EP1392367A2 - Preparation et utilisation d'une composition sous forme de suspension contenant un produit de contraste pour ultrasons - Google Patents

Preparation et utilisation d'une composition sous forme de suspension contenant un produit de contraste pour ultrasons

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Publication number
EP1392367A2
EP1392367A2 EP02737975A EP02737975A EP1392367A2 EP 1392367 A2 EP1392367 A2 EP 1392367A2 EP 02737975 A EP02737975 A EP 02737975A EP 02737975 A EP02737975 A EP 02737975A EP 1392367 A2 EP1392367 A2 EP 1392367A2
Authority
EP
European Patent Office
Prior art keywords
suspension
suspension composition
cells
composition according
tissue
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.)
Withdrawn
Application number
EP02737975A
Other languages
German (de)
English (en)
Inventor
Rainer Marksteiner
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Innovacell AG
Original Assignee
Innovacell Biotechnologie GmbH
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Innovacell Biotechnologie GmbH filed Critical Innovacell Biotechnologie GmbH
Publication of EP1392367A2 publication Critical patent/EP1392367A2/fr
Withdrawn legal-status Critical Current

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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
    • A61K49/226—Solutes, emulsions, suspensions, dispersions, semi-solid forms, e.g. hydrogels

Definitions

  • the present invention relates to a composition of matter containing one or more ultrasound contrast agents, methods for producing and using the composition of matter, devices for implementing the methods and uses of ultrasound contrast agents and suspensions of biological materials, such as. B. of cell suspensions or suspensions of natural proteins.
  • US Pat. No. 5,336,263 describes the treatment of gastro-oesophageal reflux with an injection of microparticles.
  • US Pat. No. 5,662,609 describes a method and a device for treating local diseases in hollow organs and other tissues.
  • a device which is not detailed, is defined which has an elongated tubular shaft and a distal region for insertion into the patient and a proximal region which is not inserted into the body. With the help of this device, monomers, prepolymers, polymers and a therapeutic agent are introduced into the body administered.
  • 5,976,526 describe the treatment of vesico-ureteral reflux, incontinence and diseases of the digestive tract, urogenital tract and thoracic cavity with injections of bladder muscle cells and cell-polymer suspensions.
  • No. 5,709,854 describes methods with which cell-polymer suspensions are applied into the body so that new tissue is formed.
  • the technique of manufacturing breast tissue is known from US 5 716 404.
  • Injectable hydrogel compositions which contain cells and are administered into the body are described in US Pat. No. 6,129,761.
  • Ultrasound imaging techniques have been widely used in diagnostics in the past 20 years. Ultrasound contrast agents are increasingly an integral part of the diagnostic toolkit. Vessels, blood flow in vessels, but also tumors or structures that are otherwise difficult to visualize can be better visualized using ultrasound.
  • the ultrasound contrast agents previously used were almost exclusively injected into the bloodstream in order to enable an improved examination of the blood flow in vessels, organs or tumors. These substances are then excreted primarily in the liver or kidneys.
  • US Pat. No. 4,805,628 describes a method with which devices that can be implanted or inserted into the body can be better visualized using ultrasound. These devices contain air-filled rooms.
  • a liquid containing gases and drugs is described in US 5,315,998.
  • US Pat. No. 5,770,222 describes the joint application of an ultrasound contrast medium, which consists of gas-filled microspheres, and medication as a therapeutic medication delivery system with the aid of which a large number of medications are to be administered.
  • US 5 849 727 and US 6 117 858 a method is shown with which biological agents are administered to specific target structures.
  • the substance used contains a solution of gas-filled microbubbles, which are encapsulated by proteins, and a biological agent, which is either naproxen, piroxicam, warfarin or another defined substance.
  • the gas used is a perfluorocarbon or sulfur hexafluoride.
  • US Pat. No. 6,139,819 describes a method with which the internal organs of a cardiac arrhythmia patient can be examined.
  • An ultrasound contrast medium is used that contains liposomes in an aqueous carrier solution that encapsulate a fluorinated gas.
  • this ultrasound contrast medium contains a ligand that binds to target cells or receptors that are located in coagula.
