and 3 ~m mesh width) and subsequently lyophilized. Before administration, the microparticles are suspended in water.
Example 12 Echocardiographic examination of dog 30 mg of microparticles (prepared as in Example 11, substance B, CHZC12/methanol 2:3 (vol.)) are resuspended IO in 1.5 ml of distilled water using a glass rod. This suspension is injected into a peripheral vein using an injection syringe. An ultrasound emitter of an ultrasonic apparatus (Toshiba, FSH 160a, Japan) is held on the thorax of the experimental animal so that a typical cross-section through the right and left heart is obtained.. As soon as the ultrasonic contrast agent reaches the right half of the heart it is possible to see on the monitor of the ultrasonic apparatus how the blood labeled by the contrast agent reaches the right atrium, then the right ventricle and subsequently leaves the heart again via the pulmonary artery. After passage through the lungs, the left half of the heart can be seen owing to the contrast agent. The ultrasonic contrast is of equal intensity before and after passage through the lungs so that it can be assumed that there is essentially complete retention of the air in the polymers and essen-tially loss-free transport of the microparticles to the left half of the heart.
Ultrasonic diagnosis has become very widely used in medicine because it is complication-free and straight-forward to perform. Ultrasonic waves are reflected at interfaces of different types of tissue. The echo signals i5 produced thereby are electronically amplified and displayed.
Visualization of blood vessels and internal organs by ultrasound does not in general allow visualization of the blood flow present therein. Liquids, especially blood, 20 provide ultrasonic eontrast only when there are density differences with respect to the surroundings. Used as contrast agents in medical ultrasonic diagnosis are, for example, substances which contain gases or produce gases, because the difference in ianpedance between gas and 25 surrounding blood is considerably greater than that between liquids or solids and blood (Levine R.A., J Am Coll Cardiol 3: 28, 1989; Machi I.J CU 11: 3, 1983).
Several methods for preparing and stabilizing gas bubbles are disclosed in the literature. Ua Patent 4,276,885 30 describes the preparation of small gas bubbles of defined size which are enclosed by a gelatin casing which pre-vents coalescence of the gas bubbles. The prepared small gas bubbles can be stored only in the frozen state, and A 2 - ~°~~~:~~~~
'the small gas bubbles must be returned to body tempera-ture for use.
EP-A2 0,123,235 and 0,122,624 describe ultrasonic con-trast agents which contain gases and are composed of mixtures of surface-active substances with a solid in a liquid vehicle. The ultrasonic contrast agents are prepared by an elaborate milling process with an air-jet mill. The particles prepared in this way have only a short duration of use because they rapidly lose the entrapped gases.
EP-A2 0,224,934 describes ultrasonic contrast agents in the form of gas-filled gelatin or albumin hollow bodies.
However, the disadvantage is the use o~ exogenous or denatured endogenous proteins because of the allergenic risk associated therewith.
EP-A1 0,327,490 describes microparticles which are composed of amyloses or synthetic, biodegradable polymers and of a gas andlor a liquid with a boiling point below 60°C. The disadvantages of these polymers are their sticky consistency in water or blood, their poor bio-degradability, their toxicity or the production of toxic degradation products.
It has already been proposed (German Patent Application P 40 02 736.8) to employ polyamino-dicarboxylic acid-co-imide derivatives as biodegradable depot formulations of pharmaceuticals with controlled release of active substance.
The object of the present invention was to develop ultrasonic contrast agents based on microparticles, which provide a distinct contrast from the surrounding tissue, which axe so small and stable that they reach, without considerable loss of gas and essentially quantitatively, the left half of the heart after intravenous administra-tion, are well tolerated without an allergenic potential, do not form aggregates in water or blood, and can be prepared rapidly and straightforwardly.
Microparticles which are, surprisingly, outstandingly suitable as ultrasonic contrast agents have been prepared from polyamino-dicarboxylic acid-co-imide derivatives (polydicarboxylic acid-co-AHADA derivatives). In particu-lar, the amenability of the prepared microparticles to be suspended in water is outstanding owing to the incorpora-tion of unopened imide rings (AHA1~A rings ) . The micro-IO particles do not have a sticky, greasy consistency in water-containing liquids and form scarcely any agglomer-ates. The polymers form a pharmacologically inert matrix in which the gas is entrapped. In vivo, these polymers are metabolized to non-toxic, non-allergenic and non-I5 immunogenic compounds and are excreted. It was possible to show in animal experiments that the microparticles essentially pass through the lungs without significant loss of gas and result in an ultrasonic contrast of equal intensity in both halves of the heart. The echocardio-20 grams recorded therewith show no wall-movement disturb-ances whatever during and up to 60 min after adminis-tration of the contrast agent. Furthermore, it was not possible to find any changes whatever in a six-channel ECG or in the contractility determined using a tip 25 manometer.
