CA2098710C - Dosage form for micro-bubble echo contrast agents - Google Patents
Dosage form for micro-bubble echo contrast agents Download PDFInfo
- Publication number
- CA2098710C CA2098710C CA 2098710 CA2098710A CA2098710C CA 2098710 C CA2098710 C CA 2098710C CA 2098710 CA2098710 CA 2098710 CA 2098710 A CA2098710 A CA 2098710A CA 2098710 C CA2098710 C CA 2098710C
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- Prior art keywords
- syringe
- dosage form
- mixing chamber
- micro
- contrast medium
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- 239000002961 echo contrast media Substances 0.000 title claims abstract description 26
- 239000002552 dosage form Substances 0.000 title claims abstract description 21
- 238000002156 mixing Methods 0.000 claims abstract description 49
- 239000000306 component Substances 0.000 claims description 15
- 239000002872 contrast media Substances 0.000 claims description 15
- 239000007788 liquid Substances 0.000 claims description 8
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000007789 gas Substances 0.000 description 18
- 238000000034 method Methods 0.000 description 7
- 239000007924 injection Substances 0.000 description 5
- 238000002347 injection Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 238000005086 pumping Methods 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000003570 air Substances 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000012530 fluid Substances 0.000 description 3
- 238000011835 investigation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 208000005189 Embolism Diseases 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 239000012080 ambient air Substances 0.000 description 2
- 229940039231 contrast media Drugs 0.000 description 2
- 238000005187 foaming Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 210000005241 right ventricle Anatomy 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 108010002885 Polygeline Proteins 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
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- 238000013461 design Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000002592 echocardiography Methods 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012456 homogeneous solution Substances 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 239000003978 infusion fluid Substances 0.000 description 1
- 238000001746 injection moulding Methods 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 101150093826 par1 gene Proteins 0.000 description 1
- 239000011505 plaster Substances 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 238000002604 ultrasonography Methods 0.000 description 1
- 238000003466 welding Methods 0.000 description 1
Classifications
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/717—Feed mechanisms characterised by the means for feeding the components to the mixer
- B01F35/7174—Feed mechanisms characterised by the means for feeding the components to the mixer using pistons, plungers or syringes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2096—Combination of a vial and a syringe for transferring or mixing their contents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B8/00—Diagnosis using ultrasonic, sonic or infrasonic waves
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M31/00—Devices for introducing or retaining media, e.g. remedies, in cavities of the body
- A61M31/005—Devices for introducing or retaining media, e.g. remedies, in cavities of the body for contrast media
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- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/30—Injector mixers
- B01F25/31—Injector mixers in conduits or tubes through which the main component flows
- B01F25/311—Injector mixers in conduits or tubes through which the main component flows for mixing more than two components; Devices specially adapted for generating foam
- B01F25/3111—Devices specially adapted for generating foam, e.g. air foam
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- B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
- B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
- B01F25/431—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor
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- B—PERFORMING OPERATIONS; TRANSPORTING
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- B01F25/40—Static mixers
- B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
- B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
- B01F25/431—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor
- B01F25/4317—Profiled elements, e.g. profiled blades, bars, pillars, columns or chevrons
- B01F25/43172—Profiles, pillars, chevrons, i.e. long elements having a polygonal cross-section
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- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/40—Static mixers
- B01F25/42—Static mixers in which the mixing is affected by moving the components jointly in changing directions, e.g. in tubes provided with baffles or obstructions
- B01F25/43—Mixing tubes, e.g. wherein the material is moved in a radial or partly reversed direction
- B01F25/431—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor
- B01F25/43197—Straight mixing tubes with baffles or obstructions that do not cause substantial pressure drop; Baffles therefor characterised by the mounting of the baffles or obstructions
- B01F25/431971—Mounted on the wall
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- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/40—Static mixers
- B01F25/45—Mixers in which the materials to be mixed are pressed together through orifices or interstitial spaces, e.g. between beads
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F25/00—Flow mixers; Mixers for falling materials, e.g. solid particles
- B01F25/40—Static mixers
- B01F25/45—Mixers in which the materials to be mixed are pressed together through orifices or interstitial spaces, e.g. between beads
- B01F25/452—Mixers in which the materials to be mixed are pressed together through orifices or interstitial spaces, e.g. between beads characterised by elements provided with orifices or interstitial spaces
- B01F25/4521—Mixers in which the materials to be mixed are pressed together through orifices or interstitial spaces, e.g. between beads characterised by elements provided with orifices or interstitial spaces the components being pressed through orifices in elements, e.g. flat plates or cylinders, which obstruct the whole diameter of the tube
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F31/00—Mixers with shaking, oscillating, or vibrating mechanisms
- B01F31/44—Mixers with shaking, oscillating, or vibrating mechanisms with stirrers performing an oscillatory, vibratory or shaking movement
- B01F31/441—Mixers with shaking, oscillating, or vibrating mechanisms with stirrers performing an oscillatory, vibratory or shaking movement performing a rectilinear reciprocating movement
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/50—Movable or transportable mixing devices or plants
- B01F33/501—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use
- B01F33/5011—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use portable during use, e.g. hand-held