  • the fluorinated gas used is either a perfluorocarbon or sulfur hexafluoride.
  • the unpublished patent application DE 100 58 370 describes the application of cells with the aid of an ultrasound probe described.
  • the process of injecting cells into tissue under ultrasound control can only be perceived insufficiently, especially in small amounts, since the ultrasound contrast of the tissue and the cell suspension differ little.
  • the size and especially the distribution of the cells (viruses, bacteria) in the tissue can therefore only be insufficiently tracked. This is particularly disadvantageous if the injection of cells into certain organs at a defined location is to stimulate cell growth locally or if damaged tissue of a specific location in the organ concerned is to be replaced by the injected cells.
  • the object of the invention is to provide an improved composition of matter with which the application of biomaterials in tissue can be carried out with increased accuracy and improved effectiveness.
  • the object of the invention is also to specify methods and devices for producing the suspension composition.
  • Another object of the invention is to provide dosage forms for suspension compositions and applications of the suspension compositions, in particular in the implantation of biomaterials and the treatment of tissue.
  • the basic idea of the invention is to provide a suspension composition for application in biological tissue, which contains in a suspension liquid at least one functional component in the form of at least one active ingredient, biological cells, cell components, microorganisms and / or biological or biocompatible fillers and at least one ultrasound contrast agent ,
  • This combination creates a fundamentally new application of ultrasound contrast agents. So far, contrast agents have only been used to visualize an organ (e.g. blood vein, internal organ).
  • the suspension composition according to the invention allows for the first time the ultrasound monitoring of the supply of initially foreign material into a body part, in particular tissue.
  • a suspension composition which contains at least one biological or biocompatible filler (eg collagen) and at least one ultrasound contrast agent.
  • a biological or biocompatible filler eg collagen
  • at least one ultrasound contrast agent e.g. collagen
  • the addition of fillers has particular advantages in medical treatments (e.g. the urethra) or cosmetic procedures (e.g. injecting skin folds).
  • a suspension composition which contains at least one active ingredient and at least one ultrasound contrast agent.
  • the at least one active ingredient is aimed at biologically or medically effective changes in the tissue in which the suspension composition is applied or at another location in the organism where the active ingredient is released.
  • the supply of active ingredients in combination with ultrasound contrast agents has special features Advantages in terms of the targeted placement of the active ingredients in a tissue.
  • the active ingredient preferably comprises a growth factor, such as. B. VEGF or EGF, which causes capillarization of biological tissue.
  • a growth factor such as. B. VEGF or EGF
  • the suspension composition according to the invention enables an ultrasound-targeted modification of tissue.
  • the suspension composition acts like a therapeutic.
  • the active ingredient can be contained, for example, in microbubbles which are contained in the suspension composition according to the invention.
  • the microbubbles consist, for example, of a biocompatible material, such as, for. B. a protein, a lipid or a polymer, and can simultaneously act as an ultrasound contrast agent.
  • the invention thus enables the administration of active substances enclosed in ultrasound contrast media, in particular growth factors.
  • VEGF vascular endothelial growth factor
  • EGF endothelial growth factor
  • the vascularization effected with a suspension composition according to the invention provides particular advantages when injected into hypoxic tissue sections, e.g. B. after a heart attack, or in tissue sections into which cells have been injected for therapeutic purposes.
  • a suspension composition according to the invention provides particular advantages when injected into hypoxic tissue sections, e.g. B. after a heart attack, or in tissue sections into which cells have been injected for therapeutic purposes.
  • For the revival of the Vascularization is an important prerequisite for the survival of cells in the tissue in the hypoxic area.
  • the capillary formation in the tissue ensures a rapid blood supply to the modified areas.
  • the invention leads to an expanded use of ultrasound contrast agents in comparison to conventional intravascular application.
  • the ultrasound-targeted application of suspension compositions according to the invention in the tissue enables a concentrated release of active ingredients, possibly in combination with other functional components, at the desired location in the organism.
  • the injection site and the kinetics of the drug release can be precisely documented by the combination with ultrasound contrast agents.