The ultrasonic contrast agents according to the invention bring about an improved increase in echogenicity in the myocardium and permit improved visualization of the endocardium. Tt is furthermore possible, for example, to 30 assess the following parameters better:
ventricle size, wall-movement disturbances, stroke volume, ejection fraction or intracavitary masses, for example thrombi or tumors. Furthermore, the ultrasanic contrast agents according to the invention make it 35 possible to evaluate flow patterns in cases of valvular insufficiency of the left and of the right half of the heart, intracardiac shunts, and improved visualization of the large vessels in cases of congenital malformation. A
massive enhancement of the Doppler signal has also been observed.
The invention thus relates to ultrasonic contrast agents composed of microparticles which contain a gas and a polyamino-dicarboxylic acid-co-amide derivative of the formula I, "">~-NH ,,.-C00H
(CH2)" (CH2>"- (CH ) C-R ~ ~'w=COOH
H2N ~ .0 0 x d in which n is 1 or 2 x is 1 to 500 y is Z to 500, where x + y is 2 to 1000, and R is 0-R1 or NH-R2, in. which I5 R2 is H, ( CHZ ) m-ORl, ( CH2 ) m-0-C ( o ) -Rl or ( CH2 ) m ~-C ( 0 ) -OR1, and m is 2 to 6, and R1 is H, aryl, aralkyl, arylalkenyl, alkyl or C3-C8-cycloalkyl or a biologically inactive steroid alcohol or an amino acid, where aryl is unsubstituted or is substituted by C1-C4-alkyl, CZ-C4-alkenyl, C1-C4-alkylcarbonyloxy, C1-C4-alkoxy-Carbonyl, Cl-CH-alkoxy or hydroxyl, where the alkyl radicals specified for R1 have i-22 - ~ - ~~~3~~~'~
carbon atoms and the alkenyl radicals have 2-22 caxbon atoms, which are not interrupted or are interrupted by a carbonyloxy or oxycarbonyl group, where the repeating units placed in square brackets are distributed randomly and/or in blocks in the polymer, and where both the repeating units labeled with x and those labeled with y are identical or different and where the amino acids are a- andlor ~-linked.
Hy aryl are meant aromatic hydrocarbons such as phenyl and naphthyl, especially phenyl. In the substituted aryl radicals indicated, 1 to all replaceable hydrogen atoms are replaced by identical or different substituents. The aryl radicals are preferably mono- or disubstituted.
The said alkyl and alkenyl radicals can be both straight-chain and branched.
The biologically inactive steroid alcohols are preferably linked via their OH group. A preferred steroid alcohol is cholesterol.
In the case of the amino acids specified for R1, they are preferably naturally occurring amina acids such as Tyr, Ala, Ser or Cys, particularly preferably Tyr and Ala.
They can be linked both via their hTHZ and via their C~OH
group.
The invention also relates to processes for the prepara-tion of gas-containing microparticles which are composed -of the abovementioned polymers or contain these, and to their use, also mixed with other, biocompatible andlor biodegradable polymers or physiologically acceptable 30' auxiliaries, for diagnostic or therapeutic procedures.
The invention further relates to diagnostic or thera peutic agents composed of at least one ultrasonic con trast agent as claa.med in one or more of claims 1 to 4 or of at least one ultrasonic contrast agent prepared by process 5.
-The invention additionally relates to processes for the preparation of diagnostic or therapeutic agents, which comprise converting the abovementioned ultrasonic con-trast agents with a physiological vehicle and, where appropriate, further additives and/or auxiliaries into a suitable administration form.
The invention is described in detail hereinafter.
Aspartic acid and/or glutamic acid are employed as amino dicarboxylic acids which react in a polycondensation reaction to give the corresponding polyimides (poly-anhydro-amino-dicarboxylic acids, formula II). Partial reaction with one or more compounds of the formulae ITI
and/or IV and/or NH3 HO-R1 (III) I S HZN- ( CHZ ) m OH ( I V ) r in which m and Rl are defined as above for formula I, results in an a, p-poly-D,L-amino acid ester-co-imide of the formula VIIT
0 ~'3 (C~ 2>~~COOH
Z 0 HEN i~ (CH2 )~ ( I I ) + H~-R1 ( I I I ) "''~COOH
x~.y HzN- ( OHa ) ro-OH ( I V ) ---~ f CHI ) NH CCH2 )" ( CH ) COON ('VII I ) HEN ~-R- ~ ~''~COOH
0 x 0 H .