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F33/00—Other mixers; Mixing plants; Combinations of mixers
- B01F33/50—Movable or transportable mixing devices or plants
- B01F33/501—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use
- B01F33/5011—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use portable during use, e.g. hand-held
- B01F33/50112—Movable mixing devices, i.e. readily shifted or displaced from one place to another, e.g. portable during use portable during use, e.g. hand-held of the syringe or cartridge type
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/712—Feed mechanisms for feeding fluids
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/714—Feed mechanisms for feeding predetermined amounts
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/716—Feed mechanisms characterised by the relative arrangement of the containers for feeding or mixing the components
- B01F35/7161—Feed mechanisms characterised by the relative arrangement of the containers for feeding or mixing the components the containers being connected coaxially before contacting the contents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/71—Feed mechanisms
- B01F35/716—Feed mechanisms characterised by the relative arrangement of the containers for feeding or mixing the components
- B01F35/7163—Feed mechanisms characterised by the relative arrangement of the containers for feeding or mixing the components the containers being connected in a mouth-to-mouth, end-to-end disposition, i.e. the openings are juxtaposed before contacting the contents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/80—Forming a predetermined ratio of the substances to be mixed
- B01F35/894—Measuring receptacles therefor
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
- A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
- A61J1/14—Details; Accessories therefor
- A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
- A61J1/2003—Accessories used in combination with means for transfer or mixing of fluids, e.g. for activating fluid flow, separating fluids, filtering fluid or venting
- A61J1/202—Separating means
- A61J1/2044—Separating means having slits
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01F—MIXING, e.g. DISSOLVING, EMULSIFYING OR DISPERSING
- B01F35/00—Accessories for mixers; Auxiliary operations or auxiliary devices; Parts or details of general application
- B01F35/30—Driving arrangements; Transmissions; Couplings; Brakes
- B01F35/32—Driving arrangements
- B01F35/32005—Type of drive
- B01F35/3202—Hand driven
Landscapes
- Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Health & Medical Sciences (AREA)
- Dispersion Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Heart & Thoracic Surgery (AREA)
- Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Biophysics (AREA)
- Physics & Mathematics (AREA)
- Molecular Biology (AREA)
- Surgery (AREA)
- Pathology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Radiology & Medical Imaging (AREA)
- Medical Informatics (AREA)
- Anesthesiology (AREA)
- Hematology (AREA)
- Pharmacology & Pharmacy (AREA)
- Infusion, Injection, And Reservoir Apparatuses (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Ultra Sonic Daignosis Equipment (AREA)
Abstract
A dosage form for micro bubble echo contrast media which comprises a syringe (6) and a mixing chamber (1) which is connected thereto and contains a predeter-mined amount of gas, plus a second syringe is described.
the novel dosage form allows easy, standardised preparation of echo contrast media and gives high contrast (Fig. 3).
the novel dosage form allows easy, standardised preparation of echo contrast media and gives high contrast (Fig. 3).
Description
~~~~ i :~
Dosageform for micro bubble echo contrast agents Field of the invention The invention relates to a dosage form for micro bubble echo contrast agents.
Prior art Numerous preparations which are ~~uitable as echo contrast media and contain surface-act:.ive substances which assist with the formation of micro bubbles and stabilise them have been disclosed (for example EP-A-0 07? 752). The ultrasound reflected by the micro bubbles is used to improve the ultrasonic images of cavities or vessels filled with fluid in the human and animal body.
The micro bubbles are produced only just before administration of the contrast medium. For example, the contrast medium is drawn together with air or a physiologically tolerated gas into a syringe, and expelled again into a receiver vessel, several times. It is self-evident that it is not passible in this way to prepare contrast media which can be administered in a reproducible manner and which contain a defined amount of gas in micro bubbles of maximally uniform size. Attempts have therefore been made to provide the contrast medium in a syringe. Before use, the required amount of air is drawn up. Then the syringe is connected by a connector to a second, empty syringe. Vigorous pumping of the contrast medium backwards and forwards between the two syringes produces micro bubbles. However, it has emerged that the care required to obtain reasonably utilisable suspensions of micro bubbles is unacceptable in practice. 2n addition, a very great amount of force needs to be expended. Standardisation can scarcely be achieved in practice.
D~-A 3 838 530 describes a package for a two component composition, which consists of two flexible containers for the two components. Before use, the two containers are connected together by a tubular adaptor which is provided in its interior with deflectors in a mutually offset arrangement. To mix the components, the 2fl~~'"~~~.~
Dosageform for micro bubble echo contrast agents Field of the invention The invention relates to a dosage form for micro bubble echo contrast agents.
Prior art Numerous preparations which are ~~uitable as echo contrast media and contain surface-act:.ive substances which assist with the formation of micro bubbles and stabilise them have been disclosed (for example EP-A-0 07? 752). The ultrasound reflected by the micro bubbles is used to improve the ultrasonic images of cavities or vessels filled with fluid in the human and animal body.
The micro bubbles are produced only just before administration of the contrast medium. For example, the contrast medium is drawn together with air or a physiologically tolerated gas into a syringe, and expelled again into a receiver vessel, several times. It is self-evident that it is not passible in this way to prepare contrast media which can be administered in a reproducible manner and which contain a defined amount of gas in micro bubbles of maximally uniform size. Attempts have therefore been made to provide the contrast medium in a syringe. Before use, the required amount of air is drawn up. Then the syringe is connected by a connector to a second, empty syringe. Vigorous pumping of the contrast medium backwards and forwards between the two syringes produces micro bubbles. However, it has emerged that the care required to obtain reasonably utilisable suspensions of micro bubbles is unacceptable in practice. 2n addition, a very great amount of force needs to be expended. Standardisation can scarcely be achieved in practice.
