Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Ultrasound contrast agent
Reexamination Certificate
1995-06-07
2001-01-23
Hollinden, Gary E. (Department: 1616)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Ultrasound contrast agent
C424S009362
Reexamination Certificate
active
06177062
ABSTRACT:
The invention relates to microparticles comprising a biodegradable synthetic polymer, a process for their preparation and their use as a diagnostic and therapeutic agent.
It is known that cardial echo contrasts can be achieved through peripheral injection of solutions which contain fine gas bubbles (Roelandt J, Ultrasound Med Biol 8: 471-492, 1962). These gas bubbles are obtained in physiologically compatible solutions, e.g. through shaking, other agitation or through the addition of carbon dioxide. However, they are not standardized in terms of number and size and cannot be adequately reproduced. Also, they are as a rule not stabilized so that their service life is short. Their average diameters are generally above the erythrocyte size so that it is not possible to obtain pulmonary capillary passages with subsequent contrasting of organs such as the left heart, liver, kidneys or spleen. Furthermore, they are not suitable for quantifications since the ultrasonic echo which they produce is made up from several processes which cannot be separated from each other such as the formation of the bubbles, coalescence and dissolution. Thus, it is not possible, for example, to obtain definite details on the transit times with the aid of these ultrasonic contrast agents by measuring the contrast path in the myocardium. This requires contrast agents whose dispersal bodies are not subject to their own kinetics.
In addition, there are ultrasonic contrast agents in the form of particles (Ophir, Gobuty, McWhirt, Maklad, Ultrasonic Backscatter from Contrast-producing Collagen Microspheres, Ultrasonic Imaging 2:66-67, 1980). Furthermore, solutions of a higher density are used as ultrasonic contrast agents (Ophir, McWhirt, Maklad, Aqueous Solutions as Potential Ultrasonic Contrast Agents, Ultrasonic Imaging 1:265-279, 1979 as well as Tyler, Ophir, Maklad, In-vivo Enhancement of Ultrasonic Image Luminance by Aqueous Solutions with High Speed of Sound, Ultrasonic Imaging 3:323-329, 1981). It is also known to use emulsions as ultrasonic contrast agents (Mattrey, Andre, Ultrasonic Enhancement of Myocardial Infarction with Perfluorocarbon Compounds in Dogs, Am J Cardiol 54: 206-210, 1984).
It has been seen that, overall, the gas-free contrast agents only have a low efficiency. The gas-containing preparations have the disadvantage of only a slight in-vivo stability. Furthermore, the size of the gas bubbles can generally not be standardized. As a rule, adequate contrast effects are not possible in the arterial vessel system after a peripheral veinous injection.
In EP A2 123 235 and 0 122 624 ultrasonic contrast agents are described which contain small gas bubbles and which pass through the pulmonary capillaries producing the desired contrast effect.
EP A2 0 224 934 describes ultrasonic contrast agents in the form of gas-filled gelatine or albumin hollow bodies. However, the disadvantage here is the use of foreign-body albumens or denatured albumens belonging to the body and thus the associated risk of allergy.
With none of the ultrasonic contrast agents known up until now, is it possible to represent the organs with sufficient signal intensity through selective concentration after an i.v. dose. Quantifications are therefore not possible at the present time.
Contrast agents on the basis of microparticles which in addition to a determinable and reproducible volume have a considerably longer service life that previously known, offer good comparability without allergic potential and can be concentrated intracellularly in RES and thus also in the liver or spleen.
This is achieved in accordance with the invention by microparticles which consist of amylase or a synthetic biodegradable polymer and a gas and/or a fluid with a boiling point below 60° C.
Polyesters of &agr;-,&bgr;-,&ggr;- or &egr;-hydroxy carbonic acids, polyalkyl-cyanoacrylates, polyamino acids, polyamides, polyacrylated saccharides or polyorthoesters are named as synthetic biodegradable polymers.