R' = O-Rl, HN- ( CH2 ) ~ OH, NH2 It is essential that in this reaction the polyanhydro-n, a amino-dicaxboxylic acid (II) is only partially converted into the open-chain derivatives. The proportion of unopened anhydro-amino-dicarboxylic acid units is 0.1 to 99,9, preferably 10 to 90~ (the percentages relate to the total number of repeating units in the total poly-mer). Depending on the side on which the imide ring is opened in the reaction described above, «- or p-linked amino acids are obtained. Compounds of the formulae III
and IV which are preferably employed are: 2-aminoethanol, I0 3-aminopropanol, 2-aminopropanol, alcohols with 1-18 carbon atoms, especially methanol, ethanol, isoamyl alcohol and isopropyl alcohol, A process for the preparation of «,p-poly-(2-hydroxy-ethyl)-DL-aspartimide (PHEA) (formula I; y = 0;
R = NH-CHz-CHZ-QH) is described by P. Neri, G. Antoni, F. Benvenuti, F. Cocola, G. Gazzei, in J. Med. Chem.
Vol. 16, 893 ( 1913) . A general procedure for the prepara-tion of PHEA is to be found in P. Neri, G. Antoni, Macromol. Synth. Vol. 8, 25. Express reference is made to this citation at this point. The reaction takes place in high yield to give a product of high purity. It is possible to prepare in the same way, by less than stoichiometric use of NH3 and/or compounds of the formulae III and/or IV, the analogous poly-aspartic acid derivative-co-succinimide compaunds of the formula VIII
(n = 1).
A different, more elaborate process as is described in US Patent 4,356,166 must be used to prepare pure poly-(hydroxyalkyl)-L-glutamine. This entails initially the y-COON group of the L-glutamic acid being Protected by esterification with benzyl alcohol. This y-benzyl gluta-mate is subsequently reacted with phosgene to give an N-carboxylic anhydride which then polymerizes after addition of triethylamine in an inert solvent to result in poly-y-(benzyl)-L-glutamate. The protective group is eliminated either by adding an HC1/I~Br mixture to give the free poly-«-L-glutamic acid or else in the presence -of hydroxyalkylamines to give the analogous poly-a-(hydroxyalkyl)-h-glutamines. A general procedure for 'the preparation of poly-a-(hydroxypropyl)-h-glutamine is to be found in US Patent 4,355,166, to which express refer-s ence is made at this point. It is also possible in the same way, by using NH;~ and/or compounds of the formula ITT
and/or IV, to prepare the analogous compounds of the formula VIII (n = 2).
Compared with the elaborate preparation of pure poly-glutamic acid and its derivatives, it is possible to incorporate glutamic acid i.n up to high proportions on simple condensation of aspartic acid using phosphoric acid to give polyanhydroaspartic said-co-glutamic acid.
The polyamino-amide-co-imides of the formula VIIT
(R'= HN- (CHZ)m 0H) can now, if necessary, be reacted in the following reaction step with one or more different biologically inactive compounds of the formula V and/or VI and/or VIT
X-R1 (V) X-C-R~ (VI) X-C-OR1 (VII) 2 0 ~I II
to give further polyamino-dicarboxylic acid-co-AHADA
derivatives. In this case, X is a leaving group which allows mild esterification of the polymer alcohol group.
Chlorine, bromine, iodine, ianidazolides, anhydrides or hydroxyl, especially chlorine, are preferred.
The reaction with the compounds of the formula V, VI or VII type can be carried out both with a single compound of this type and with any desired combinations of these compounds, or else with compounds which have different radicals Rl, for example differing in the nature of their branching, in particular in their chain length.
The last-mentioned alkylation or acylation on the polymer is carried out by known processes of organic chemistry.
It takes place selectively on the hydroxyl group ( formula VI I I , F~' = HIS- ( C~i~ ) ~-OH ) to give ethers , esters , or carbonates without attacking other groups on the initial polymer. Particularly suitable is the Einhorn variant of the Schotten-Baumann acylation in the presence of gyridine. In this case, very high levels of. derivitiza tion (greater than 70~) axe achieved under mild condi tions.
The molecular weight of the polymers is 200 to 100,000, preferably 3,000 to 70,000.
Compounds of the formula V type can be bought or, if not, synthesized in a straightforward manner by processes known from the literature.
The chloroformic esters (foranula VxI) are obtained by reacting phosgene with the appropriate biologically inactive, physiologically acceptable, aromatic, araliphatic, aliphatic or cycloaliphatic, especially unbranched alcohols. The alcohols which are particularly preferably employed are those which have an even number of carbon atoms. The chloroformylated steroids are also obtained in this way. Thus, in principle, all bio-logically inactive steroids having reactive hydroxyl groups can be obtained. Examples which may be mentioned here are: cholesterol, cholestanoi, coprostanol, ergosterol, sitosterol or stigmasterol.