D~-A 3 838 530 describes a package for a two component composition, which consists of two flexible containers for the two components. Before use, the two containers are connected together by a tubular adaptor which is provided in its interior with deflectors in a mutually offset arrangement. To mix the components, the 2fl~~'"~~~.~
contents of the containers are forced backwards and forwards through the adaptor several times.
EP-~A 0 148 116 discloses a connector with two female connecting pieces for two syringe s to be inserted.
The channel through the connector has a constriction which is intended to assist turbulent flow of the fluid which is pumped backwards and forwards between the two syringes.
US-C 4,049,241 discloses a mixing chamber for fluid materials, in which a plurality of rod-like mixing elements are provided in a tubular housing and are inclined with respect to the axis of the tube.
Summary of the invention The invention has the object of providing a dosageform for echo contrast media which permits the user to administer the micro bubble echo contrast media in a standardised and optimised manner without unacceptable effort. Another aim of the invention is to improve the quality of the images of body structures obtainable with a micro bubble echo contrast medium and to improve the reproducibility of the images.
Another aim of the invention is to increase the safety of use by avoiding the production of gas bubbles which, because their diameter is too large, expose 'the patient to the risk of embolism.
Another aim of the invention is to avoid a risk of infection.
These objects are achieved according to the invention by the dosage form for echo contrast media comprising a syringe and a mixing chamber which is unreleasably connected thereto and contains a pre-determined amount of gas, plus a second syringe.
The invention ~tlxerefore relates to a dosage form_ for micro bubble echo contrast media comprising a first syringe and a mixing chamber which is unreleasably connected thereto and contains a predetermined amount of gas, plus a second syringe. Further subject-matter is evident from the patent claims. The invention further relates to a syringe for echo contrast media, which is 2~~~'~~.
EP-~A 0 148 116 discloses a connector with two female connecting pieces for two syringe s to be inserted.
The channel through the connector has a constriction which is intended to assist turbulent flow of the fluid which is pumped backwards and forwards between the two syringes.
US-C 4,049,241 discloses a mixing chamber for fluid materials, in which a plurality of rod-like mixing elements are provided in a tubular housing and are inclined with respect to the axis of the tube.
Summary of the invention The invention has the object of providing a dosageform for echo contrast media which permits the user to administer the micro bubble echo contrast media in a standardised and optimised manner without unacceptable effort. Another aim of the invention is to improve the quality of the images of body structures obtainable with a micro bubble echo contrast medium and to improve the reproducibility of the images.
Another aim of the invention is to increase the safety of use by avoiding the production of gas bubbles which, because their diameter is too large, expose 'the patient to the risk of embolism.
Another aim of the invention is to avoid a risk of infection.
These objects are achieved according to the invention by the dosage form for echo contrast media comprising a syringe and a mixing chamber which is unreleasably connected thereto and contains a pre-determined amount of gas, plus a second syringe.
The invention ~tlxerefore relates to a dosage form_ for micro bubble echo contrast media comprising a first syringe and a mixing chamber which is unreleasably connected thereto and contains a predetermined amount of gas, plus a second syringe. Further subject-matter is evident from the patent claims. The invention further relates to a syringe for echo contrast media, which is 2~~~'~~.
characterised in that it is unreleasably connected to a tubular mixing chamber which has mixing elements in its inner lumen.
The mixing chamber is preferably tubular and has S mixing elements in its inner lumen.
In a preferred embodiment, the mixing elements are designed in the form of spikes, that is to say the mixing elements preferably stand at right angles to the inner wall of the mixing chamber and thus point in the direction of the long axis of the mixing chamber tube. It is expedient to design the mixing elements with sharp edges, that is to say to produce separation edges. There is preferably a mutually offset helical arrangement of the mixing elements. Additional separation edges can be achieved by one or more perforated diaphragms.
Echo contrast media which are in the form of a homogeneous solution are, according to the invention, provided in a syringe or drawn up air-free into a syringe from a storage container such as, for example, an ampoule before use. The syringe is then connected to the free end of the mixing chamber which is firmly connected to a syringe and whose interior volume contains the predeter-mined amount of gas. The echo contrast medium is pumped through the mixing chamber into the second, empty syringe and subsequently back again into the first syringe: A
relatively stable micro bubble suspension has been formed after only a few repetitions of the pumping process. The echo contrast medium is now ready for administration. The user now replaces the empty syringe by an injection needle and injects the contrast medium. It is expedient to inject from the syringe with mixing chamber because in this case injection directly entails passage through the mixing chamber once more.
The syringe with mixing chamber is produced by processes known to the person skilled in the art out of materials customary for such medical articles. For example, the mixing chamber is produced by the injection moulding process and connected unreleasably tn the connecting piece of a conventional syringe, for example _ ~~~~~a~~?
by adhesive or ultrasonic welding or is produced from the outset in one piece together with the syringe barrel. The free end of the mixing chamber can have the form of a male or female connecting piece. In the case where the free end is designed as male connecting piece, 'the second syringe has a female connecting piece, or an adaptor with two female connectors is fitted on the :male connecting piECe of the second syringe. In the case where the free end is designed as female connecting piece, the injection needle is fitted via an adaptor with two male connecting pieces.
