AU687360B2 - Microparticle preparations made from biodegradable copolymers - Google Patents
Microparticle preparations made from biodegradable copolymers Download PDFInfo
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- AU687360B2 AU687360B2 AU49592/93A AU4959293A AU687360B2 AU 687360 B2 AU687360 B2 AU 687360B2 AU 49592/93 A AU49592/93 A AU 49592/93A AU 4959293 A AU4959293 A AU 4959293A AU 687360 B2 AU687360 B2 AU 687360B2
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- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 1
- JJGWLCLUQNFDIS-GTSONSFRSA-M sodium;1-[6-[5-[(3as,4s,6ar)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoylamino]hexanoyloxy]-2,5-dioxopyrrolidine-3-sulfonate Chemical compound [Na+].O=C1C(S(=O)(=O)[O-])CC(=O)N1OC(=O)CCCCCNC(=O)CCCC[C@H]1[C@H]2NC(=O)N[C@H]2CS1 JJGWLCLUQNFDIS-GTSONSFRSA-M 0.000 description 1
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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
- A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels
Landscapes
- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Physics & Mathematics (AREA)
- Acoustics & Sound (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Chemical & Material Sciences (AREA)
- Dispersion Chemistry (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicinal Preparation (AREA)
- Polyesters Or Polycarbonates (AREA)
- Compositions Of Macromolecular Compounds (AREA)
- Manufacturing Of Micro-Capsules (AREA)
Abstract
The invention concerns microparticle preparations made from biodegradable copolymers for therapeutic and diagnostic use, in particular for ultrasonic examinations, plus a method of producing such preparations.
Description
OPI DATE 26/04/94 APPIN. 10) 49592j93 flIIl AOJP DATE 14/07/94 PCT NUMB[R PCT/EP93f02422 IlINhl l I~IllIIIlI AU9349592 INTI:RNATIONAI Zt'SA.\kF1NARBfA1 AI D[\I Ndi6lA311-1 S ll IS P (51) Internationale Patent klassif Mat ion 5 (11) Intenationale Ver6ffentlichung'inummer: NVO 94/07 T539 A61 K 49/ 00 Al (43) lntcrnationales Vcriiffentlichungsdatun: 14. April 1994 h14.04.94) (21) lnternationales Aktenzeichen: PCT F1193 02422 (22) Internationales Anmeldedatum: 8. September 1993 (48.09-93) Prioritfitsda ten: P 42 32 7155.5 26. September 1992 (26.09.92) L)U i (71) Anmelder (Iir alle Beiiiinnungssrainn ausser USi: SCHIF- RNG AKTIENGESELLSCHAFT [DE IDE], Muillerstrasse 178, Postfach 65 03 11, D-13342 Berlin (IDE).
(72) Erfinder; and Erfinder/Anmelder (nur .fir L'S FRITZSCH, Thomas Elisenstrasse 2,1)-12169 Berlin FIELD)- MANN, D~ieter [DEh Krefelder Strasse 3, D)-10555 Berlin WEITSCI-IES, Werner [I)E 1I)E], Jagov-! 20, D-10555 Berlin (DE).
(81) Bestinimiungsstaaten: At'. A. 1-1. lHt'. JP. KR. NO. NZ.
VS, europ.Osche'. patent (AT, 13F. DL, K. 1:5S. FR.
G11. GiR. If-, IT. Lt. Pl, SF), Verfffentlicht Al1it intrnutionuUiLn Rechcrten h('ricia.
f ir Ahlatif de'r lar *Indt'rn~in der An~pnait 'IU~' nen Erist. I't-rillCiitIt~l ht', wird si iederhl't JlW, Andlenin- (54)Title: MICROPARTICLE PREPARATIONS MAD)E FROM BIOD)EGRAD)ABLE ('OPOLYM ERS (54) Bezeichnung: MIKROPARTIKELPRAPARATIONEN AUS BIOLOGISCH ABBAUBARFN NIISCHPOLYNIERE-N (57) Abstract The invention concerns microparticle preparations made from biodegradable copolymer, for therapeutic and diagnostic use, in particular for ultrasonic examinations, plus a method of producing such preparations.
(57) Zusammenfassung Die Erfindung betrifft Mikropartikelpriiparationen aus biologisch abbaubaren ("opolymeren zur Verwendung in Therapie und LDiagnostik, inshesondere der Ultraschalldiagnostik, sosvie emn Verfahren zu deren Herstellung.
-I I I I 4 1 Microparticle Preparations Made of Biodegradable Copolymers The invention relates to the object characterized in the claims, microparticles produced from biopolymers, monomers capable of polymerization, active ingredients and/or diagnostically detectable components, a process for their production as well as their use in diagnosis and treatment, especially as contrast media in ultrasonic diagnosis.
It is known that particles, whose diameter is smaller or in the range of the size of red blood cells, can circulate within the circulatory system after injection in the circulatory pathway. Pharmaceutical preparations of such microparticles are thus suitable as vehicle systems injectable in the circulatory system for active ingredients or diagnostic agents in medicine.
As vehicle materials, in principle all biodegradable, compatible and non-water-soluble substances are suitable. So far, above all fats, waxes, lipids soybean lecithin), denatured biopolymers albumin, gelatin) and synthetically biodegradable polymers polylactic acid, polyhydroxybutyric acid, polyalkylcyanoacrylates, poly-L-lysine) are described.
There is a difference in how quickly and in the numbers in which the microparticles circulating in the circulatory pathway are recognized, as a function of their physical and chemical properties, by the cells of the monocytic phagocytizing system (MPS) and taken up (mainly in the liver, lung and spleen). The particle charge, the particle size, the properties (molecular weight, amphiphilia) on the particle surface of adsorbed I II I I- I substances, as well as the affinity of the particle surface for blood components such as fibronectin, albumin, etc. are considered as essential factors, which determine the kinetics of the absorption of the microparticles by the cells of the MPS. By specific variation of the physicochemical surface properties of microparticles, the kinetics of the phagocytosis can be influenced by the cells of the MPS and the extent of the concentration of the particles within the corresponding organs liver, lung, spleen, bone marrow) (passive targeting). A specific concentration of microparticles in target tissues or body structures, which are not among the organs of the RES, is in this way not possible. It can rather be achieved only by the combination of the microparticles with substances which have site-specific, structure-specific or tissue-specific binding properties (homing devices). But the particles previously described for use in ultrasonic diagnosis are suitable only insufficiently as preparations suitable for the combination with homing devices.
Thus, it has to be accepted in the case of the contrast media described in EP 0 458 079 and DE 38 03 972 that they can be produced only with the help of expensive processes, which make necessary the use of organic solvents, whose use is harmful for reasons of protection of the environment and work place safety.
In addition, before using the preparations, there has to be assurance that the used organic solvents are no longer contained in the product to be used pharmaceutically. Moreover, surfaceactive adjuvants surfactants) are necessary for the I_ production, which are frequently considered as harmful in the case of injection preparations. Further, a control of the concentration behavior in various organs is not controllable in the case of these particles, a linkage of the particles of DE 38 03 972 with selectively accumulating compounds (so-called homing devices, such as, monoclonal antibodies) is not possible.