The acid chlorides (formula VI) which can likewise be employed are obtained, for example, from the correspond-ing carboxylic acids by reaction with phosphorus tri-chloride, phosphorus pentachloride, oxalyl chloride or thionyl chloride.
Compounds of the formula V, VI or VII type in which an alkyl chain is interrupted by an oxycarbonyl or carbonyloxy group are prepared, for example, by reaction of cyclic dicarboxylic acid anhydrides with alcohols. The dicarboxylic monoesters obtained in this way are then reacted in analogy to the carboxylic acids described above, for example with oxalyl chloride, to give the corresponding acid chlorides.
An advantageaus process for the preparation of the ultrasonic contrast agents comprises dissolving one or more of the polyamino-dicarboxylic acid-co-imide deriva-tines of the formula I in a solvent or solvent mixture with high melting point, or mixing these derivatives with one or more other polymers and/or physiologically accept-able auxiliaries, and dissolving in a solvent or solvent mixture with high melting point, and adding dropwise to a condensed cold gas, for example liquid nitrogen. This results, owing to the Leidenfrost phenomenon, in absolutely round particles. examples of solvents which can be employed are alcohols, dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, dioxane, acetonitrile or mixtures with alcohols. The high-melting and water-miscible solvent is dissolved out, for example by transferring the microparticles into water, and the polymer is precipitated thereby, with retention of the spherical shape of the microparticles.
If the organic solvent which is used not only has a high melting point but also has a low boiling point, this dropwise addition process can be further simplified by the possibility of removing the solvent, far example tart-butanol, directly and under mild conditions by freeze-drying.
Another process for the preparation of the ultrasonic contrast agents comprises one or more of the polyamino-dicarboxylic acid-co-imide derivatives of the formula I
being dissolved in a solvent or solvent mixture and, where appropriate after addition of another solvent and/or of one or more further polymers, being - 1 7. - e.rl ~~
precipitated or dispersed in water. Examples of other polymers which are suitable are polyvinyl alcohol (~Mowiol 28-99) ar polyoxyethylene-polyoxypropylene (~pluronic ~' 127 ) . Ethers, for example, can be used as further solvents. 7Microparticles with a diameter of 0.5 to 15 ~cm are obtained by vigorous stirring, far example with a mixer (25,000 rpm). The solvents are subsequently removed, for example by lyophilization.
A particularly advantageous process comprises obtaining the microparticles by spray-drying. For this, one or more polyamino-dicarboxylic acid-co-imide derivatives of the formula T are dissolved, or these derivatives are mixed with one or more other polymers and/or physiologically acceptable auxiliaries and dissolved. Examples of suit-able solvents or solvent mixtures are alcohol, dimethyl-formamide, dimethyl sulfoxide, tetrahydrofuran, methylene chloride, dioxane or acetonitrile. The solution is then sprayed to give microparticles in a spray drier.
The polymers of the formula I can be used alone or else as mixture of various polymers of the formula I in the described process . These polymers can also be employed in mixtures with other biodegradable and/or biocompatible polymers (far example ~Pluronic F68, PHEA, dextrans, polyethylene glycols, hydroxyethyl starch and other degradable or excretable polysaccharides) or physio-logically acceptable auxiliaries (for example polymer plasticizers).
The microparticles contain gas, for example air, nitro-gen, noble gases such as helium, neon, argon or krypton, hydrogen, carbon dioxide, oxygen or mixtures thereof. The microparticles are charged with a gas by, for example, the microparticles being stored in an appropriate gas atmosphere after the lyophilization or, in the case of spray-drying, are obtained directly on preparation in an appropriate gas atmosphere.
- 12 - ~.~ra~ ~.~ c'~~~
The ultrasonic contrast agents according to the invention are converted before administration into a suitable diag-nostic or therapeutic administration farm by addition of one or more physiologically acceptable vehicles and, where appropriate, further additives and/or auxiliaries.
The ultrasonic contrast agents are, for example, sus-pended before administration by addition of water and mixing.
Physiological isotanicity of the particle suspension can be set up by addition of substances with osmotic activ-ity, for example sodium chloride, galactose, glucose or fructose.
The described process for the preparation of the ultra-sonic contrast agents according to the invention can result in particle sizes in which 90~ of the particles are between 0.1 ~m and 15 ~sm. Using the spray-drying process it is possible to obtain particle size distribu-tions in which 90~ of the particles are smaller than 3 yam. Larger particles are removed by screening out, fox example with a 15 ~cm screen fabric and/or 3 ~m screen fabric. When these microparticles are used as ultrasonic contrast agents for the diagnosis of cardiovascular disorders, particle sizes of 0.1 ~m to 7 ~,m have proven suitable, and particle sizes of 0.1 gem to 3 yam are preferably employed. The ultrasonic contrast agents are injected, for example, into the blood circulation. Per injection, 0.1 mg to 1000 mg of the microparticles, preferably 1 mg to 100 mg, are employed.