It has emerged that the second syringe can be dispensed with when the formation of stable micro bubbles of suitable size is possible with relatively low energy expenditure with the echo contrast medium formulations used. In favourable cases, even the single passage through the mixing chamber on injection suffices to form micro bubbles whose quality and amount are adequate. This procedure is expedient, for example, in investigations of the right ventricle.
The dosage form according to the invention for micro bubble echo contrast media is preferably provided in a set ready for use. If the echo contrast medium consists of a single liquid component, the latter can be, for example, contained in a normal syringe or present in a vial from which. it is drawn up air-free into the syringe. The preset amount of gas to be dispersed :is located in the mixing chamber. It has proved to be expedient to choose the free interior volume of the mixing chamber such that it corresponds to the volume of the predetermined amount of gas which yields an optimal micro bubble echo contrast medium with the contrast medium components. The connecting pieces of the two syringes are closed with appropriate caps or stoppers. It is expedient to provide the said parts together with an injection needle and, if required, with further aids customary for i.v. use, such as alcohol swab and plaster dressing, sterile in a pack, for example a conventional blister pack.
Suitable contrast medium components are those compositions which yield sufficiently stable micro bubbles on foaming with gases for ultrasonic investigations, The components contain surface-active substances and, if required, further substances promoting the stabilisation of micro bubbles, such as, for example, substances which increase the viscosity. Suitable components are described, for example in EP 0 077 752 and EP 0 212 568.
The dosage form according to the invention for micro bubble echo contrast media contains 1 to 20 ml, preferably 2 to 8 ml, and particularly preferably 5 ml, of liquid contrast medium component. The dosage form according to the invention contains 0.01 to O.I, prefer-ably 0.04 to 0.06 ml of gas par 1 ml of liquid contrast medium component.
A preferred embodiment of the dosage form according to the invention comprises two syringes with an inner volume of 5 ml, of which one is unreleasably connected to a mixing chamber which has an inner volume of 0.18 ml. The syringe which is unreleasably connected to the mixing chamber is empty. The mixing chamber contains 0.18 ml of gas, preferably sterile air, and is closed by either a stopper or a cap. The second syringe contains 3 ml of a liquid contrast medium component. This syringe is also closed by a stopper or cap.
The invention is to be explained in more detail hereinafter by means of Figures 1 to 4.
Fig. 1 shows a longitudinal section through a mixing chamber.
Fig. 2 shows a cross-section through a mixing chamber along the line 1I in Fig. 1.
Fig. 3 shows a side view of a syringe with mixing chamber.
Fig. 4 shows a side view of a syringe with mixing chamber with second syringe attached>
Fig. 1 depicts an embodiment of the mixing chamber 1 in longitudinal section. The cylindrical tubular sleeve 2 has mixing elements 3 which stand at right angles to its interior wall and have a mutually offset helical or spiral arrangement. A connecting piece 4 is shaped at the left-hand end and is designed as male Luer connection. A connecting piece 5 is shaped on the right-hand end and is designed as female Luer connection.
It appears expedient, for reasons of production tech-nique, to fabricate the mixing chamber from three parts, that is to say from the 'tubular sleeve 2 with the mixing elements 3 and the two connecting pieces 4, 5 and to connect in a suitable manner. The connection lines are designated 8 and 9 in Fig. 1. The connecting piece 5 can be directly replaced by a corresponding connecting part of a piston syringe. As mentioned hereinbefore, the connecting piece 4 can also be in the form of a female Luer connection. If required, a perforated diaphragm 12 is provided in the connecting piece 4. An intensification of the dispersion can be achieved by this optional perforated diaphragm 12.
Fig. 2 shows a cross-section through a mixing chamber along the line II in Fig. 1. The mixing elements 3 in the form of spikes standing at right angles on the inner wall of the tubular sleeve 2 are seen.
Fig. 3 depicts a syringe 6 with mixing chamber 1 with male connecting piece, where the mixing chamber 1 is directly shaped on the base of the syringe barrel.
Fig. 4 shows the syringe 6 with mixing chamber 1 which is shaped on and onto whose male connecting pieces is fitted a second syringe 10 which contains the echo contrast medium 11. The amount of gas required for 'the micro bubbles is contained in mixing chamber 1. The micro bubble suspension ready for administration is prepared by pumping the echo contrast medium 11 backwards and forwards between syringe 10 and syringe 6 through mixing chamber 1.
The dosage ~orm according to tl-Ae invention achieves increased safety of use. It should be particu-larly emphasised in this connection that, owing to the predetermined amount of gas, exactly the amount of gas which is optimally suited to the composition and amount f ~~~~a~~
_~_ of the liquid component is used, and thus leads 'to a maximum information content of the obtainable images.
Errors which may arise through conventional drawing up of too much or too little gas are reliably avoided thereby.
In particular, the drawing up of too much gas might result in a risk of embolism for the patient. However, even the drawing up of too little gas in the conventional method may make repetition of the investigation necessary because of deficient imaging. In addition, the risk of infection for the patient is considerably reduced by the dosage form according to the invention because, in contrast to the drawing up of ambient air which has been hitherto customary, sterile gas is used and no ambient air which may be contaminated with resistant hospital organisms enters the blood circulation of the patient via the micro bubbles. An additional factor is that connec-tion procedures are avoided, owing to the unreleasable connection between mixing chamber and syringe, with regard to possible intrusion of organisms.