The micriparticles made of polymerized aldehydes described in DE 40 04 430 are also not suitable as vehicles for substancespecific or structure-specific substances because of the unclear biodegradability. Another drawback is that also in this case surface-active adjuvants are necessary for the production of the particles.
The microparticles made of proteins, especially of albumin, described in EP 0 224 934 exhibit an only very low in vitro and in vivo stability.
It was therefore the object of the invention to provide microparticle preparations especially for use in ultrasonic diagnosis, which get by without the use of physiologically harmful solvents or adjuvants surfactants), are easily producible and biodegradable, which either contain substances with site-specific, structure-specific or tissue-specific binding properties in the wall material or can be linked covalently with such and which exhibit a sufficient in vitro and in vivo stability.
According to the invention, this object is achieved by microparticles whose shell is formed from the combination of
M
II
biopolymers preferably polypeptides (also glycosylated) and synthetic material polymerized during the production.
Therefore, microparticles made of a copolymer of at least one synthetic polymer and at least one biopolymer are an object of the invention, and polypeptides. preferably natural ones, or produced synthetically or partially synthetically or obtained by genetic engineering as biopolymers, such as, albumin, collagen decomposition products, gelatin, fibrinogen, fibronectin, polygeline, oxypolygelatin, their decomposition products as well as poly-L-lysine are suitable. The biopolymers can also be glycosylated. As polymerizable monomers, preferably alkylcyanoacrylates, acrylic acid, acrylamide, acrylic acid chloride and acrylic acid glycide ester are suitable.
The microparticles according to the invention are suitable in the production in gas-saturated solution by the inclusion of the gas, especially as a contrast medium for ultrasonic studies.
They act as highly effective scatter elements in the ultrasonic field because of the contained gas. In addition, they can be excited by diagnostic ultrasound to radiate independent signals, which can be evaluated, with the help of the color Doppler technology.
As gases, air, nitrogen, carbon dioxide, oxygen, helium, neon, argon, krypton or their mixtures are suitable. The charge with the corresponding gas or gas mixture takes place by production of the particles in an aqueous solution saturated with the respective gas or gas mixture.
I I _ls-l _L I The microparticles can also (optionally in addition) contain other substances, detectable with the help of medicinallydiagnostic processes, such as magnetic resonance tomography, magnetic resonance spectroscopy, scintigraphy or highly sensitive magnetic field measurements with suitable magnetometers (biomagnetism), both microencapsulated and in the wall material and (optionally with the help of suitable substances, such as, chelating agents) coupled to the wall material. Thus, it is possible, in using radioactive isotopes, to use the microparticles according to the invention in scintigraphy.
Likewise, its use as contrast medium in magnetic resonance tomography, magnetic resonance spectroscopy or in measurements of the magnetic field is possible by the microencapsulation or incorporation in the wall material of suitable para-, superpara-, ferri- or ferromagnetic substances.
Surprisingly, it has been found that in the production of the particles according to the invention (in maintaining sufficient concentrations of biopclymers), the addition of surface-active substances, such as, surfactants, is not necessary. This represents a decisive advantage in comparison with the previously known production process for microparticles based on synthetic polymers, since the surfactants usually necessary for reducing the interfacial tension and for preventing the particle aggregation are considered as physiologically harmful and therefore are to be removed again from the preparations before the use in the organism up to compatible residue contents.
P1 J r' As a further advantage of the microparticle preparations according to the invention, the varied particle properties that can be matched to the respective use can be mentioned, which are easily controllable by variation of various production parameters. Thus, the pharmacokinetic parameters of the microparticle preparations,(organ distribution, retention period in the circulatory pathway) can be influenced by the selection of the respectively used biopolymers or by changes of the functional groups of the biopolymer by acylation with dicarboxylic anhydrides, such as succinic acid, diglycolic acid, glutaric acid, maleic acid or fumaric acid anhydride or by acetylation with monocarboxylic anhydrides, such as acetic anhydride or propionic acid anhydride).
Further, the content of the biopolymer in the wall material can be varied in a wide scope, by which it is possible to influence the period of the biodegradation of the capsule material in vivo and to match it to the desired use. This content can be controlled directly by the portion of the biopolymer in the production solution. Thus, for example, the wall material consists of microparticles according to the invention, made of 55% biopolymers, produced according to example 1 from an autoclaved aqueous solution containing 1% (V/V) butylcyanoacrylic acid and 5% gelatin, while with the same use of butylcyanoacrylate with microparticles produced in 2.5% aqueous autoclaved gelatin solution, the wall material consists of biopolymers, with microparticles produced in 7.5% aqueous L d L II I~b autoclaved gelatin solution, the wall material consists of biopolymers.
Surprisingly, the microparticles according to the invention can be freeze-dried without adding other adjuvants such as lactose, mannitol or sorbitol, as they are usually used as skeleton formers for freeze-drying. These skeleton formers are responsible, after drying, for the mechanical destruction of a considerable part of the microcapsules, which then is no longer usable for the imaging. In contrast to this, in the case of the microparticles according to the invention, the biopolymer of the wall material used in excess is used as a skeleton former, by which surprisingly the ratio of intact to destroyed microcapsules is drastically improved. Because of this more favorable ratio, the dose necessary for imaging can clearly be reduced.
But the microparticles according to the invention can also optionally in addition contain incorporated pharmaceutical active ingredients, by, the opacifying agent (in the case of contrast media for ultrasonic studies, a gas or gas mixture is involved here) and one or more active ingredients in the particles being microencapsulated. Preferably, the active ingredients can also be incorporated in the wall material with the methods described for the site-specific, structure-specific or tissue-specific substances. If the active ingredients are biopolymers, they can also partially form the wall material themselves, by being used in the production either exclusively or in a mixture with other suitable biopolymers gelatin, albumin, fibronectin, poly-L-lysine) as initial material for RA4 wA- C- I microparticle preparation with the addition of a polymerizable monomer or oligomer. The special advantage of coupling active ingredients to the biopolymer portion of the capsule material lies in the fact that active ingredients, which, are bound by peptide bonds to the biopolymer portion of the capsule material, can be released by enzymatic decomposition in vivo.
The microparticles according to the invention are used especially to detect or to treat thromboses and atherosclerotic changes. In this case, the use of antibodies or antibody fragments against fibrin, fibrin-bonding plasma proteins or their partial structures, tissue plasminogen activators or partial structures of them type I-homology and doughnut sequences), protein components of lipoproteins (also partial structures) as homing devices can be considered as especially advantageous.
Other fields of use for the microparticles according to the invention can be, also the diagnosis or the treatment of hormonal functions (in this case, the use of peptide hormones or their modified products with the capability for receptor bonding as homing devices is to be considered as especially advantageous), or the diagnosis or treatment of lesions of vascular endothelia (in this case, either the use of antibodies or antibody fragments against substances of the integrin group, especially tlihe selectins such as, LAM-1, ELAM-1 and GMP- 140, or the use of receptors or their bond-imparting fragments for substances of the integrin group, especially the selectins such as, LAM-1, ELAM-1 and GMP-140, as homing devices is to ~1~11 be considered as especially advantageous). Moreover, the microparticles according to the invention can also ob used for diagnosis or treatment of tumors, by antibodies or antibody mixtures being used as homing devices against surface antigens of tumors.