The ultrasonic contrast agents described above can be used for both diagnostic and therapeutic procedures. The use of the ultrasonic contrast agents according to the invention is not confined just to the visualization of the blood flow in the right-ventricular part of the blood circulation after venous administration. The ultrasonic contrast agents can be used with exceptional success for investigating the left side of the heart and the myocardium. Furthermare, it is also possible to visualize other organs with a blood supply, such as the liver, spleen, kidney or brain, using these contrast agents.
The ultrasonic contrast agents according to the invention are, however, also suitable for the visualization of cavities in humans, animals or plants, for example the urinary bladder, ureter, uterus or vagina.
The invention is described in detail in the examples which follow. Unless otherwise indicated, percentages relate to weight.
Example 1 Preparation of polysuccinianide-co-«,p-(hydroxyethyl)-D,Z-aspartamide (70x30) 10 g (103 mmol) of polyanhydroaspartic acid are dissolved in about 40 ml of N,N-dimethylformamide (DMF'), if neces-sary warming gently. To this solution are added dropwise 1.~3 g (30 mmol) of freshly distilled 2-aminoethanol and stirred at room temperature overnight. The reaction mixture is precipitated in butanol and washed several times with dry acetone. The drying is carried out at elevated temperature in vacuo. The white, water-soluble product is obtained in approximately 100 yield and is examined by NMR spectroscopy for residues of DMF and butanol. The molar ratio of polyanhydroaspartic acid to aminoethanol employed corresponds approximately to the copolymer composition.
Example 2 Preparation of n-butyl 4-chloro-4-oxobutyrate Excess thionyl chloride and one drop of DMF are added to monobutyl succinate. The reaction takes place with evolution of gas. The mixture is left to stir with exclusion of moisture overnight and subsequently the excess thionyl chloride is removed by distillation under 14 °- s;
atmospheric pressure. The remaining crude product is fractionally distilled under 0.05 mbar, and the pure product is obtained at about 7U°C. The characterization of the product by IR spectroscopy shows bands at 1800 cm-1 (acid chloride) and 1740 cm 1 (ester) of equal intensity.
Example 3 Preparation of polysuccinimide-co-«,p-(butyloxycarbonyl-propionyloxyethyl)-D,L-aspartamide (70:30) 6 g of polysuccinimide-co-«,~-(hydroxyethyl)-D,L-aspart-amide (= 16 mmol of hydroxyethyl groups), prepared as described in Example 1, are dissolved in 100 ml of dry N,N-dimethylformamide (DMF). Addition of 4 g (50 mmol) of pyridine is followed by cooling to 0°C and addition, while stirring, of 4.8 g (25 mmol) of n-butyl 4-chloro-4-oxobutyrate (see Example 2) over the course of 15 minutes. The mixture is stirred overnight and precipi-tated in 0.5 1 of ether. The precipitate is filtered off with suction and washed with ether, acetone, water, acetone and ether. The result is about 8 g of a white polymer with an approximately 100$ degree of substitution (can be checked by NMR spectroscopy). The resulting polymer is sohable, for example, in acetonitrile with a trace of dimethyl sulfoxide (DMSO), in DMSO or DMF.
Example 4 Preparation of polysuccinimide-co-«,~9-(nonylcarbonyloxy-ethyl)-D,L-aspartamide (50a50) 6 g of a polysuccinimide-co-«,~9-(hydroxyethyl)-D,L-aspartamide (50:50) (= 24 mmol of hydroxyethyl groups), which was prepared in analogy to Example 1 from poly-anhydroaspartic acid (MW = 14000) and 2-aminoethanol (molar ratio 2 > 1 ) , are dissolved in 100 rnl of dry DMA', and 8 g (100 mmol) of dry pyridine are added and cooled to 0°C. 9.6 g of distilled decanoyl chloride are slowly added dropwise, arid further operations are in analogy to Example 3. About 8 g of a white, completely substituted d,J z...~-15 _ polymer (~TI~IFt check) which is soluble, for example, in dichloromethane and T~F with, in each case, a trace of DMSO or in methanol/dichloromethane mixtures are obtained.
