CA2077712C - Process and device for the production of a contrast medium from a concentrate - Google Patents
Process and device for the production of a contrast medium from a concentrate Download PDFInfo
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- CA2077712C CA2077712C CA002077712A CA2077712A CA2077712C CA 2077712 C CA2077712 C CA 2077712C CA 002077712 A CA002077712 A CA 002077712A CA 2077712 A CA2077712 A CA 2077712A CA 2077712 C CA2077712 C CA 2077712C
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- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/0002—General or multifunctional contrast agents, e.g. chelated agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/04—X-ray contrast preparations
- A61K49/0433—X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K49/18—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes
- A61K49/1818—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by a special physical form, e.g. emulsions, microcapsules, liposomes particles, e.g. uncoated or non-functionalised microparticles or nanoparticles
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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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- 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
- A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
- A61M5/14—Infusion devices, e.g. infusing by gravity; Blood infusion; Accessories therefor
- A61M5/168—Means for controlling media flow to the body or for metering media to the body, e.g. drip meters, counters ; Monitoring media flow to the body
- A61M5/16804—Flow controllers
- A61M5/16827—Flow controllers controlling delivery of multiple fluids, e.g. sequencing, mixing or via separate flow-paths
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Engineering & Computer Science (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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- Biotechnology (AREA)
- Biophysics (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Medical Preparation Storing Or Oral Administration Devices (AREA)
Abstract
Process for the production of a contrast medium from a contrast medium concentrate in an amount of 350-450 I/ml or 0.5-4 mol of contrast medium compound/liter in a container of 0.1-100 liters by mixing with an aqueous solution.
Description
~.~,~~r~'aN'1r" .~ '-.9' Description ~<u... s :l ~..~
The invention relates to a process for the production of a contrast medium in usable dosage forms. It further relates to a device for the production of an administrable contrast medium consisting of at least one concentrate and at least one diluent.
Contrast media have become important auxiliary agents for diagnostic processes, such as ultrasonic, x-ray or nuclear resonance diagnoses. Thus, for example, the administration of a contrast medium to a patient improves the evaluation of an x-ray image, since as a result, higher--contrast images are obtained.
Because of this fact, the medical personnel can better evaluate the data made available by such an image.
Regarding the dosage, numerous factors are to be considered in the determination of the dosage amount and dosage concentration of the contrast medium to be administered, for example, the type of the diagnostic examination used, how this diagnostic examination is performed, the k~ody area of the patient to be tested as well as the age, the body weight and the state of health of the patient. In view of these numerous factors, contrast media, such as x-ray contrast media, can be obtained in a number of concentrations, for example, 120-400 mg of I/ml, and in a plurality of dosage amounts, for example, 1 ml-250 ml.
Despite the numerous concentrations and dosage amounts, however, not every individual situation of the individual patient can be taken into account.
Despite this multiplicity ofidosages, which are commercially available (concentrations and sizes), it is often unavoidable r3 >~n~1r. ~i rd ~. ~ :J ?
in clinical use that only a partial amount is necessary for the test and the remaining amount is discarded. A reuse is excluded in this connection, since this would represent a contraindication.
Because of the numerous diagnostic tests and the high prices of modern contrast media, however, such a waste represents a considerable cost factor for clinical practice or medical practice. In addition, numerous forms of contrast media have to be kept in stock, by which the stand-by costs increase considerably. In the cases in which a new testing technique requires new forms of preparation, the often long time intervals for the development and approval of new bottle sizes and/or concentrations also represent a drawback.
In thelsame manner, the plurality of forms of administration of contrast media on the production side also represents a drawback, since only relatively small production batches can be produced, the storage requirement is increased, the logistics are difficult, and more expensive and extended development and approval times are the result. In addition, only little:
flexibility in the contrast media production exists for changes of the preparation forms, as they are required by the market.
These drawbacks have not been eliminated to this day.
In the pharmaceutical field, a plurality of filling devices are known, with which solutions can be mixed in portions, for' example, from WO 84/00139 or De-OS 33 15 031.
WO 84/00139 thus describes a mixing device, which exhibits suitable agents for monitoring the filling of pharmaceutical solutions. In this way, solutions ar<~ filled, which are taken from various cc>ntairm,:rs. F3ut: a spec:i fic mixture to guarantee uniform concentr:~ti~:>na in the finished, solution appropriate to use does not occur_ Also, only infusion ~;o:Lut icns E<:~r ipar~ent:eral feeding are mixed with the mixing device known cram DF-OS 33 15 031, without reference being made to the pr<obl.ems of the production of cc>ntrast medic.zm solutic>n:>.
Moreover, both known devi_c~~s are not suitable for mixing liquids with greatly di.f_ferE.mt cler~sities, single a simple bringing together ~:of such liquids does not r_ause a uniformly diluted soluti~~n, as is necessary for the mcsntioned uses .