The production of micyoparticles according to the invention takes place by the polymerization of a suitable reactive monomer or oligomer cyanoacrylic acid butyl ester, cyanoacrylic acid isobutyl ester, cyanoacrylic acid isopropyl ester, cyanoacrylic acid propyl ester, cyanoacrylic acid isohexyl ester, cyanoacrylic acid hexyl ester, cyanoacrylic acid methyl ester, acrylic acid, acrylamide, acrylic acid glycide ester, acrylic acid chloride) in a concentration relative to the total volume of the production solution of 0.01-10% (preferably 0.1-10%) under suitable conditions by selection of the pH, by adding radicals, and by UV irradiation) with dispersion in aqueous phase, which contains a biopolymer, albumin, gelatin, oxypolyge.atin, polygeline, fibronectin, poly-L-lysine dissolved in a concentration of 0.5-20% (preferably 1%-15% By using collagen decomposition products, such as, e.g., gelatin, polygeline or oxypolygelatin, it is often advantageous to autoclave the solutions before the microparticle production.
After completion of the polymerization, the resulting microparticles are separated depending on density and particle size by one-time or repeated centrifuging, filtration or flotation, optionally further purified by dialysis and suspended in a physiologically compatible suspending agent (preferably -LI I Ir water for injection purposes) until the desired concentration.
The suspensions can be isotonized by the addition of suitable water-soluble substances, such as, glucose, mannitol, sorbitol, common salt, galactose, lactose, fructose, trehalose.
The size distribution of the microparticles developing in the production can be controlled within wide ranges by the type of stirring device used and the number of revolutions.
The production of gas-filled microparticles takes place by the reaction being performed in a solution saturated with the desired gas. In this connection, the density of the resulting microparticles, i.e. the ratio between wall material and gas portion, can be controlled both by the stirring conditions and especially by the portion of biopolymers during the production process.
If microparticles are to be obtained, in which the core consists of the same material as the shell, attention must be paid in the production that by the selection of a suitable stirring device and a suitable stirring speed, a foaming of the reaction solution is avoided.
The required ability for combination with site-specific, structure-specific or tissue-specific substances, which are to assure an additional concentration of the microparticles in target fields outside the organs of the RES (homing devices), takes place either by the coupling of the substances to the polypeptides co-forming the shell material, performed before the microparticle preparation or afterwards, with known methods of biochemistry for coupling amino acids W. K6nig, R. Geiger: I Eine neue Metnode zur Synthese von Peptiden: Aktivierung der Carboxylgruppe mit Dicyclohexylcarbodiimid unter Zusatz von 1- Hydroxy-benzotriazolen [A New Method to Synthesize Peptides: Activation of the Carboxyl Group with Dicyclohexylcarbodiimide while Adding l-Hydroxy-benzotriazoles], Chem. Ber. 103, 788-798 (1970)), or in that the miproparticles are produced in an aqueous solution of the site-specific, structure-specific or tissuespecific substance, if the latter represents a polypeptide, so that the substance is used directly as a component of the shell material.
As site-specific, structure-specific or tissue-specific substances that can be coupled to the microparticles or coforming the shell material, preferably antibodies, conjugated antibodies, hormones (especially peptide hormones), transferrin, fibronectin, heparin, transcobalamin, epidermal growth factors, lipoproteins, plasma proteins as well as their specificityimparting partial structures and oligopeptides such as RGD, RGDS, RGDV and RGDT are suitable.
As chelating ligands that can be coupled to the microparticles, diethylenetriaminepentaacetic acid or its derivatives are suitable. The linkage of these ligands with the particl-s takes place in a way known in the art [Hanatowich et al., Science 220 (1983) 613]. Then, the particles are reacted with the desired metal ions to the respective particle-fixed metal complex.
The selection of the used metal ion depends on the desired area of use. In the field of NMR diagnosis, paramagnetic metal
C
C' slLi~I.
12 ions, preferred according to the invention, of tl lements of atomic numbers 21-29 and 57-70, especially gadolinium(III) ions, are used. For the use in scintigraphy, suitable emitters of radioactive radiation, preferably 1 'In or 99 Tc, 1231 and 1311 are used.
The finished microparticle suspensions can be used directly for the respectively predetermined use, but it has proven advantageous to improve the storage stability, to freeze and then to freeze-dry the suspensions while adding skeleton formers (such as, trehalose, polyvinylpyrrolidone, lactose, mannitol, sorbitol, glycine), which also can be used to set the tonicity.
It has proven especially advantageous to use the biopolymer used in excess itself as skeleton former. In both cases, it is suitable to move the suspensions during the freezing to prevent uneven particle distributions in the frozen material by sedimentation or flotation. The production of ready-to-use, injectable suspensions from the freeze-dried preparations takes place by resuspending the lyophilizate in a pharmaceutically acceptable suspension medium such as, water aqueous solutions of one or more inorganic salts such as physiological electrolyte solutions, aqueous solutions of monosaccharides or disaccharides ouch as glucose or lactose, sugar alcohols such as mannitol, but preferably in water suitable for injection purposes. The total concentration of the optionally dissolved substances is 0-20% by weight.
The concentration of the ready-to-use contrast medium can be set in the range of 0.01 to 20 mg, preferably 0.5 to 6 mg of 1 7 of if II 13 particles/ml of suspension medium. The injected dose depends on the respective use; in ultrasonic diagnostic studies in the study of vessels, it lies in the range of 1 to 500 pg, preferably between 10 and 100 pg of particles/kg of body weight, in the study of liver and spleen by color Doppler sonography in the range of 50 to 1000, preferably between 200 and 600 jg/kg of body weight. The invention is explained by the following examples:
I
I Example 1 In 300 ml of distilled water, 15 g of gelatin (300 bloom) is dissolved and adjusted to pH 3.0 with hydrochloric acid. The solution is autoclaved for 30 minutes at 121 0 C. After cooling to room temperature, the pH of the solution is corrected to pH (with sodium hydroxide solution) and stirred in a 2000 ml beaker with a quick-running stirrer at 10000 rpm. 3 ml of cyanoacrylic acid butyl ester is slowly (10 minutes) instilled in the solution with stirring. Stirring of the resulting microparticles is continued for 60 minutes. Then, the suspension is floated in a separatory funnel for 2 days. The subnatant is drained and the supernatant is supplemented with distilled water to 100 ml. The suspension contains gas-filled, sound-active microparticles in a size of about 0.1-8 Am, and by additional flotation or filtration, if necessary, the particle sizes can be further concentrated to 0.5-3 Am). The capsule wall of the microparticle item consists to about 55% of polypeptides and to about 45% of polycyanoacrylic acid butyl ester. The particles can be dispersed in water without the addition of surface-active adjuvants. They do not tend toward aggregation.
By adding a suitable adjuvant glucose, sodium chloride, mannitol, lactose, galactose), the suspension can be isotonized.
The suspension can be freeze-dried, if necessary, to increase the storage stability without losing its suitability as a contrast medium for ultrasonic studies, preferably after adding a cryoprotector, such as, lactose, polyvinylpyrrolidone, mannitol, glycine.
I I Example 2 500 mg of poly-L-lysine (MG 5000) is dissolved in 20 ml of distilled water and adjusted to pH 4.5 with phosphate buffer.