Example 5 Preparation of polysuccinimi.de-.co-«,p-(nonylcarbonyloxy-ethyl)-D,L-aspartamide of diverse copolymer composition and various molecular weights Tn analogy to Example 1, various polysuccinimide-co-«,p-(hydroxyethyl)-D,L-aspartamides of, inter alia, the compositions 70x30, 50s50 and 30:70 were prepared from polyanhydroaspartic acids of various molecular weights (MW = 7000; about 13000; 30000) and reacted with decanoyl chloride as described in Example 4 to give the corres-ponding polysuccinimide-co-«,p-(nonylcarbonyloxyethyl)-D,L-aspartamides.
a) - polysuccinimide-co-a,~-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (MW = 7000); characterized by 1~MR
b) - polysuccinimide-co-«,~9-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30] from polyanhydroaspartic acid (MW = 14000); characterized by ~TMR
c) - polysuccinimide-co-«,p-(nonylcarbonyloxyethyl)-D,L-aspartamide (70:30) from polyanhydroaspartic acid (lbiWW = 30000); characterized by NMR
d) - polysuccinimide-co-«,p-(nonylcarbonyloxyethyl)-D,L-aspartamide (30:70) from polyanhydroaspartic acid (~T = 12000); characterized by ATMR
Example 6 Preparation of polysuccinimide-.co-a,p-{octyloxycarbonyl-oxyethyl)-D,L-aspartamide (70:30) 6 g of polysuccini.wide-co-a,,B-(hydroxyethyl)-D,L-aspart-amide {70:30) (= 16 mmol of hydroxyethyl groups), pre-pared as described in Example 1 from polyanhydroaspartic acid, (Mw = 37000) and aminoethanol, are reacted in analogy to Example 3 with 4.8 g (25 mmol) of octyl chloroformate and worked up correspondingly. About 8 g of a white, completely substituted polymer which is soluble in THF or methanol/dichloromethane mixtures are obtained.
Example 7 Preparation of polysuccinimide-co-a,~-(nonylcarbonyloxy-ethyl)-co-a,~-(hydroxyethyl)-D,L-aspartamide (60:20:20) 6 g of polysuccinimide-co-a "B-(hydroxyethyl)-D,L-aspart-amide (60:40) (= 20 mmol of hydroxyethyl groups), which was prepared in analogy to Example 1 from polyanhydro-aspartic acid and 2-aminoethanol (molar ratio 6:4), are reacted in analogy to Example 3 with 2.3 g of decanoyl chloride (= 12 mmol). Hecause reaction was incomplete (relatively low excess of acid chloride), only half the free OH groups are esterified. The result is about 7 g of a white polymer. Microparticles of this substance show a firm consistency in water and are easily suspendible.
Example 8 Preparation of polysuccini.wide-co-a,~-(oleyloxyethyl)-D,L-aspartamide (10:90) 6 g of polysuccinimide-co-a,p-(hydroxyethyl)-D,L-aspart-amide (10:90) (= 40 mmol of hydroxyethyl groups), pre-pared in analogy to Example ~, with a 1:9 molar ratio of polyanhydroaspartic acid to 2-aminoethanol, are reacted with 20 g of distilled oleyl chloride in analogy to Example 3. The heterogeneous reaction mixture becomes homogeneous on addition of dichloromethane. Tt is ~a~~
precipitated twice in methanol which is cooled to -20°C.
The yellowish-colored polymer is thermoplastic, Example 9 a) Preparation of microparticles 40 mg of polysuccinimide-co-«,,e-(nonylcarbonyloxyethyl)-D,L-aspartamide (50050) from Example 4 are dissolved in 1 ml of methylene chloride/methanol (proportion 5011 by volume). The solution is introduced while stirring (800 rpm) into a beaker containing 60 m1 of 0.1~ by weight of aqueous polyvinyl alcohol solution (~Mowiol 28-99) which is saturated with 0.3 ml of methylene chloride/methanol (50/1). At the same time, the solution is finely dispersed with a mixer (25,000 rpm).
After 5 minutes, the contents axe poured into a beaker containing 200 ml of water and stirred for 30 minutes (200 rpm). The supernatant water is decanted off and the microparticles are lyophilized (diameter after lyophil-ization: 0.5 to 15 dam) .
Example 10 Preparation of microparticles 80 mg of polysuccini.wide-co-«,p-(octylcarbonyloxyethyl)-D,L-aspartamide (70:30) from Example 6 are dissolved at 50°C in 1 ml of dimethyl sulfoxide, and 20 mg of hydroxy-propylcellulose (~Klucel M.) are added. The solution of the two polymers is added dropwise, using a needle (disposable syringe, external diameter of needle 0.6 mm), to previously introduced liquid nitrogen (100 ml).
The resulting microparticles are transferred into 200 ml of water and extracted from remaining solvent for 2 hours. Excess water is decanted off, and the micrp-particles are lyophilized (diameter after lyophilization:
1-2 dam) .