The safety of use is also greatly improved by the possibility now of considerably reducing the number of backward and forward pumping procedures, while there is a simultaneous increase in the quality of the micro bubble suspension. Since, in addition, the force expenditure necessary for the pumping backwards and forwards is considerably reduced, there is an increased readiness of the user to carry out the foaming procedure in accordance with the instructions until the state of the micro bubble echo contrast medium is optimal for the 3a intended purpose.
The dosage form according to the invention results in micro bubble suspensions which are distin-guished by a surprising improved quality of contrast.
In addition, it has been observed that, after disappearance of the contrast Pram the lumen of the body cavities investigated, the inner surfaces of the body cavities surprisingly remain readily visible for a substantial period. For example, 'this marking of surfaces, which has to date been observed only with.
'~ ~~1~
_ g _ dosage forms according to the invention, is outstandingly suitable for diagnosis of the heart. It appears that the presentation according to the invention favours the formation of micro bubbles adhering to interior body surfaces.
In a comparative test, 3 ml samples of an infu-sion solution containing crosslinked polypeptides (Haemaccel~ supplied by Behringwerke), which is suitable for the preparation of micro bubble contrast media, were pumped backwards and forwards together with 0.18 ml of air, on the one hand five times between two syringes connected by a three-way tap (test A), and on 'the other hand five times in a ~osa~e form according to the invention between the syringe connected to a mixing chamber and a syringe attached to the mixing chamber (test B). Subsequently formulations A and B were administered i.v. to conscious dogs. Echocardiography of the right ventricle was carried out with a Sonoscope 4 at 3.5 MHz. The resulting video printouts were evaluated by densitometry. The densitometer (Gretag D182) measures changes in the brightness in the range from 0.00 to 2.50 DU (density units) in 100 steps. The calibration is based on the calibration card which is provided by the manufacturer and complies with DIN 16536 (calibration reference), where the brightest white is assigned the value 1.64 and the darkest black is assigned the value 0.00. The value for each animal is determined from the mean of four individual measurements within a square centimetre.
The following results were obtained:
Contrast maximum 10 sec 20 sec ~ '~
quality intensity after after admini.s--adminis-tration tration Test poor - 1.06 0.39 0.19 A
Test goad 1.56 1.09 0.58 B
It is evident, that in addition to the easier and _ g safer use, the dosage form according to the invention results not on:Ly in a considerably improved contrast quality but also in a surprising increase in intensity, and the qualitatively and guantitatively superior con-s trast is in fact observable for very much longer too.
The novel dosage form for macro bubble echo contrast media not only simplifies the manipulation of echo contrast media and increases safety on use but, in particular, achieves a considerable additional gain in diagnostic information.
The mixing chamber is preferably tubular and has S mixing elements in its inner lumen.
In a preferred embodiment, the mixing elements are designed in the form of spikes, that is to say the mixing elements preferably stand at right angles to the inner wall of the mixing chamber and thus point in the direction of the long axis of the mixing chamber tube. It is expedient to design the mixing elements with sharp edges, that is to say to produce separation edges. There is preferably a mutually offset helical arrangement of the mixing elements. Additional separation edges can be achieved by one or more perforated diaphragms.
Echo contrast media which are in the form of a homogeneous solution are, according to the invention, provided in a syringe or drawn up air-free into a syringe from a storage container such as, for example, an ampoule before use. The syringe is then connected to the free end of the mixing chamber which is firmly connected to a syringe and whose interior volume contains the predeter-mined amount of gas. The echo contrast medium is pumped through the mixing chamber into the second, empty syringe and subsequently back again into the first syringe: A
relatively stable micro bubble suspension has been formed after only a few repetitions of the pumping process. The echo contrast medium is now ready for administration. The user now replaces the empty syringe by an injection needle and injects the contrast medium. It is expedient to inject from the syringe with mixing chamber because in this case injection directly entails passage through the mixing chamber once more.
The syringe with mixing chamber is produced by processes known to the person skilled in the art out of materials customary for such medical articles. For example, the mixing chamber is produced by the injection moulding process and connected unreleasably tn the connecting piece of a conventional syringe, for example _ ~~~~~a~~?
by adhesive or ultrasonic welding or is produced from the outset in one piece together with the syringe barrel. The free end of the mixing chamber can have the form of a male or female connecting piece. In the case where the free end is designed as male connecting piece, 'the second syringe has a female connecting piece, or an adaptor with two female connectors is fitted on the :male connecting piECe of the second syringe. In the case where the free end is designed as female connecting piece, the injection needle is fitted via an adaptor with two male connecting pieces.
It has emerged that the second syringe can be dispensed with when the formation of stable micro bubbles of suitable size is possible with relatively low energy expenditure with the echo contrast medium formulations used. In favourable cases, even the single passage through the mixing chamber on injection suffices to form micro bubbles whose quality and amount are adequate. This procedure is expedient, for example, in investigations of the right ventricle.
The dosage form according to the invention for micro bubble echo contrast media is preferably provided in a set ready for use. If the echo contrast medium consists of a single liquid component, the latter can be, for example, contained in a normal syringe or present in a vial from which. it is drawn up air-free into the syringe. The preset amount of gas to be dispersed :is located in the mixing chamber. It has proved to be expedient to choose the free interior volume of the mixing chamber such that it corresponds to the volume of the predetermined amount of gas which yields an optimal micro bubble echo contrast medium with the contrast medium components. The connecting pieces of the two syringes are closed with appropriate caps or stoppers. It is expedient to provide the said parts together with an injection needle and, if required, with further aids customary for i.v. use, such as alcohol swab and plaster dressing, sterile in a pack, for example a conventional blister pack.