The object. of the i:n~~~ention therefore i.s to make available a process of t:~f, above-mentr~oned type, with which patient-specific, indica L c orl-:~peci t is ~~ont cast medium compositions with appropriate dosage can be produced, without a plurality of f~.~a:ms ~;f admina. ~tration having to be kept ready for use and/o:r considerable amo~.~nts of waste occurring.
Moreover, contrast mE~ciia and opt:i.~~rlally desired "additives" can be administ.erod in one dosage by which the comfort for the patient :Ls increased.
The present invention provider a process for the production of a diagnostic contrast. medium comprising at lE:ast one contrast agent anc-1 an aqueous solution, the process comprising delive~-i.ng, under st~eri 1_e conditions, a predetermined amount of at= least: a first contrast medium concentrate containing 3'~0-45() mg of IJm:l <>f X-ray contrast accent, 0.5-4 mol of NMR c:cynt_rast agent!1_:iter, or an ultrasound contrast agent., from at least a first container by a first pipe to a mix:i_rog cr:amber, deli.vc>rinc~ a predetermined amount of c~ii_luent from a se:~c:md cJontainer by a second pipe to the mixing cruan~ber, wherein the .i 8 predetermined amounts ar~~ rni~.ed tc> form <~ phy:~iologic.ally compatible preparation, an<v d~~li..vfer::inca tloc;~ re:>ui_tant.
mixture to a di scharge :~t~~t i.c.~n .
The present invention also provides <i devic:e for production of a contrast medium, the alevic°e comprising at least one concentrate container contairoinc~ concentrated contrast media, at least c>ne dil.uerot cvonta:ainer containing a diluent suitable for use with contrast mecvl:i.a, a first feed pipe and a second feed pipc> in connect: i.orr with, respectively, the concentrate container and the diluent container, the feed pipes also being in f=lui_d communication with a mixing chamber, a delivery pipe in fluid communication with the fecad pipes, a rn:ixi.ng ch.arruber provided between the feed pipes and tr~f:a dE:livery pipe, metering elements in the feed pipes wl~:ich meter, respectively, predetermined a°.nounts of the concentrated contrast media and the diluent, means for determination of mitered amounts of the concentrated cc-_>rntrast media and the diluent, metering device iro t'~oe del.i..vrm:y pipe, which discharges contrast medium from an end of t:he delivery pipe, and control unit which _ontrols i::he metering elements.
The present invention also provides a kit for p=roduction of a contrast rnedi~.~rn, comprising a concentrate containing 350-450 mg of I/ml of X-ray contrast agent, 0.5-4 mol/liter of NMR corrt:rast agent c:~r a concentrated ultrasound contrast agent, in a first container with a volume of 0.1-100 1, and an a~~lueous di.l.uent in a second container with a content of 1-100 liters.
In the process accerciinct to the invention, one or more contrast; medium conce~nt rates <rre used in suitable containers, which are flowab.l.e and highly concentrated. These concentrates are used in the form of solutions, dispersions or as fl.owable ° ~~~aMw~~y~,~ °.'~
ac:~ ~.. ~' a a .~. .
(free-flowing) powders and are introduced in suitable concentrate containers.
In addition, one or more diluents are used fox mixing with the concentrates, for example, sterile or unsterile water. But on the other hand, pharmaceutical solutions can also be used as diluents and/or solvents or dispersing agents for the dilution of the concentrate. Finally, even diluted contrast medium solutions can be used for mixing with the contrast medium concentrates.
The contrast medium concentrates can exhibit concentrations which lie above the values which were produced previously for administration reasons (e.g., viscosity). Thus, for example, x-ray contrast medium concentrates with a content of 350-450 mg of I/ml are used or NMR contrast media in solution or dispersion with 0.5 mol/liter in the form of Gadopentetat-dimeglumines or other NMR contrast media based on paramagnetic ions. But different contrast medium concentrates can also be used for different medical techniques, for example, for x-ray, nuclear resonance or ultrasonic diagnosis.
If the contrast medium concentrates are present in,powder form, these powders can consist to 100% of the respective contrast medium or optionally contain other solid galenical auxiliary agents (which, e.g., improve the flowability of the contrast medium).
The weight ratio of contrast medium to auxiliary agent can be selected at will.
X-ray contrast media can contain, for example, iotrolan, iopromide, iohexol, iosimide, metrizamide, salts of amidoacetic dal <.. .7 .l v) .x.
acid, iotroxic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodo-isophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5-[N-{2-hydroxyethyl)-acetamido]-2,4,6-triiodo-benzoic acid-[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl]amide and dispersions of slightly soluble x-ray contrast media, such as iodipamide ethyl ester.
For example, gadolinium DTPA, gadolinium DOTA, the gadolinium complex of 10(1-hydroxymethyl-2,3-dihydroxypropyl]-1,4,7-tris-[(carboxymethyl)-1,4,7,10-tetraazacyclodecane], iron or manganese porphyrin chelates and stable magnetite dispersions belong to NMR contrast media.