~i _ 1g Example 11 Preparation of microparticles 4 g each of polysuccinimide-co-a,p-(octyloxycarbonyloxy ethyl)-D,L-aspartamide (A) (Example 6) and polysuccin imide-co-cz,,e-(nonylcarbonyloxyethyl}-D,L-aspartamide (B) (Example 5 d) are made into 2~ solutions in the solvents indicated in Table 1. The polymers are subsedu.ently sprayed to give microparticles in a spray drier (Biichi 190 mini spray drier supplied by Biichi, West Germany).
Table is Sub- Solvent Particle size stance 10~ smaller 50~ smaller90~ smaller than than than A THF 1.6 dam 3.6 ~sm 6.7 hem B CH2C12 2.4 ~sm 3.6 ~sm 6.7 ~m B CHZCIz/ 1.3 ~cm 1.9 ~m 3.0 yam methanol 3.6:1 (vol.) B CHzClz/ 1.2 ~cm 1.0 ~m 2.6 ~m methanol 2a3 (vol.) B THF/methanol 1.3 ~sm 1.9 ~m 2.7 ~m 3.6e1 (vol.) The size of the microparticleswas deter-distribution mined in a Cilas granulometer.
In each portions of the mic ropartieles case, mg prepared above are dispersed in 1.5 ml of suspension aid.
The suspension dextran aids 40 are composed of 150 mg o~
30 (supplied polysorbate by Roth, West Germany), 7.5 mg o~
- 1~
and 13.5 mg of T~aCI in 1.5 ml of distilled water. The suspensions are filtered using screen fabrics (15 ~sm and 3 ~m mesh width) and subsequently lyophilized. Before administration, the microparticles are suspended in water.
Example 12 Echocardiographic examination of dog 30 mg of microparticles (prepared as in Example 11, substance B, CHZC12/methanol 2:3 (vol.)) are resuspended IO in 1.5 ml of distilled water using a glass rod. This suspension is injected into a peripheral vein using an injection syringe. An ultrasound emitter of an ultrasonic apparatus (Toshiba, FSH 160a, Japan) is held on the thorax of the experimental animal so that a typical cross-section through the right and left heart is obtained.. As soon as the ultrasonic contrast agent reaches the right half of the heart it is possible to see on the monitor of the ultrasonic apparatus how the blood labeled by the contrast agent reaches the right atrium, then the right ventricle and subsequently leaves the heart again via the pulmonary artery. After passage through the lungs, the left half of the heart can be seen owing to the contrast agent. The ultrasonic contrast is of equal intensity before and after passage through the lungs so that it can be assumed that there is essentially complete retention of the air in the polymers and essen-tially loss-free transport of the microparticles to the left half of the heart.
Claims (12)
1. An ultrasonic contrast agent composed of micro-particles which contains a gas and a polyamino-dicarboxylic acid-co-imide derivative of the formula I, in which n is 1 or 2 x is 1 to 500 y is 1 to 500, where x + y is 2 to 1000, and R is 0-R1 or NH-R2, in which R2 is H, (CH2)m-OR1, (CH2)m-O-C(O)-R1 or (CH2)m-O-C(O)-OR1, and m is 2 to 6, and R1 is H, aryl, aralkyl, arylalkenyl, alkyl or C3-C8-cycloalkyl or a biologically inactive steroid alcohol or an amino acid, where aryl is unsubstituted or is substituted by C1-C4-alkyl, C2-C4-alkenyl, C1-C4-alkylcarbonyloxy, C1-C4-alkoxy-carbonyl, C1-C4-alkoxy or hydroxyl, where the alkyl radicals specified for R1 have 1-22 carbon atoms and the alkenyl radicals have 2-22 carbon atoms, which are not interrupted or are interrupted by a carbonyloxy or oxycarbonyl group, where the repeating units placed in square brackets axe distributed randomly and/or in blocks in the polymer, and where both the repeating units labeled with x and those labeled with y are identical or different and where the amino acids are .alpha.- and/or .beta.-linked.
2. An ultrasonic contrast agent as claimed in claim 1, wherein in formula I
R is NH-R2 and m is 2 and R1 is H, aryl, aralkyl, alkyl or C5-C6-cycloalkyl, where the alkyl radicals have 1-22 carbon atoms.
R is NH-R2 and m is 2 and R1 is H, aryl, aralkyl, alkyl or C5-C6-cycloalkyl, where the alkyl radicals have 1-22 carbon atoms.
3. An ultrasonic contrast agent as claimed in claim 1, wherein in formula I
R is NH-R2 and R1 is aryl, aralkyl, alkyl or C5-C6-cycloalkyl, where the alkyl radicals have 1-22 carbon atoms.