100 mg of acrylic acid glycide ester is added, the mixture is stirred with a quick-running stirrer under cooling at 20 0 C. mg of ammonium peroxydisulfate and 0.1 ml of tetramethylenediamine are added. It is stirred for another minutes. The resulting gas-filled microparticles are separated by flotation. The particle size of the microparticles is between 0.2 and 6 Am.
Example 3 g of polygeline is dissolved in 200 ml of water for injection purposes. The solution is adjusted to pH 3.0 with phosphoric acid and supplemented with water for injection purposes to 300 ml. The solution is filtered through a 0.22 Am filter for sterilization by filtration and stirred with a quickrotating dissolver at 6000 rpm. With stirring, a mixture of ml of cyanoacrylic acid isopropyl ester and 1.5 ml of cyanoacrylic acid butyl ester is slowly instilled. Stirring is continued for 120 minutes. The resulting suspension is floated for three days in a separatory funnel. The further course of action corresponds to example 1. The resulting microparticles contain gas. They are suitable as contrast media for ultrasonic studies. Their wall material consists to about 22% of biopolymer, to about 40% of polycyanoacrylic acid butyl ester and to about 38% of polycyanoacrylic acid isopropyl I I sr II ester. They can be dispersed in water without adding surfaceactive adjuvants without in this connection aggregating. Their particle size is about 0.2-6 Am.
Example 4 g of human serum albumin is dissolved in 200 ml of water for injection purposes. The solution is adjusted to pH 4.0 with hydrochloric acid and supplemented with water for injection purposes to 300 ml. The solution is filtered through a 0.22 im filter for sterilization by filtration and stirred with a quickrotating dissolver at 10000 rpm. With stirring, 2 ml of cyanoacrylic acid isopropyl ester is slowly instilled. Stirring is continued for 60 minutes. The resulting suspension is floated for three days in a separatory funnel. The further course of action corresponds to example 1. The resulting microparticles contain gas. They are suitable as contrast media for ultrasonic studies. Their wall material consists to about 30% of human serum albumin and to about 70% of polycyanoacrylic acid isopropyl ester. They can be dispersed in water without adding surface-active adjuvants without in this connection aggregating. Their particle size is on the average about 0.2-3 /m.
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Example 250 ml of oxypolygelatin solution is adjusted to pH 2.5 with hydrochloric acid and supplemented with water for injection purposes to 300 ml. The solution is filtered through a 0.22 pm filter for sterilization by filtration and stirred with a quickrotating rotor-stator-stirrer at 8000 rpm. With stirring, 3 ml of cyanoacrylic acid butyl ester is slowly instilled. Stirring is continued for 90 minutes. The resulting suspension is floated for three days in a separatory funnel. The further course of action corresponds to example 1. The resulting microparticles contain gas. They are suitable as contrast media for ultrasonic studies. Their wall material consists to about 25% of oxypolygelatin and to about 75% of polycyanoacrylic acid butyl ester. They can be dispersed in water without adding surface-active adjuvants without in this connection aggregating.
Their particle size is about 0.2-4 im.
Example 6 500 mg of fibronectin is dissolved in 5 ml of distilled water and adjusted to pH 3.5 with hydrochloric acid. The solution is filtered through a 0.22 um filter for sterilization by filtration and stirred with a quick-rotating rotor-statorstirrer in a cooled 15 ml vessel (15 0 C) at 8000 rpm. With stirring, 0.3 ml of cyanoacrylic acid butyl ester is slowly instilled. Stirring is continued for 90 minutes. The resulting suspension is floated for three days in a separatory funnel. The JI I I I ILd
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supernatant is suspended in 2 ml of water for injection purposes, which contains 100 mg of mannitol. The suspension is frozen at 0 C with shaking and freeze-dried. Before use, the microparticles are redispersed with 2 ml of water for injection purposes. The particle size of the microparticles is on the average 0.8 Am. They are suitable as contrast media for ultrasonic studies. The wall material of the microparticles consists to about 35% of fibronectin and to about 65% (M/M) of polycyanoacrylic acid butyl ester.
Example 7 100 mg of an antibody against fibrin is dissolved in 4 ml of phosphate buffer (pH The solution is filtered through a 0.22 um filter for sterilization by filtration and stirred in a double-walled stirrer vessel (10 ml capacity) with a quickrotating dissolver-stirrer under cooling at 6000 rpm. During the stirring, 0.2 ml of cyanoacrylic acid butyl ester is slowly instilled. Stirring is continued for 60 minutes. The resulting suspension is floated for two days in a separatory funnel. The subnatant is drained, the supernatant is mixed with 200 mg of lactose and 2 ml of water for injection purposes. The suspension is frozen at -40 0 C with shaking in a cold bath and then freezedried. Before use, the microparticles are resuspended with 2 ml of water for injection purposes. They are gas-filled and suitable as contrast media for ultrasonic studies. Their particle size is about 1 um on the average. The wall material of II I 1 the microparticles consists to about 20% of the antibody and to about 80% of polycyanoacrylic acid butyl ester.
Example 8 g of polygeline is dissolved in 50 ml of water for injection purposes, 2 N sodium hydroxide solution is added drop by drop under pH control. A total of 2 g of diglycolic acid anhydride is added gradually, and the pH is kept between 7.5 and After completion of the reaction, the excess diglycolic acid is removed from the solution by repeated ultrafiltration (exclusion limit MG 1000). The acylated polygeline solution is supplemented with water for injection purposes to 300 ml and filtered through a 0.22 Am filter. 3 ml of cyanoacrylic acid butyl ester is slowly added with stirring at 10000 rpm. After completion of the addition, stirring is continued for 60 minutes.
The resulting gas-filled microparticles are separated by centrifuging at 1500 rpT (30 minutes) and taken up in 50 ml of water for injection purposes. They can be dispersed in water without adding surface-active adjuvants without aggregating.
Their particle size is approximately 0.1-6 im. The wall material of the microparticles consists to about 45% of acylated polygeline and to about 55% of polycyanoacrylic acid butyl ester.
Example 9 ml of the gas-containing microparticles produced according to example 3 is taken up in 20 ml of phosphate buffer 4R
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I: Ij i 1'oli /V o:: _Iq_ of pH 4.5. The suspension is stirred at 4 0 C (100 rpm) and 25 mg of (3-dimethylaminopropyl)-N'-ethylcarbodiimide-HC1 is added to the mixture. After 60 minutes, 25 mg of fibronectin, which was previously dissolved in 10 ml of phosphate buffer, is added to the microparticle suspension. It is stirred for 60 minutes at 4 0 C and for another 120 minutes at room temperature. Then, the suspension is dialyzed three times against phosphate buffer of pH (exclusion limit MG 1000) and floated for two days in a separatory funnel. The supernatant is taken up in 20 ml of water for injection purposes, mixed with 5% polyvinylpyrrolidone frozen at -40 0 C with shaking and freeze-dried.
Example The lyophilizate of example 9 is resuspendc- with 20 ml of glucose solution. 0.1 ml of it is added to 10 ml of PBS solution of 37 0 C, which contains a freshly produced fibrin clot (diameter 1 mm). After 10 minutes of incubation with shaking in a water bath, the clot is removed, washed five times with 10 ml of PBS (pH 7.4) each and then sonographically studied. In the color Doppler, signals of clinging microparticles can be clearly detected. The procedure is analogous with the particles of example 3 (without the reaction with fibronectin shown in example In the sonographic study of the clots, no clinging microparticles can be detected (also in the color Doppler).