Suitable contrast medium components are those compositions which yield sufficiently stable micro bubbles on foaming with gases for ultrasonic investigations, The components contain surface-active substances and, if required, further substances promoting the stabilisation of micro bubbles, such as, for example, substances which increase the viscosity. Suitable components are described, for example in EP 0 077 752 and EP 0 212 568.
The dosage form according to the invention for micro bubble echo contrast media contains 1 to 20 ml, preferably 2 to 8 ml, and particularly preferably 5 ml, of liquid contrast medium component. The dosage form according to the invention contains 0.01 to O.I, prefer-ably 0.04 to 0.06 ml of gas par 1 ml of liquid contrast medium component.
A preferred embodiment of the dosage form according to the invention comprises two syringes with an inner volume of 5 ml, of which one is unreleasably connected to a mixing chamber which has an inner volume of 0.18 ml. The syringe which is unreleasably connected to the mixing chamber is empty. The mixing chamber contains 0.18 ml of gas, preferably sterile air, and is closed by either a stopper or a cap. The second syringe contains 3 ml of a liquid contrast medium component. This syringe is also closed by a stopper or cap.
The invention is to be explained in more detail hereinafter by means of Figures 1 to 4.
Fig. 1 shows a longitudinal section through a mixing chamber.
Fig. 2 shows a cross-section through a mixing chamber along the line 1I in Fig. 1.
Fig. 3 shows a side view of a syringe with mixing chamber.
Fig. 4 shows a side view of a syringe with mixing chamber with second syringe attached>
Fig. 1 depicts an embodiment of the mixing chamber 1 in longitudinal section. The cylindrical tubular sleeve 2 has mixing elements 3 which stand at right angles to its interior wall and have a mutually offset helical or spiral arrangement. A connecting piece 4 is shaped at the left-hand end and is designed as male Luer connection. A connecting piece 5 is shaped on the right-hand end and is designed as female Luer connection.
It appears expedient, for reasons of production tech-nique, to fabricate the mixing chamber from three parts, that is to say from the 'tubular sleeve 2 with the mixing elements 3 and the two connecting pieces 4, 5 and to connect in a suitable manner. The connection lines are designated 8 and 9 in Fig. 1. The connecting piece 5 can be directly replaced by a corresponding connecting part of a piston syringe. As mentioned hereinbefore, the connecting piece 4 can also be in the form of a female Luer connection. If required, a perforated diaphragm 12 is provided in the connecting piece 4. An intensification of the dispersion can be achieved by this optional perforated diaphragm 12.
Fig. 2 shows a cross-section through a mixing chamber along the line II in Fig. 1. The mixing elements 3 in the form of spikes standing at right angles on the inner wall of the tubular sleeve 2 are seen.
Fig. 3 depicts a syringe 6 with mixing chamber 1 with male connecting piece, where the mixing chamber 1 is directly shaped on the base of the syringe barrel.
Fig. 4 shows the syringe 6 with mixing chamber 1 which is shaped on and onto whose male connecting pieces is fitted a second syringe 10 which contains the echo contrast medium 11. The amount of gas required for 'the micro bubbles is contained in mixing chamber 1. The micro bubble suspension ready for administration is prepared by pumping the echo contrast medium 11 backwards and forwards between syringe 10 and syringe 6 through mixing chamber 1.
The dosage ~orm according to tl-Ae invention achieves increased safety of use. It should be particu-larly emphasised in this connection that, owing to the predetermined amount of gas, exactly the amount of gas which is optimally suited to the composition and amount f ~~~~a~~
_~_ of the liquid component is used, and thus leads 'to a maximum information content of the obtainable images.
Errors which may arise through conventional drawing up of too much or too little gas are reliably avoided thereby.
In particular, the drawing up of too much gas might result in a risk of embolism for the patient. However, even the drawing up of too little gas in the conventional method may make repetition of the investigation necessary because of deficient imaging. In addition, the risk of infection for the patient is considerably reduced by the dosage form according to the invention because, in contrast to the drawing up of ambient air which has been hitherto customary, sterile gas is used and no ambient air which may be contaminated with resistant hospital organisms enters the blood circulation of the patient via the micro bubbles. An additional factor is that connec-tion procedures are avoided, owing to the unreleasable connection between mixing chamber and syringe, with regard to possible intrusion of organisms.
The safety of use is also greatly improved by the possibility now of considerably reducing the number of backward and forward pumping procedures, while there is a simultaneous increase in the quality of the micro bubble suspension. Since, in addition, the force expenditure necessary for the pumping backwards and forwards is considerably reduced, there is an increased readiness of the user to carry out the foaming procedure in accordance with the instructions until the state of the micro bubble echo contrast medium is optimal for the 3a intended purpose.
The dosage form according to the invention results in micro bubble suspensions which are distin-guished by a surprising improved quality of contrast.
In addition, it has been observed that, after disappearance of the contrast Pram the lumen of the body cavities investigated, the inner surfaces of the body cavities surprisingly remain readily visible for a substantial period. For example, 'this marking of surfaces, which has to date been observed only with.