  • ultrasound contrast agents When the active ingredients are applied in microbubbles, which also serve as ultrasound contrast agents, ultrasound observation can be used to determine where an active ingredient has been released. Only the intact microbubbles, in which the active ingredient is still contained, have a contrast-enhancing effect.
  • the bubbles disintegrate, the included substances are released. The ultrasound contrast in the affected tissue area is reduced. The disintegration of the bubbles can take place spontaneously or induced by ultrasound.
  • the invention relates in particular to the composition, production and use of a suspension of cells, viruses and / or bacteria which contains an ultrasound contrast medium.
  • This new therapeutic agent creates the prerequisites for the fact that living cells can be injected into the body in a targeted or monitored manner using injection systems. Through the simultaneous Injection of the ultrasound contrast medium and the cells, the injection can be observed and documented using ultrasound techniques. This technique enables even the smallest cell quantities to be placed precisely in a patient's body. In addition, the position of the applied depot of the cells can be checked and thus the success of the therapy can be documented and monitored.
  • the ultrasound contrast medium in the suspension composition according to the invention is connected to biological cells which are provided as a functional component.
  • the ultrasound contrast medium is contained in the cells, for example.
  • the ultrasound contrast agents applied with the suspension are locally broken down and / or transported away.
  • the ultrasound contrast medium is transported in the body in conjunction with biological cells.
  • the joint administration of cells, additives and ingredients, carrier media and ultrasound contrast agents represents a significant advance in the application of cells for the treatment of a large number of diseases.
  • the preparation and provision of the therapeutic dosage form according to the invention in many cases only provide the basis for the sensible use of the techniques of "tissue engineering" for diseases in hollow organs, body cavities, vessels, joints, internal organs and also in open operations.
  • the invention also relates to a method for producing the suspension composition, which is distinguished in particular by the fact that the at least one functional component and the at least one ultrasound contrast agent are mixed into the body before or during the injection.
  • the mixing of the at least one functional component with a contrast agent solution or suspension takes place with the provision of such concentration ratios that the suspension composition applied in the body has the correct concentration of the functional component for the intended effect and an osmolality adapted to the injection site.
  • the at least one functional component is provided for mixing in dissolved or suspended form or alternatively in solvent-free or low-solvent form (e.g. as a centrifuged pellet). In the latter case, for example, a centrifuged cell pellet is added to the contrast medium solution or suspension.
  • cultivation can take place in the presence of the contrast medium.
  • macrophages absorb the ultrasound contrast medium during cultivation.
  • the macrophages are treated with the ultrasound contrast agent Functional component transferred into the suspension composition according to the invention.
  • the osmolality of the contrast medium solution or suspension for the preparation of the suspension composition according to the invention is increased.
  • the mixing takes place in such a way that the osmolality of the suspension composition is preferably in the range from 340 mOsm / kg to 380 mOsm / kg, particularly preferably 350 mOsm / kg to 360 mOsm / kg.
  • the mixing takes place in a sterile container and / or in a mixing and / or application device, which is set up in addition to the injection of the suspension composition into a body.
  • the ultrasound contrast medium is provided, for example, dissolved or suspended in water.
  • a physiological electrolyte or salt solution which contains in particular NaCl and KC1 is preferred.
  • the electrolyte solution comprises, for example, 140 mM NaCL and 5 mM KC1.
  • PBS phosphate buffered saline
  • additives such as. B. glucose, vitamins or pH buffer.
  • the composition mentioned here has the advantage that when the suspension composition according to the invention is used, the functional component does not change as a result of osmosis and ion removal. If the functional component consists of biological cells, bacteria or viruses, for example, an osmotic shock is avoided. The functional component survives the absorption in the suspension solution and the storage before use on the tissue.
  • the suspension kit according to the invention is characterized by an arrangement of one or more containers which contains or contain the suspension composition according to the invention in the mixed state or separated by components and is designed for installation in a mixing and application device.
  • the suspension kit contains the components of the suspension composition in pre-set proportions.
  • the suspension kit allows a simplified and error-free delivery of biomaterial suspensions into the tissues to be treated.
  • the suspension kit can also comprise only a container with at least one ultrasound contrast agent in a physiological solution or suspension. This suspension kit is used in combination with low or no media functional components (e.g. pellet).