Example 11 ml of the gas-containing microparticles produced according to example 3 is taken up in 5 ml of phosphate buffer of pH The suspension is stirred at 4 0 C (100 rpm), and 10 mg of (3dimethylaminopropyl)-N'-ethylcarbodiimide-HCl is added to the mixture. After five minutes, 2.5 mg of an antibody against fibrin (No. 0541 clone E8, Immunotech, Marseilles, France), which was previously dissolved in 1 ml of phosphate buffer, is added to the microparticle suspension. It is stirred for 60 minutes at 4 0 C and for another 120 minutes at room temperature. Then, the suspension is dialyzed three times against phosphate buffer of pH (exclusion limit MG 1000) and floated for two days in a separatory funnel. The supernatant is taken up in 2 ml of water for injection purposes, mixed with 5% polyvinylpyrrolidone frozen at -40 0 C with shaking and freeze-dried.
Example 12 The lyophilizate of example 11 is resuspended with 2 ml of glucose solution. 0.1 ml of it is added to 10 ml of PBS solution of 37 0 C, which contains a freshly produced fibrin clot (diameter 1 mm). After 10 minutes of incubation with shaking in a water bath, the clot is removed, washed five times with 10 ml of PBS (pH 7.4) each and then sonographically studied. In the color Doppler, signals of clinging microparticles can be clearly detected. With the particles of example 3 (without the reaction with the antibody against fibrin shown in example 11), the procedure is analogous. In the sonographic study of the clots,
_I
no clinging microparticles can be detected (also in the color Doppler).
Example 13 0.1 ml of the resuspended particles of example 6 is examined for their fibrin bond in an experimental set-up analogous to example 11. In the sonographic study, microparticles bound to the clot can be clearly detected.
Example 14 0.1 ml of the resuspended particles of example 7 is examined for their fibrin bond in an experimental set-up analogous to example 11. In the sonographic study, microparticles bound to the clot can be clearly detected.
Example ml of the microparticles produced according to example 8 is taken up in 10 ml of phosphate buffer of pH 4.5, and 20 mg of l-hydroxybenzotriazole is added. After cooling to 4 0 C, it is stirred (100 rpm), and 10 mg of (3-dimethylaminopropyl)-N'ethylcarbodiimide-HCl is added. Stirring is continued for minutes at 4 0 C. Then, it is stirred for another 60 minutes at room temperature. 10 mg of pancreozymin, which was previously dissolved in 5 ml of phosphate buffer, is added to the suspension at room temperature. It is stirred for 120 minutes at room temperature. Then, the suspension is dialyzed five times against phosphate buffer of pH 4.5 (exclusion limit MG 1000) and floated
I
for two days in a separatory funnel. The supernatant is taken up in 10 ml of water for injection purposes, mixed with polyvinylpyrrolidone frozen at -40 0 C with shaking and then freeze-dried.
Example 16 The lyophilizate of example 15 is resuspended with 10 ml of water for injection purposes. 0.1 ml of the suspension is injected in the caudal vein of a rat. After 10 minutes, the pancreas is removed and sonographically studied in a water bath.
In the color Doppler, ultrasonic signals of the microparticles can be detected.
Example 17 ml of the gas-containing microparticles produced according to example 3 is taken up in 5 ml of phosphate buffer of pH The suspension is stirred at 40C (100 rpm), and 1u a: of (3dimethylaminop;opyl)-N'-ethylcarbodiimide-HCl is added to the mixture. Afte. five minutes, 5 mg of tPA, which was previously dissolved in 1 ml of phosphate buffer, is added to the microparticle suspension. Stirring is continued for 24 hours at Then, the suspension is dialyzed three times against phosphate buffer of pH 4.5 (exclusion limit MG 1000) and floated for two days in a separatory funnel. The supernatant is taken up in 2 ml of water for injection purposes.
I 1 Example 18 Two fibrin clots (weight about 50 mg each) are produced, which are added to 20 ml of plasma. 0.05 ml of the particle suspension produced according to example 17 is added to the clots. After 10 minutes, the clots are removed from the plasma, in the sonographic study, signals of clinging microparticles appear in the color Doppler.
Example 19 0.6 g of gelatin is dissolved in 20 ml of an aqueous suspension of magnetite particles (about 20 mmol of iron/ml, diameter of the particles about 20 nm). The solution is adjusted to pH 3 with hydrochloric acid. With stirring (3000 rpm), 0.2 ml of cyanoacrylic acid isobutyl ester is slowly added. After completion of the addition, stirring is continued for 90 minutes.
The suspension is centrifuged (2000 rpm, 60 minutes). The supernatant is discarded, the subnatant is taken up in 10 ml of PBS of pH 7.4 (10 mmol). The suspension is cooled to 4 0 C and with stirriii (100 rpm), 10 mg of (3-dimethylaminopropyl)-N'ethylcarbodiimide-HCl is added. Stirring is continued for minutes at 4 0 C. Then, 5 mg of an antibody against fibrin (no.
0541 clone E8, Immunotech, Marseilles, France) is added.
Stirring is continued for 60 minutes at 4 0 C and then for 120 minutes at room temperature. The suspension is ultrafiltered (exclusion limit MG 5000) five times against PBS of pH 7.4 mmol). Then, the suspension is centrifuged (2000 rpm, minutes). The subnatant is taken up in 5 ml of water for
I
injection purposes, which contains 5% mannitol and is filtered through a 5 pm membrane filter. The filtrate is frozen at -40 0 C and then freeze-dried.
Example g of gelatin (300 Ploom) is dissolved at 80 0 C in 150 ml of water for injection purposes. After the cooling, the solution is adjusted to pH 2.5 with 0.1 N HC1 and supplemented with water for injection purposes to 300 ml. The solution is autoclaved (process A 121, Deutsches Arzneibuch [German Pharmacopoeia] 9th Edition'. The pH of the autoclaved solution is controlled and if necessary corrected to pH 2.5. 3 ml of cyanoacrylic acid isobutyl ester is added to the solution with stirring. Stirring is continued for 90 minutes. The resulting microparticle suspension is centrifuged at 1000 rpm for 60 minutes, the supernatant is taken up in 50 ml of water for injection purposes and again centrifuged at 1000 rpm for 60 minutes. This is repeated a total of 5 times. The supernatant of the final centrifuging is taken up in 50 ml of PBS (pH 7.0) and added with stirring to 0.1 mg of solid diethylenetriaminepentaacetic acid dianhydride Hnatowich et al. (1983) Science 220: 613). It is stirred for 5 minutes. The suspension is centrifuged at 1000 rpm for 60 minutes, the supernatant is taken up in 50 ml of water for injection purposes. lhe centrifuging against water for injection purposes is repeated another 4 times. The supernatant of the final centrifuging is taken up with 50 ml of water for injection purposes and filtered through a filter column from HDC- I I II pore filters of pore sizes 70, 40, 20 and 10 pm. The filtrate contains about 2 x 109 particles/ml, which have DTPA groups on their surface. The average particle size is about 2 im. The particles can be labeled with the known methods with radioactive metal ions In-Ill or Tc-99).