'~ ~~1~
_ g _ dosage forms according to the invention, is outstandingly suitable for diagnosis of the heart. It appears that the presentation according to the invention favours the formation of micro bubbles adhering to interior body surfaces.
In a comparative test, 3 ml samples of an infu-sion solution containing crosslinked polypeptides (Haemaccel~ supplied by Behringwerke), which is suitable for the preparation of micro bubble contrast media, were pumped backwards and forwards together with 0.18 ml of air, on the one hand five times between two syringes connected by a three-way tap (test A), and on 'the other hand five times in a ~osa~e form according to the invention between the syringe connected to a mixing chamber and a syringe attached to the mixing chamber (test B). Subsequently formulations A and B were administered i.v. to conscious dogs. Echocardiography of the right ventricle was carried out with a Sonoscope 4 at 3.5 MHz. The resulting video printouts were evaluated by densitometry. The densitometer (Gretag D182) measures changes in the brightness in the range from 0.00 to 2.50 DU (density units) in 100 steps. The calibration is based on the calibration card which is provided by the manufacturer and complies with DIN 16536 (calibration reference), where the brightest white is assigned the value 1.64 and the darkest black is assigned the value 0.00. The value for each animal is determined from the mean of four individual measurements within a square centimetre.
The following results were obtained:
Contrast maximum 10 sec 20 sec ~ '~
quality intensity after after admini.s--adminis-tration tration Test poor - 1.06 0.39 0.19 A
Test goad 1.56 1.09 0.58 B
It is evident, that in addition to the easier and _ g safer use, the dosage form according to the invention results not on:Ly in a considerably improved contrast quality but also in a surprising increase in intensity, and the qualitatively and guantitatively superior con-s trast is in fact observable for very much longer too.
The novel dosage form for macro bubble echo contrast media not only simplifies the manipulation of echo contrast media and increases safety on use but, in particular, achieves a considerable additional gain in diagnostic information.
Claims (5)
1. Dosage form for micro bubble echo contrast media comprising a first syringe (6) which is unreleasably connected to a mixing chamber (1) which is provided in its interior with mixing elements (3) which, on operation of the syringe (6), bring about turbulence of the gaseous and liquid components of the contrast medium, the mixing chamber (1) containing the predetermined amount, which is needed to produce the micro bubbles, of a suitable sterile gas and being closed by a stopper or cap.
2. Dosage form according to claim 1, additionally comprising a second syringe (10).
3. Dosage form according to claim 2, characterized in that the second syringe (10) contains the liquid contrast medium component.
4. Dosage form according to claim 2, additionally comprising a vial containing the liquid contrast medium component.
5. Dosage form according to any one of claims 1 to 4 characterized in that it is in the form of a set ready for use.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH4132/90-0 | 1990-12-28 | ||
| CH413290 | 1990-12-28 | ||
| PCT/EP1991/002497 WO1992011928A1 (en) | 1990-12-28 | 1991-12-23 | Dosage form for micro-bubble echo contrast agents |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2098710A1 CA2098710A1 (en) | 1992-06-29 |
| CA2098710C true CA2098710C (en) | 2002-05-28 |
Family
ID=4270434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA 2098710 Expired - Lifetime CA2098710C (en) | 1990-12-28 | 1991-12-23 | Dosage form for micro-bubble echo contrast agents |
Country Status (19)
| Country | Link |
|---|---|
| EP (1) | EP0564505B1 (en) |
| JP (2) | JP3325565B2 (en) |
| KR (1) | KR100191689B1 (en) |
| AR (1) | AR244998A1 (en) |
| AT (1) | ATE123930T1 (en) |
| AU (1) | AU9103391A (en) |
| CA (1) | CA2098710C (en) |
| CZ (1) | CZ283184B6 (en) |
| DE (2) | DE59105805D1 (en) |
| DK (1) | DK0564505T3 (en) |
| ES (1) | ES2076739T3 (en) |
| GR (1) | GR3017442T3 (en) |
| HU (1) | HU216376B (en) |
| IE (1) | IE69668B1 (en) |
| MX (1) | MX9102814A (en) |
| NZ (1) | NZ241212A (en) |
| RU (1) | RU2097014C1 (en) |
| WO (1) | WO1992011928A1 (en) |
| ZA (1) | ZA9110191B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2282712A2 (en) * | 2008-05-05 | 2011-02-16 | Artenga Inc. | Medical microbubble generation |
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| WO1997027938A1 (en) * | 1996-01-31 | 1997-08-07 | Alfred Von Schuckmann | Device for mixing air bubbles into an echo-contrast agent |
| US6042263A (en) * | 1998-04-29 | 2000-03-28 | Mentzer; Marvin R. | Mixed phase ruff body flow diffuser |