  • Another object of the invention is a method for feeding the suspension composition according to the invention into the body's own tissue for therapeutic or cosmetic purposes.
  • the injection is preferably carried out with a syringe needle or a catheter, the inventive one Suspension composition is passed as a liquid stream or in encapsulated form through the respective tool.
  • the suspension composition is supplied using an ultrasound probe as described in the unpublished German patent application DE 100 58 370, possibly in combination with an endoscope device.
  • the invention also relates to a method for modifying biological cells with an ultrasound contrast medium, in which the latter is absorbed by the cells.
  • the biological cells preferably comprise cells which are active in the immune system of an organism.
  • the ultrasound contrast medium is loaded by incubating the cells with the contrast medium in a medium, e.g. B. in a cultivation vessel in a nutrient solution.
  • the modified cells are used as a functional component of the suspension composition described above.
  • the uptake of synthetic particles in macrophages is, for example, by Dayton et al. in "Biophysical Journal", vol. 80, 2001, pages 1547-1556.
  • the modification of cells according to the invention in particular enables a new method for taking ultrasound contrast agents.
  • the ultrasound contrast media may be loaded with active substances.
  • the loaded cells in the organism can advantageously be detected using high-resolution ultrasound methods.
  • the modified cells can migrate in the body's immune system and accumulate in lymph nodes.
  • Another object of the invention is a method for imaging with an ultrasound imaging device, in which at least one ultrasound image is taken on the tissue or on parts thereof after or during an injection of the suspension composition according to the invention into biological tissue.
  • the method according to the invention has the advantage that the distribution of the suspension composition in the tissue, for example when a depot of the functional component is formed, can be determined. According to a preferred embodiment of the method, for example, geometric properties of the distribution and / or its temporal development are tracked.
  • the images determined according to the invention serve as intermediate results, on the basis of which subsequent medical diagnosis or treatment steps can be selected or carried out.
  • any ultrasound imaging device can be used, as is known per se from medical technology.
  • the image is preferably taken after or during the injection of the suspension composition according to the invention into the urethra on the urethral tissue or into the heart muscle.
  • Fig. 1 a schematic illustration of various components
  • FIGS. 2 to 5 different embodiments of mixing and application devices for manufacturing development of suspension compositions according to the invention.
  • Fig. 6 a schematic sectional view of a urethra with an inserted ultrasound head.
  • suspension compositions according to the invention are produced from suspensions of at least one functional component which is formed by the biomaterial to be applied, at least one ultrasound contrast agent and, if appropriate, at least one additive and ingredient.
  • at least one functional component which is formed by the biomaterial to be applied
  • at least one ultrasound contrast agent and, if appropriate, at least one additive and ingredient.
  • one or more of the constituents mentioned are selected from the following groups and combined in a suspension composition.
  • Biological cells bacteria, viruses and / or biological or biocompatible fillers, in particular stem cells, precursor cells (e.g. myoblasts, fibroblasts, chondroblasts, neuroblasts, osteoblasts, cells of the hematopoietic system), differentiated cells (e.g. Chondrocytes, osteocytes, myocytes, fibrocytes, cells contained in blood, epithelial cells, hormone-forming cells, neurocytes, parenchyma cells from internal organs, endothelial cells, cells of the immune system) or genetically modified cells or microorganisms.
  • precursor cells e.g. myoblasts, fibroblasts, chondroblasts, neuroblasts, osteoblasts, cells of the hematopoietic system
  • differentiated cells e.g. Chondrocytes, osteocytes, myocytes, fibrocytes, cells contained in blood, epithelial cells, hormone-forming cells, neurocytes, parenchyma cells from
  • the contrast media available per se are preferably used as ultrasound contrast media.
  • these consist of suspended particles (e.g. bubbles) that are smaller than the red blood cells.
  • the ultrasound scatter at the application site ie. H. z. B. in the tissue varies.
  • ultrasound contrast agents were used for the injection into vessels prior to the invention and were used in particular to distinguish the vessels from the surrounding solid tissue, the invention surprisingly found that the ultrasound contrast agents also lead to an evaluable ultrasound contrast in the solid tissue.