Example 21 Fibrin clots as examples for sound application lead to detection only with a gamma counter instead of with Doppler.
Example 22 g of polygeline is dissolved at 80 0 C in 150 ml of water for injection purposes. After cooling, the solution is adjusted to pH 3 with 0.1 N HC1 and supplemented with water for injection purposes to 300 ml. The solution is autoclaved (process A 121, German Pharmacopoeia 9th Edition). The pH of the autoclaved solution is corrected to pH 2. 3 ml of cyanoacrylic acid butyl ester is added to the solution with stirring. Stirring is continued for 90 minutes. The resulting microparticle suspension is centrifuged at 1000 rpm for 60 minutes, the supernatant is taken up in 50 ml of water for injection purposes and again centrifuged at 1000 rpm for 60 minutes. This is repeated a total of 5 times. The supernatant of the final centrifuging is taken up in 50 ml of PBS (pH 7.4) and cooled to 4 0 C. With stirring at 4 0 C, 50 mg of streptavidin and 5 mg of EDC are added. Stirring is continued for 1 hour. The suspension is centrifuged 3 times (1000 rpm, 60 minutes). After each centrifuging, the supernatant
I
is taken up with 50 ml of PBS (pH 7.0, 10 mmol of phosphate).
The antibody against fibrin is labeled in a molar ratio of with sulfosuccinimidyl-6-(biotinamido)-hexanoate (NHS-LC-biotin) according to the method of D. J. Hnatovitch et al., J. Nucl. Med.
28 (1987), 1294-1302.
Example 23 mg of the biotin-labeled antibody against fibrin of example 22 is intravenously injected in a rabbit fed with a diet containing cholesterol. After 3 hours, the particles of example 22 are then injected. 10 minutes later, the carotid is removed from the previously killed animal, and the atherosclerotic arterial sections are examined in a water bath in the Doppler mode for contrast media signals. Sound signals of clinging particles can clearly be detected.
Example 24 a) 20 ml of the microparticle suspension produced according to ex:.:,ple 8 is brought to a pH of 4.5 by 5 ml of phosphate buffer and then mixed with 50 mg of a 125-iodine labeled antibody against fibrin (5 pCi). With stirring at 4 0 C, 500 mg of (3dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride is added to the reaction mixture. Then, stirring is continued for 8 hours under cooling, the microparticles are separated by centrifuging and washed a total of three times with 20 ml each of water for injection purposes, and each individual washing process takes place in the way that the particles are resuspended in water and then centrifuged. After the final washing process, the particles are resuspended in 20 ml of water for injection purposes.
The degree of bonding of the antibody to the particle is determined with a gamma counter based on the 125-iodine activity.
Then, 93% of the originally used amount of antibodies is bound permanently to the particle surface.
b) Microparticles produced according to example 4 of DE 38 03 972 are reacted in an amount corresponding to example 24a) with 50 mg of a 125-iodine labeled antibody against fibrin ~Ci) under otherwise identical reaction conditions.
A comparison of the degree of bonding with the particles according to example 24a) shows a considerably lower value of only 1%.
I
Claims (14)
1. Microcapsules for the diagnosis and/or treatment of biodegradable polymers, characterized in that the wall material consists of a copolymer made of at least one synthetically polymeric material and at least one biopolymer, which a) exhibits site-specific, structure-specific or tissue- specific properties or b) has functional groups, by which optionally chelating ligands or their metal complexes and/or site-specific, structure- specific or tissue-specific substances are bound, and optionally in addition contains one or more pharmaceutical active ingredient(s) and in that the core of the capsules consists of a) a gas or gas mixtures and/or b) a pharmaceutical active ingredient or active ingredient mixture or c) the same material as the capsule wall, provided that the synthetically polymeric material is not made of polymerizable aldehydes, in that the weight ratio of biopolymer to synthetic polymer is in the range of 10:90 to 80:20 and that the microcapsule size is 0.5 to 8 jm.
2. Microcapsules according to claim 1, wherein the synthetic polymer is made of monomeric acrylic acid, acrylamide, acrylic acid chloride, acrylic acid glycide ester or monomeric alkylcyanoacrylates.
3. Microcapsules according to claim 1, wherein tht. biopolymer is an optionally glycosylated polypeptide, preferably albumin, fibrinogen, fibronectin or a collagen decomposition product, preferably gelatin, polygeline, oxypolygelatin or poly- L-lysine.
4. Microcapsules according to claim 1, wherein the site- specific, structure-specific and tissue-specific substances optionally bound by the functional groups of the biopolymer are antibodies, conjugated antibodies, hormones, transferrin, fibronectin, heparin, transcobalamin, epidermal growth factor, lipoproteins, plasma proteins, peptides or oligopeptides, which preferably contain the amino acid sequences RGD, RGDS, RGDV or RGDT. Microcapsules according to claim 1, wherein the biopolymer is a polypeptide with site-specific, structure- specific and tissue-specific properties.
6. Microcapsules according to claims 1-5 for use in ultrasonic diagnosis, wherein the wall material encloses a gas, preferably air, nitrogen, carbon dioxide, oxygen, helium, neon, argon, krypton or a mixture of at least two of these gases.
7. Microcapsules according to claims 1-5, wherein the radicals bound by the functional groups of the biopolymer are chelating ligands.
8. Microcapsules according to claims 1-5 and 7 containing ethylenediaminepentaacetic acid radicals or their derivatives as chelating ligands.
9. Microcapsules according to claims 1-5, 7 and 8, wherein the radicals bound by the functional groups of the biopolymer are chelate complexes of a metal ion. I I II Microcapsules according to claims 1-5 and 7-9, wherein the complex bound metal ions are paramagnetic, preferably gadolinium ions.
11. Microcapsules according to claims 9-10 for use in NMR diagnosis.
12. Microcapsules according to claims 1-5 and 7-9, wherein the complex bound metal ions are radioisotopes, preferably 99 mtechnetium or 111 indium ions.
13. Microcapsules according to claim 12 for use in scintigraphy.
14. Process for the production of microcapsules according to claim 1, wherein the monomer is polymerized in a concentration of 0.01-10% preferably 0.1-10% relative to the total volume of the production solution with dispersion in gas-saturated, optionally autoclaved aqueous phase, which contains a dissolved biopolymer in a concentratio- of 0.5-20% preferably 1%-15% as well as optionally, in addition, magnetic particles, provided that the weight ratio of biopolymer to synthetic polymer is 10:90 to 80:20, after completion of the polymerization, the resulting microparticles are separated depending on density and particle size by one-time cr repeated centrifuging, filtration, sedimentation or flotation, optionally further purified by dialysis and suspended in a physiologically compatible suspending agent and then optionally reacted with chelating agents, metal chelates and/or site-specific, structure-specific or tissue- specific substances and this suspension is freeze-dried, preferably by adding skeleton formers. 32 Cont:-ast medium, wherein the microparticles according to claim 1 are resuspended in a pharmaceutically acceptable suspension medium.
16. Contrast medium according to claim 15, wherein as a pharmaceutically acceptable suspension medium, water for injection purposes is used, which optionally contains an addition of common salt, glucose, mannitol and/or lactose and optionally in addition a multivalent alcohol.