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| DE10226803B4 (en) * | 2001-06-19 | 2007-01-18 | Chemische Fabrik Kreussler & Co. Gmbh | Mixing device for the production of reproducible medical foam |
| US8512680B2 (en) | 2001-08-08 | 2013-08-20 | Btg International Ltd. | Injectables in foam, new pharmaceutical applications |
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| US8048439B2 (en) | 2003-11-17 | 2011-11-01 | Btg International Ltd. | Therapeutic foam |
| SI1694292T1 (en) | 2003-11-17 | 2009-12-31 | Btg Int Ltd | Therapeutic foam comprising a sclerosing solution and a low quanitiy of gaseous nitrogen |
| JP4534123B2 (en) * | 2003-12-26 | 2010-09-01 | エス・ピー・ジーテクノ株式会社 | Emulsion preparation device and method |
| US20050215954A1 (en) * | 2004-03-29 | 2005-09-29 | Mallinckrodt Inc. | Apparatus and method for maintaining suspendible agents in suspension |
| DE102004048749B4 (en) * | 2004-10-05 | 2007-03-29 | Chemische Fabrik Kreussler & Co. Gmbh | Device for producing a medical foam |
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| DE102009037765B4 (en) * | 2009-08-17 | 2011-12-29 | Gottfried Hesse | Method and device for producing a gas mixture |
| DE202010005131U1 (en) | 2010-04-09 | 2011-08-30 | Jakob Hoiss | Apparatus for filling a syringe body with a gas mixture for subsequent injection of a mixture of the gas mixture and a medicament into the human or animal body |
| US10207053B2 (en) | 2012-03-16 | 2019-02-19 | Becton, Dickinson And Company | Drug delivery device for drug suspensions |
| JP6755035B2 (en) * | 2015-07-15 | 2020-09-16 | 国立大学法人 鹿児島大学 | Bubble generation device and bubble generation method |
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1991
- 1991-12-23 AT AT92901391T patent/ATE123930T1/en not_active IP Right Cessation
- 1991-12-23 DE DE59105805T patent/DE59105805D1/en not_active Expired - Lifetime
- 1991-12-23 AU AU91033/91A patent/AU9103391A/en not_active Abandoned
- 1991-12-23 RU RU93042871/14A patent/RU2097014C1/en not_active IP Right Cessation
- 1991-12-23 CA CA 2098710 patent/CA2098710C/en not_active Expired - Lifetime
- 1991-12-23 DK DK92901391T patent/DK0564505T3/en active
- 1991-12-23 CZ CZ931266A patent/CZ283184B6/en not_active IP Right Cessation
- 1991-12-23 JP JP50140992A patent/JP3325565B2/en not_active Expired - Lifetime
- 1991-12-23 DE DE4193414T patent/DE4193414D2/en not_active Expired - Lifetime
- 1991-12-23 ES ES92901391T patent/ES2076739T3/en not_active Expired - Lifetime
- 1991-12-23 HU HU9301702A patent/HU216376B/en unknown
- 1991-12-23 KR KR1019930701808A patent/KR100191689B1/en not_active IP Right Cessation
- 1991-12-23 EP EP92901391A patent/EP0564505B1/en not_active Expired - Lifetime
- 1991-12-23 WO PCT/EP1991/002497 patent/WO1992011928A1/en active IP Right Grant
- 1991-12-26 MX MX9102814A patent/MX9102814A/en unknown
- 1991-12-27 AR AR32152691A patent/AR244998A1/en active
- 1991-12-27 ZA ZA9110191A patent/ZA9110191B/en unknown
- 1991-12-30 IE IE456391A patent/IE69668B1/en not_active IP Right Cessation
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1992
- 1992-01-06 NZ NZ241212A patent/NZ241212A/en not_active IP Right Cessation
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1995
- 1995-09-20 GR GR950402568T patent/GR3017442T3/en unknown
-
2002
- 2002-02-14 JP JP2002036751A patent/JP3637022B2/en not_active Expired - Lifetime
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP2282712A2 (en) * | 2008-05-05 | 2011-02-16 | Artenga Inc. | Medical microbubble generation |
| EP2282712A4 (en) * | 2008-05-05 | 2015-04-01 | Artenga Inc | Medical microbubble generation |
Also Published As
| Publication number | Publication date |
|---|---|
| KR100191689B1 (en) | 1999-06-15 |
| JP3325565B2 (en) | 2002-09-17 |
| RU2097014C1 (en) | 1997-11-27 |
| ES2076739T3 (en) | 1995-11-01 |
| MX9102814A (en) | 1994-03-31 |
| CA2098710A1 (en) | 1992-06-29 |
| ZA9110191B (en) | 1992-09-30 |
| DE4193414D2 (en) | 1997-07-24 |
| CZ126693A3 (en) | 1993-11-17 |
| JP2002301150A (en) | 2002-10-15 |
| IE69668B1 (en) | 1996-10-02 |
| JP3637022B2 (en) | 2005-04-06 |
| WO1992011928A1 (en) | 1992-07-23 |
| KR930703066A (en) | 1993-11-29 |
| DK0564505T3 (en) | 1995-11-06 |
| EP0564505B1 (en) | 1995-06-21 |
| HU9301702D0 (en) | 1993-09-28 |
| AR244998A1 (en) | 1993-12-30 |
| GR3017442T3 (en) | 1995-12-31 |
| ATE123930T1 (en) | 1995-07-15 |
| JPH06503976A (en) | 1994-05-12 |
| EP0564505A1 (en) | 1993-10-13 |
| NZ241212A (en) | 1994-08-26 |
| HU216376B (en) | 1999-06-28 |
| CZ283184B6 (en) | 1998-01-14 |
| IE914563A1 (en) | 1992-07-01 |
| AU9103391A (en) | 1992-08-17 |
| HUT65298A (en) | 1994-05-02 |
| DE59105805D1 (en) | 1995-07-27 |
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