  • a distinction is made between two methods for producing contrasting microbubbles, namely the production of free or enveloped gas bubbles. Depending on the stability of coating substances, easily soluble, poorly soluble or insoluble gas bubbles are distinguished.
  • ultrasound contrast media free gas bubbles, precursors of gases, gas bubbles encapsulated by organic or inorganic substances, solutions, colloidal solutions, suspensions, dispersions, ionophores, dissolved microparticles, dissolved polymer spheres, dissolved organic and / or inorganic Molecules, sugar-containing solutions, microparticles, ferro- or paramagnetic metals, micro-aggregates, porous particles of organic and / or inorganic material, lipid-containing microspheres and / or emulsions, the gas bubbles preferably being air, nitrogen, oxygen, carbon dioxide, fluorinated gas and / or a contain other biocompatible gas.
  • Additives and ingredients preferably being air, nitrogen, oxygen, carbon dioxide, fluorinated gas and / or a contain other biocompatible gas.
  • Salts carbohydrates, e.g. B. dextrose, lipids, proteins, lipoproteins, one or more amino acids, fatty acids, simple sugar molecules, growth factors, hormones, iron, biologically active cell mediators, blood derivatives, enzymes, vitamins, peptides, bulking agents, biocompatible polymers (such as B.
  • collagen, hyaluronic acid, synthetic polymers or fibrin matrix molecules made of organic and / or inorganic material, a porous solid matrix, messenger substances, neurotransmitters and / or medications (in particular antibiotics, tuberculostats, fungicides, anti-allergics, antiviral substances, anti-coagulants, thrombolytics, drugs against protozoa, drugs against arteriosclerosis, anti-inflammatory drugs, narcotics, opiates, cardiac glycosides, vascular active substances, metabolic potentiators, substances against angiogenesis, substances for angiogenesis, chemotactic substances, nerve growth factors, sedative muscle blockers , Local anesthetics, anesthetics, radioactive substances, antique body, genetic material, RNA, DNA, antisense RNA, antisense DNA, ribozymes, antigenic nucleic acids, cytostatics, photoactive agents, photosensitizers, contrast agents for X-rays, a contrast medium for MRI studies, the immune response
  • Suspension liquid synthetically produced solution (e.g. physiological saline) and / or tissue liquid made from human and / or animal material.
  • suspension composition according to the invention exists in the case of improved imaging of biological tissue, in particular in the living organism.
  • Further preferred applications of the suspension composition according to the invention consist in the therapy of urinary incontinence and / or faecal incontinence, vesico-ureteral reflux, gastro-oesophageal reflux of volume defects and / or wrinkles in plastic surgery (for example by subcutaneous administration of Fibroblasts or other cells), and / or of muscle diseases, diseases of the respiratory tract, urogenital system and gastrointestinal tract, diseases of the nervous system, diseases of organs, diseases of the hematopoietic system, diseases of the hormonal system (such as e.g. Diabetes mellitus), tumors, inflammation, infections, arthrosis and joint damage, diseases of the dermis, epidermis and subcutis, and / or trauma and injured organs, bones, joints, ligaments and muscles.
  • urinary incontinence and / or faecal incontinence vesico-ureteral
  • FIG. 1 schematically illustrates different embodiments of suspension compositions according to the invention.
  • a first variant (I) the functional component and the at least one ultrasound contrast agent are contained as separate components in a suspension solution.
  • This variant has the advantage that the suspension composition according to the invention can be prepared and applied particularly easily.
  • modified variants (II, III) the functional component and the ultrasound contrast agent are connected to one another, the functional component being contained in the ultrasound contrast agent (II) or the ultrasound contrast agent in the functional component (III). Alternatively, an adherent combination of the two components (not shown) would also be possible.
  • Variants II and III have the advantage of an extended applicability of the suspension composition. In the following, the supply of the suspension composition with a mixing and application device according to the invention is explained according to various exemplary embodiments.
  • the cells, the additives and ingredients, the carrier medium and the ultrasound contrast agent used are mixed with a suspension cylinder Z in a syringe-like liquid delivery device before administration.