17. Contrast medium that can be produced according to the process described in claim 14, wherein a final freeze-drying is dispensed with. I 33 Abstract The invention relates to microparticle preparations made of biodegradable copolymers for use in treatment and diagnosis, especially ultrasonic diagnosis, as well as a process for their production. I II INf1U1INATI0NAL SICARCII IECOPIR Internm al Apphaion No PCT/EP 93/02422 A. CI.ASSII:ICATION OF SUBJIiCI' MATI'IER IPC 5 A61K49/00 According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation scarcid (classificaton system followed by classification symbols) IPC 5 A61K Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted dunng the internatonal search (name of data base and, where practcal, sear.h terms used) C. DOCUMENTS CONSIDERED TO BE RELEVANT Category Citanon o r docurmnt, with indication, where appropnate, of the relevant passages Relevant to claim No. X,Y EP,A,0 458 745 (SINTETICA) 27 November 1-17 1991 see column 9, line 2 line see column 10, line 9 line 33; claims Y EP,A,0 441 468 (SCHERING AG.) 14 August 1-17 1991 cited in the application see column 31, line 9 column 46; claims A EP,A,0 327 490 (SCHERING AG) 9 August 1989 1-17 cited in the application see column 2, line 24 line 51; claims P,X, WO,A,92 17213 (NYCOMED AS) 15 October 1992 1-17 Y see page 7, line 6 line 20; claims Y Further documents are listed in the connuation of box C. Patent family members are listed in annex. Special categonres of cted documents later document published after the international filing date Sd d t g s o or priority date and not in conflict with the application but A document defining the general state of the art which is not cied to understand the prnciple or theory underlying the considered to be of particular relevance mventon earlier document but published on or after the international document of particular relevance; the claimed invention filing date cannot be considered novel or cannot be considered to document which may throw doubts on pnority claim(s) or involve an inventive step when the document is taken alone which is ated to establish the publication date of another document of particular relevance; the claimed invention citation or other special reason (as specified) cannot be considered to involve an inventive step when the document referrng to an oral disclosure, use, exhibition or document is combined with one or more other such docu- other means ments, such combination being obvious to a person skilled document pubhshed prior to the international fill g date but in the art. later than the prnonty date claimed document member of the same patent family Date of the actual completion of the internatonal search Date of maiing of the international search report 28 January 1994 0 g. 02. 9 Name and mailing address of the ISA Authorized officer European Patent Office, P.B. 5818 Patentlaan 2 NL 2280 HV Rijswilk Tel. 31-70) 340-2040, Tx. 31 651 epo n, Berte, M Fax 31-70) 340-3016, Form PCT/ISIA/10 (second iheet) (July 1992) page 1 of 2 IN'rICINATIONAI. SLOAII RTOrRT PCT/EP 9/22 (:."Continuation) D)OCUMENT'S CONSIDEREDI 1TO DL~ REEVANTr Category *ICitation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. Y BRITISH MEDICAL JOURNAL vol. 1, no. 5952 February 1975 (LONDON) pages 247 249 J.P. BOLTON ET AL. 'INCIDENCE OF EARLY POST-OPERATIVE ILIOFEMORAL THROMBOSIS' see page 247, column 1, paragraph 1 1-17 Form PCTISZ-IlG (eontinuation of second sheet) (July 1992) page 2 of 2 I NTERlNATIIONAL SWAIRCH I RI;,owr' lntemrAt Applicittuon No Information on patent family tnemhlcrs PCT/EP 93/02422 Patent document Publicaton Patent family I Publication cited in -earch report date jmember(s) date EP-A-0458745 27-11-91 AU-B- 636481 29-04-93 AU-A- 7614491 21-11-91 CA-A- 2042722 19-11-91 CN-A- 1056634 04-12-91 JP-A- 4226923 17-08-92 NZ-A- 238160 23-12-93 EP-A-0441468 14-08-91 DE-A- 4004430 14-08-91 AU-A- 7098291 17-10-91 JP-A- 5009132 19-01-93 EP-A-0327490 09-08-89 OE-C- 3803971 07-09-89 DE-A- 3803972 10-08-89 AU--B- 635200 18-03-93 AU-A- 3035189 25-08-89 WO-A- 8906978 10-08-89 EP-A- 0398935 28-11-90 jP-T- 3503634 15-08-91 WO-A-9217213 15-10-92 AU-A- 1428392 0 11-92 AU-A- 1443992 02-11-92 CA-A-- 2107106 29-09-92 CA-A- 2107107 29-09-92 WO-A- 9217436 15-10-92 EP-A- 0577659 12-01-94 EP-A- 0576521 05-01-94 Form PCTIISA'310 (pstent taxnily annex) (July 1992)
Applications Claiming Priority (3)
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|---|---|---|---|
| DE4232755 | 1992-09-26 | ||
| DE4232755A DE4232755A1 (en) | 1992-09-26 | 1992-09-26 | Microparticle preparations made from biodegradable copolymers |
| PCT/EP1993/002422 WO1994007539A1 (en) | 1992-09-26 | 1993-09-08 | Microparticle preparations made from biodegradable copolymers |
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| JP (1) | JPH08504398A (en) |
| KR (1) | KR100287975B1 (en) |
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| WO (1) | WO1994007539A1 (en) |
| ZA (1) | ZA937099B (en) |
Cited By (1)
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|---|---|---|---|---|
| EP2474327A1 (en) * | 2011-01-07 | 2012-07-11 | RWTH Aachen | Microdosing of ultrasound contrast agents |
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| US5922304A (en) * | 1989-12-22 | 1999-07-13 | Imarx Pharmaceutical Corp. | Gaseous precursor filled microspheres as magnetic resonance imaging contrast agents |
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| EP0727225A3 (en) * | 1995-02-14 | 1997-01-15 | Sonus Pharma Inc | Compositions and methods for directed ultrasound imaging |
| DE19510690A1 (en) | 1995-03-14 | 1996-09-19 | Schering Ag | Polymeric nano- and / or microparticles, processes for their production, and use in medical diagnostics and therapy |
| DE69632401T2 (en) * | 1995-06-07 | 2005-05-19 | Imarx Pharmaceutical Corp., Tucson | NEW TARGETED MEANS FOR DIAGNOSTIC AND THERAPEUTIC USE |
| US6821506B2 (en) | 1995-06-08 | 2004-11-23 | Barnes-Jewish Hospital | Site specific binding system, imaging compositions and methods |
| US5780010A (en) * | 1995-06-08 | 1998-07-14 | Barnes-Jewish Hospital | Method of MRI using avidin-biotin conjugated emulsions as a site specific binding system |
| US6548046B1 (en) | 1995-06-08 | 2003-04-15 | Barnes-Jewish Hospital | Site specific binding system, imaging compositions and methods |
| WO1997022409A1 (en) * | 1995-12-21 | 1997-06-26 | Drexel University | Hollow polymer microcapsules and method of producing |
| US5849727A (en) * | 1996-06-28 | 1998-12-15 | Board Of Regents Of The University Of Nebraska | Compositions and methods for altering the biodistribution of biological agents |