The following have proved particularly suitable:
polylactic acid,
poly-&egr;-caprolactone,
a copolymer of lactic acid and glycol acid or &egr;-caprolactone,
polyhydroxybutyric acid,
polyhydroxyvaleric acid,
copolymers of hydroxybutyric and hydroxyvaleric acid,
polymers of glutamic acid and/or lysine,
polydioxanone,
polymers or copolymers of amino acids and/or
terephthalic acid, phthalic acid or sebacic acid,
polyacryldextran,
polyacryl starch,
polyacrylamide,
polyurethane,
polyester,
polyacetal,
polyaminotriazole or
polyalkylcyanoacrylate.
Starch or starch derivatives can also be contained in the microparticles. Amyloses have proved particularly suitable since these starch derivatives have excellent water solubility and the ability to form inclusion compounds.
Amyloses which are particularly suitable are the cyclodextrins and their derivatives, by way of example &agr;, &bgr;, and &ggr;-cyclodextrin.
The microparticles contain gases and/or fluids with a boiling point below 60° C. in free or bonded form. The use of a gas-fluid mixture in the ultrasonic contrast agents is likewise possible.
Gases used can be for example air, nitrogen, inert gases, hydrogen, carbon dioxide, ammonia, oxygen, methane, ethane, propane, butane, ethylene or other hydrocarbons or their mixtures.
Preferred fluids which can be included are:
1,1-dichloroethylene,
2-methyl-2-butene,
isopropyl chloride,
2-methyl-1,3-butadiene,
2-butyne,
2-methyl-1-butene,
dibromodifluoromethane,
furan,
3-methyl-1-butene,
isopentane,
diethylether,
3,3-dimethyl-1-butyne,
dimethylaminoacetone,
propylene oxide,
N-ethylmethylamine,
bromomethane,
n-ethyldimethylamine,
methylene chloride,
pentane,
cyclopentane,
2,3-pentadiene,
cyclopentene
or mixtures thereof.
The microparticles can also contain advantageously substances with low steam pressures and/or low boiling points, in particular ethereal oils.
It is particularly advantageous to coat the microparticles which consist of amylase with a coating substance. The microparticles can thereby be encased in oils, fats and/or surface-active substances and suspended in an aqueous medium.
It is particularly advantageous to encase the microparticles which consist of amylase in a matrix, more particularly of a polymer structure.
The physiological isotony can be set by the addition of osmotically active substances such as cooking salt, galactose, glucose, or fructose.
An advantageous process for preparing the ultrasonic contrast agents according to the invention consists in dissolving a polymer or copolymer in one or more organic solvents which are not miscible with water, followed by emulsification in water, possibly with the addition of a further solvent, and then filtering and, if required, drying the emulsion obtained.
A further process consists in dissolving a polymer or copolymer in one or more solvents which contain gas bubbles, after which it is precipitated or emulsified in water, if required with the addition of a further solvent or a further polymer, and then the suspension or emulsion which has been obtained is then filtered and, if required, dried. The freeze-drying process is also suitable as a finishing process.
The products obtained can advantageously be finely ground.
In the processes described, the solvents used can be for example furan, pentane, acetone, dioxen, ethyl acetate, xylol, methylene chloride, cyclohexane or hexane or solvent mixtures. Emulsifiers can also be added to the emulsion.
In a further variation of the manufacturing process, instead of polymers, monomers are used as the starting product from which the polymer is formed. With this process, a monomer is dissolved in one or more organic solvents and then emulsified in 5-30 parts water or 0.01-0.1 N hydrochloric acid, if required with the addition of emulsifiers or buffer substances at a temperature below the boiling point of the organic solvent, after which a 0.2%-20% aqueous solution of a second monomer or, if required, the solution of a substance increasing the pH-value is added to this emulsion and dried if required.
In another method of operation, a monomer is dissolved or dispe
Fritzsch Thomas
Heldmann Dieter
Roessling Georg
Siegert Joachim
Stein Michael
Hollinden Gary E.
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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