  • the suspension cylinder Z has an interior that forms two partial volumes.
  • the contrast medium KM is located in a first partial volume between the piston K and the syringe needle S, while the second partial volume, which is also referred to as volume reserve VR, is formed on the rear of the piston K.
  • the suspension of the at least one functional component and optionally the additives and ingredients is sucked into the suspension cylinder by actuating the piston K using the liquid delivery device.
  • the contrast medium KM and the drawn up suspension are mixed with one another.
  • the suspension composition is then injected into a tissue by the movement of the piston K via the syringe needle S.
  • the ultrasound contrast medium consists in this case, for. B. from stable gas bubbles, which are enclosed by a lipid-containing membrane.
  • the specific design of the liquid delivery device illustrated in FIG. 2 is selected depending on the application.
  • the dimension of the suspension cylinder depends in particular on the suspension quantities to be applied depending on the case.
  • additional devices such as. B. endoscopy devices and / or an ultrasound probe intended.
  • the syringe needle S is extended to form the injection tool in accordance with the dimensions of the implement.
  • the structure of the suspension cylinder Z, the piston K and the contrast medium KM taken up in the first partial volume with an initially closed attachment for a syringe needle forms a finished kit for the production of the suspension composition.
  • the following procedure is used to provide a suspension composition composed of biological cells and an ultrasound contrast medium.
  • the cells are removed from an incubator.
  • the cell culture medium is centrifuged off in a manner known per se.
  • There is a cell pellet which is added to the suspension solution with the contrast medium.
  • the pellet is introduced into the contrast medium KM, for example in an arrangement according to FIG. 2, with the piston K removed.
  • the proportion of the contrast medium in the suspension composition is advantageously so low that the osmolality is hardly changed.
  • the suspension solution has, for example, a composition of 140 mM NaCl, 4 M KCl and 1.5 mM CaCl 2 .
  • the pH is, for example, in the range from 7 to 7.4.
  • the liquid delivery device has two chambers Kai, Ka2 in the suspension cylinder Z.
  • the chamber Kai is separated from the suspension cylinder Z by a container attached to the piston K, the wall of which is formed on the side facing the chamber Ka2 by a membrane M (e.g. film).
  • a perforation or puncture device P runs in the piston K, which is let into the piston K in a liquid-tight manner and can be actuated from the outside to pierce the membrane M.
  • the syringe needle S can optionally also be fixedly attached to the kit according to the invention.
  • the chamber Ka2 with the suspension of the at least one functional component is contained in the prepared kit or that the suspension is drawn up by the syringe needle S immediately before use.
  • the functional component and the contrast medium are initially still separated by the membrane M. As a result, it does not come immediately after recording z.
  • B. of suspended cells in the liquid delivery device for mixing the contrast agent and the cell suspension A particular advantage of this design is that the cell suspension and the ultrasound contrast medium can be transported without the two components mixing. Mixing takes place immediately before application. The mixing of ultrasound contrast medium and cells takes place, for. B. by piercing the membrane with the perforation device P.
  • the perforation device P can deviate from the illustration in Figure 3 on other parts of the liquid delivery device, for. B. be provided on the side of the chamber Ka2.
  • the suspended cells, the additives and ingredients, the suspension or carrier medium and the ultrasound contrast medium used are mixed together in a syringe only immediately before administration.
  • the ultrasound contrast medium K used consists, for. B. from gaklaktose-picric acid particles and is in its own second container.
  • a syringe with the cells, the additives and ingredients and the carrier medium and the vessel with the ultrasound contrast medium are connected and mixed gently.
  • the resulting mixture is then drawn up in the syringe, which now contains small gas bubbles, and attached to the injection needle.
  • the suspended cells, the additives and ingredients, the carrier medium and the suspended ultrasound contrast medium are located in two separate suspension cylinders ZI, Z2 of a liquid delivery device.
  • the suspension cylinders ZI, Z2, like syringe cylinders known per se, are each constructed with a piston Kl, K2.
  • the pistons K1, K2 are connected by a coupling part KT and can at the same time be moved in the direction of the arrow, so that the ultrasound contrast medium from the suspension cylinder ZI and the cells from the suspension cylinder Z2 mix in the T-shaped connecting part and at the same time as an assembly according to the invention emerge from the common syringe needle.