| US6331289B1 (en) | 1996-10-28 | 2001-12-18 | Nycomed Imaging As | Targeted diagnostic/therapeutic agents having more than one different vectors |
| WO1998018498A2 (en) * | 1996-10-28 | 1998-05-07 | Marsden, John, Christopher | Improvements in or relating to diagnostic/therapeutic agents |
| US6261537B1 (en) | 1996-10-28 | 2001-07-17 | Nycomed Imaging As | Diagnostic/therapeutic agents having microbubbles coupled to one or more vectors |
| US6264917B1 (en) | 1996-10-28 | 2001-07-24 | Nycomed Imaging As | Targeted ultrasound contrast agents |
| US20010003580A1 (en) | 1998-01-14 | 2001-06-14 | Poh K. Hui | Preparation of a lipid blend and a phospholipid suspension containing the lipid blend |
| DE19925311B4 (en) | 1999-05-27 | 2004-06-09 | Schering Ag | Multi-stage process for the production of gas-filled microcapsules |
| US7220401B2 (en) | 1999-09-24 | 2007-05-22 | Barnes-Jewish Hospital | Blood clot-targeted nanoparticles |
| DE10013850A1 (en) * | 2000-03-15 | 2001-09-20 | Schering Ag | Gas-filled microcapsules, useful for ultrasonic diagnosis, are prepared from functionalized poly(alkyl cyanoacrylate), allowing attachment of e.g. specific-binding agents |
| DE10119522A1 (en) * | 2001-04-20 | 2002-12-05 | Innovacell Biotechnologie Gmbh | Preparation and application of a suspension composition with an ultrasound contrast medium |
| US7462366B2 (en) | 2002-03-29 | 2008-12-09 | Boston Scientific Scimed, Inc. | Drug delivery particle |
| US7842377B2 (en) | 2003-08-08 | 2010-11-30 | Boston Scientific Scimed, Inc. | Porous polymeric particle comprising polyvinyl alcohol and having interior to surface porosity-gradient |
| US8012454B2 (en) | 2002-08-30 | 2011-09-06 | Boston Scientific Scimed, Inc. | Embolization |
| US7883490B2 (en) | 2002-10-23 | 2011-02-08 | Boston Scientific Scimed, Inc. | Mixing and delivery of therapeutic compositions |
| US7976823B2 (en) | 2003-08-29 | 2011-07-12 | Boston Scientific Scimed, Inc. | Ferromagnetic particles and methods |
| US7901770B2 (en) | 2003-11-04 | 2011-03-08 | Boston Scientific Scimed, Inc. | Embolic compositions |
| US7736671B2 (en) | 2004-03-02 | 2010-06-15 | Boston Scientific Scimed, Inc. | Embolization |
| US8173176B2 (en) | 2004-03-30 | 2012-05-08 | Boston Scientific Scimed, Inc. | Embolization |
| US7311861B2 (en) | 2004-06-01 | 2007-12-25 | Boston Scientific Scimed, Inc. | Embolization |
| CA2585675A1 (en) | 2004-11-03 | 2006-12-28 | Iris Molecular Diagnostics, Inc. | Microbubbles for affinity separation |
| JP5188808B2 (en) | 2004-11-03 | 2013-04-24 | アイリス モレキュラー ダイアグノスティクス， インコーポレイテッド | Homogeneous analyte detection |
| US7858183B2 (en) | 2005-03-02 | 2010-12-28 | Boston Scientific Scimed, Inc. | Particles |
| US7727555B2 (en) | 2005-03-02 | 2010-06-01 | Boston Scientific Scimed, Inc. | Particles |
| US7963287B2 (en) | 2005-04-28 | 2011-06-21 | Boston Scientific Scimed, Inc. | Tissue-treatment methods |
| US9463426B2 (en) | 2005-06-24 | 2016-10-11 | Boston Scientific Scimed, Inc. | Methods and systems for coating particles |
| US7947368B2 (en) | 2005-12-21 | 2011-05-24 | Boston Scientific Scimed, Inc. | Block copolymer particles |
| KR100845010B1 (en) * | 2007-08-29 | 2008-07-08 | 한국생명공학연구원 | Polymer particles for nir/mr bimodal molecular imaging and method for preparing thereof |
| CN101518780B (en) * | 2008-12-31 | 2011-09-14 | 广东省生态环境与土壤研究所 | Complexing agent microcapsule for plant soil restoration and preparation method thereof |
| CA3196421A1 (en) * | 2020-11-20 | 2022-05-27 | Encapsys, Llc | Biodegradable, controlled release microcapsules |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0586875A1 (en) * | 1988-02-05 | 1994-03-16 | Schering Aktiengesellschaft | Ultrasonic contrast agents, process for producing them and their use as diagnostic and therapeutic agents |
| DE4004430A1 (en) * | 1990-02-09 | 1991-08-14 | Schering Ag | CONSTRUCTED POLYALDEHYDE CONSTITUENTS |
| 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 |
| GB9106686D0 (en) * | 1991-03-28 | 1991-05-15 | Hafslund Nycomed As | Improvements in or relating to contrast agents |
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1992
- 1992-09-26 DE DE4232755A patent/DE4232755A1/en not_active Ceased
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1993
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- 1993-09-08 DE DE59308479T patent/DE59308479D1/en not_active Expired - Fee Related
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- 1993-09-08 HU HU9500876A patent/HU221972B1/en not_active IP Right Cessation
- 1993-09-08 EP EP93919293A patent/EP0662005B1/en not_active Expired - Lifetime
- 1993-09-08 KR KR1019950701155A patent/KR100287975B1/en not_active IP Right Cessation
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- 1993-09-08 DK DK93919293T patent/DK0662005T3/en active
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- 1993-09-24 ZA ZA937099A patent/ZA937099B/en unknown
- 1993-09-25 CN CN93118159A patent/CN1078815C/en not_active Expired - Fee Related
- 1993-09-26 IL IL107108A patent/IL107108A/en not_active IP Right Cessation
- 1993-10-04 TW TW082108177A patent/TW394688B/en not_active IP Right Cessation
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1995
- 1995-03-23 FI FI951379A patent/FI117124B/en not_active IP Right Cessation
- 1995-03-24 NO NO951138A patent/NO307692B1/en unknown
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2474327A1 (en) * | 2011-01-07 | 2012-07-11 | RWTH Aachen | Microdosing of ultrasound contrast agents |
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| KR950703367A (en) | 1995-09-20 |
| DE59308479D1 (en) | 1998-06-04 |
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| NZ255409A (en) | 1997-02-24 |
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| HU9500876D0 (en) | 1995-05-29 |
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| ZA937099B (en) | 1995-03-24 |
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| AU4959293A (en) | 1994-04-26 |
| HU221972B1 (en) | 2003-03-28 |
| IL107108A0 (en) | 1993-12-28 |
| TW394688B (en) | 2000-06-21 |
| NO951138D0 (en) | 1995-03-24 |
| EP0662005A1 (en) | 1995-07-12 |
| IL107108A (en) | 1998-01-04 |
| WO1994007539A1 (en) | 1994-04-14 |
| FI951379A0 (en) | 1995-03-23 |
| CN1078815C (en) | 2002-02-06 |
| DE4232755A1 (en) | 1994-03-31 |
| FI951379A (en) | 1995-03-23 |
| CA2145505C (en) | 2004-02-17 |
| CA2145505A1 (en) | 1994-04-14 |
| NO951138L (en) | 1995-03-24 |
| JPH08504398A (en) | 1996-05-14 |
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