R is NH-R2 and R1 is aryl, aralkyl, alkyl or C5-C6-cycloalkyl, where the alkyl radicals have 1-22 carbon atoms.
4. An ultrasonic contrast agent as claimed in one or more of claims 1 to 3, wherein the microparticles contain air, nitrogen, noble gases, hydrogen, carbon dioxide, oxygen or mixtures of these gases as gas.
5. A process for the preparation of an ultrasonic contrast agent as claimed in claim 1, which comprises a) a solution of one or more polyamino-dicarboxylic acid-co-imide derivatives of the formula I or a solution of this or these derivatives which addition-ally contains one or more other polymers and/or physiologically acceptable auxiliaries being spray-dried, or b) one or more polyamino-dicarboxylic acid-co-imide derivatives of the formula I being dissolved in a solvent or solvent mixture with high melting point, or these derivatives being mixed with one or more other polymers and/or physiologically acceptable auxiliaries and dissolved in a solvent mixture with high melting point and then added dropwise to a condensed cold gas and subsequently the solvent being removed, or c) one or more polyamino-dicarboxylic acid-co-imide derivatives of the formula I being dissolved in a solvent or solvent mixture and subsequently being precipitated or dispersed in water, and the resulting suspension being freed of solvents.
6. A process according to claim 5 wherein step (c) further comprises addition of another solvent and/or of one or more other polymers to the derivatives dissolved in the solvent or solvent mixture before precipitating or dispersing in water.
7. The use of ultrasonic contrast agents as claimed in one or more of claims 1 to 4 for preparing diagnostic or therapeutic agents.
8. The use of ultrasonic contrast agents as claimed in one or more of claims 1 to 4 for investigating cavities in humans, animals or plants.
9. The use of ultrasonic contrast agents as claimed in one or more of claims 1 to 4 for diagnosing cardiovascular disorders.
10. A diagnostic or therapeutic agent composed of at least one ultrasonic contrast agent as claimed in one or more of claims 1 to 4 or of at least one ultrasonic contrast agent prepared by the process of claim 5 or 6.
11. A process for the preparation of a diagnostic or therapeutic agent as claimed in claim 10, which comprises converting at least one ultrasonic contrast agent as claimed in one or more of claims 1 to 4 with a physiological vehicle into a suitable administration form.
12. A process according to claim 11, which comprises converting at least one ultrasonic contrast agent as claimed in one or more of claims 1 to 4 with a physiological vehicle and further additives and/or auxiliaries into a suitable administration form.
Applications Claiming Priority (2)
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DEP4013231.5 | 1990-04-26 | ||
DE4013231 | 1990-04-26 |
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CA2041260A1 CA2041260A1 (en) | 1991-10-27 |
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US (1) | US5137928A (en) |
EP (1) | EP0458079B1 (en) |
JP (1) | JP3381930B2 (en) |
AT (1) | ATE108666T1 (en) |
CA (1) | CA2041260C (en) |
DE (1) | DE59102225D1 (en) |
DK (1) | DK0458079T3 (en) |
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-
1991
- 1991-04-24 US US07/690,761 patent/US5137928A/en not_active Expired - Lifetime
- 1991-04-25 DK DK91106660.3T patent/DK0458079T3/en active
- 1991-04-25 DE DE59102225T patent/DE59102225D1/en not_active Expired - Lifetime
- 1991-04-25 IE IE138591A patent/IE65065B1/en not_active IP Right Cessation
- 1991-04-25 EP EP91106660A patent/EP0458079B1/en not_active Expired - Lifetime
- 1991-04-25 CA CA002041260A patent/CA2041260C/en not_active Expired - Lifetime
- 1991-04-25 JP JP12184591A patent/JP3381930B2/en not_active Expired - Lifetime
- 1991-04-25 AT AT91106660T patent/ATE108666T1/en not_active IP Right Cessation
- 1991-04-25 ES ES91106660T patent/ES2058978T3/en not_active Expired - Lifetime
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ES2058978T3 (en) | 1994-11-01 |
IE65065B1 (en) | 1995-10-04 |
US5137928A (en) | 1992-08-11 |
JP3381930B2 (en) | 2003-03-04 |
DK0458079T3 (en) | 1994-11-21 |
EP0458079A2 (en) | 1991-11-27 |
EP0458079B1 (en) | 1994-07-20 |
ATE108666T1 (en) | 1994-08-15 |
CA2041260A1 (en) | 1991-10-27 |
IE911385A1 (en) | 1991-11-06 |
EP0458079A3 (en) | 1992-01-02 |
JPH04225926A (en) | 1992-08-14 |
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