  • the liquid delivery device according to FIG. 4 is prepared by using the suspension cylinders ZI, Z2 provided as a kit. Alternatively, it is also possible to equip the T-shaped connecting part T with a valve arrangement and to feed the suspension cylinders ZI, Z2 separately via the syringe needle S.
  • the suspended cells, the additives and ingredients, the carrier medium and the ultrasound contrast medium used are located in separate suspension cylinders ZI, Z2.
  • the pistons K1, K2 of the suspension cylinders ZI, Z2 can be actuated separately with separate control devices SV1, SV2.
  • the entire arrangement is used in an electrically operated application device AG.
  • the individual components of the suspension composition according to the invention are only mixed during the injection and injected into the body. The mixing ratio of the individual components is either pre-programmed or can be selected before the injection.
  • the application device contains a handle and one or more control units that move the pistons.
  • a medical working device which can be used with particular advantage for the injection of the suspension composition according to the invention is described in the unpublished patent application PCT / EP 01/13535, the disclosure content of which is included in the present patent application in particular with regard to the structure of the working device.
  • the aforementioned implement which is set up for injection and ultrasound measurement, is initially in the part of the body to be treated (e.g. hollow organ, tissue).
  • the tissue to be treated is visually observed with an endoscope device.
  • An injection tool e.g. syringe, hollow needle, catheter
  • the suspension composition is then applied via the tool into the tissue area of interest.
  • the progress of the application is monitored by image recordings with an ultrasound probe.
  • FIG. 6 The implementation of the image recording method according to the invention when the suspension composition is injected into the human urethra is illustrated schematically in FIG. 6.
  • An ultrasound head UK is arranged in the urethra, which is essentially built up in layers from the mucosa mu, the submucosa smu and sphincter muscle SM.
  • Myoblasts are injected into the muscle ring SM with the suspension according to the invention.
  • the ultrasound head is part of an ultrasound imaging device with which the distribution of the suspension in the muscle ring is recorded.
  • the myoblast supply improves the contractility of the urethra.
  • contractility measurements can be carried out directly with the implement, in particular with the ultrasound probe. For this purpose, the distance D between the ultrasound head UK and the sphincter muscle SM is measured. Depending on the distance values that can be achieved, it is determined whether sufficient myoblasts have been delivered or whether another injection is required.

Abstract

La présente invention concerne une composition sous forme de suspension qui contient au moins un constituant fonctionnel efficace dans des tissus biologiques, ainsi qu'une forme d'administration pour l'application à des tissus. Le constituant fonctionnel se trouve en suspension ou dissous dans un liquide de suspension et contient au moins un principe actif, des cellules biologiques, des bactéries, des virus et / ou matières de charge biologiques ou biocompatibles. Un produit de contraste pour ultrasons est contenu dans le liquide en suspension. La présente invention concerne en outre des utilisations de ladite composition sous forme de suspension, en particulier pour des injections dans des tissus biologiques.
EP02737975A 2001-04-20 2002-04-19 Preparation et utilisation d'une composition sous forme de suspension contenant un produit de contraste pour ultrasons Withdrawn EP1392367A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10119522 2001-04-20
DE10119522A DE10119522A1 (de) 2001-04-20 2001-04-20 Herstellung und Anwendung einer Suspensionszusammensetzung mit einem Ultraschall-Kontrastmittel
PCT/EP2002/004363 WO2002085325A2 (fr) 2001-04-20 2002-04-19 Preparation et utilisation d'une composition sous forme de suspension contenant un produit de contraste pour ultrasons

Publications (1)

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EP1392367A2 true EP1392367A2 (fr) 2004-03-03

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US (1) US20040151702A1 (fr)
EP (1) EP1392367A2 (fr)
AU (1) AU2002312837A1 (fr)
CA (1) CA2444615A1 (fr)
DE (1) DE10119522A1 (fr)
WO (1) WO2002085325A2 (fr)

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CA2444615A1 (fr) 2002-10-31
US20040151702A1 (en) 2004-08-05

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