For example, dispersions of galactose microparticles with or without additives in water or a galactose solution and dispersions of microbeads of enclosed air (for example, cyanacrylates or albumin microbeads) as well as other injectable microparticles belong to ultrasonic contrast media.
According to the process of the invention, a predetermined amount of contrast medium concentrate is mixed with a predetermined amount of diluent and optionally other additives to formulate the desired dosage form of the contrast medium.
Contrast media can also be mixed with ol~e another for different fields of use. In this way, two or more different tests can be performed on patients with only one dosage, which represents a marked improvement of the comfort of the patient..
Such a mixture of two or more~contrast media is usually consumed immediately after the mixings so that no stability problems occur.
s 9~.a~~~~?rv~y~J~r~
As diluent, for example, a physiologically compatible liquid vehicle is suitable which contains optionally usable additives.
Thus, for example, as diluent, sterile or unsterile water can be used, which optionally exhibits buffer substances and/or additives having an isotonic effect, as well as optionally complexing agents, such as CaNa2EDTA.
As diluent, a comparatively less concentrated contrast medium can also be used, for example, in a concentration of 0--0.5 mol/1 or 0-350 mg of I/1 or 0-100 mg of particles/ml.
Usable additives are, for example, inorganic or organic salts or buffer substances, such as sodium chloride, Iris-buffer, phosphate buffer, citrate buffer, glycine buffer, citrate phosphate buffer, maleate buffer and the like. Further, they include monosaccharides or disaccharides, such as glucose, lactose, saccharose or trehalose, sugar alcohols, such as mannitol, sorbitol, xylite or glycerol, or water-soluble polymers, such as dextrans or polyethylene glycols.
The process according to the invention can further be used for the production of dosage forms which are usable for:,a plurality of administration techniques, for example, for intravascular, subarachnoid, intraneural and. oral administration.
Further, the process according to the invention makes possible, depending on the diagnostic formulation of the problem, a concentration or volume change of the contrast medium in the course of the administration.
Thus, different concentrations or volumes automated in succession can be produced and administered in situ.
Also, it is possible to change the originally provided dosage form during the test relative to concentration or volume if the originally administered dose still was not able to produce the desired diagnostic result.
The contrast medium concentrate is present in a flowable form, for example, as solution, dispersion or powder. In the last-mentioned case, the solvent can act as solvating agent and/or dispersion medium.
The device according to the invention for performing the process according to the invention first exhibits at least one contrast medium concentrate container and at least one diluent container. A predetermined amount of fluid is removed in each case from these containers, and the removal can be performed either simultaneously or successively. The respectively removed predetermined amounts of fluid are fed to a mixing zone or a mixing chamber, in which both fluids are mixed, and a uniform contrast medium in the usable dosage farm is achieved. The concentrate container and the diluent container are each connected by pipes with the mixing zone. The conveying:of the fluids can take place either automatically because of the effect of gravity or by active pumping action by a pump, for example, a vacuum pump or a peristaltic pump.
If the conveying takes place under the effect of gravity, in each case shutoff devices, far example, valves, are provided in the inflow pipes to the mixing zone, which are activated by a control unit in a predetermin,sd way. In this way, the amount of the fluid present in the respective container and the pipe cross ~~~ r~~N'1~y ~ '~~
P~ __~ a' J ~.a~.. .s section as well as the pipe length determine the amount of inflowing fluid as well as the inflow rate of the fluid.
:If, however, pumps axe used, a peristaltic pump in the non-activated state acts as a shutoff unit, but in the activated state pumps the fluid from the respective container to the mixing zone. If the fluid is pumped into the mixing zone with the help of a vacuum, shutoff elements are again placed in the inflow pipes, which are activated together with the vacuum unit.
The inflow pipes can be connected either directly with the mixing chamber or else also can be combined in front of the mixing chamber, and a single pipe goes from the junction point to the mixing chamber, so that a Y-connection is made.
The above-described pump and shutoff devices usually do not operate precisely enough, so that for the precise determination of the amount and the concentration of the dosage form, advantageously a unit for the determination of the amounts of fluid is provided, with which the amount of fluid removed from the respective container can be determined. Such units include, for example, flow sensors in the inflow pipes, with which the amount of fluid that has flowed through per unit of time can be determined. On the other hand, weighing machines can also be used, which determine either the increase of the amounts of fluid in the mixing chamber or else the respective reduction of the amounts of fluid in the respective container. Finally, volumetrically operating units can also be placed in the mixing chamber or the output container, with which the inflowing volume or the outflowing volumes can be determined.
s~ ~'~i x ~ ~~a .bra.
In each case, the outflawing or inflowing amounts of fluid or fluid volumes can be determined exactly with these sensors as a function of the activation time of the shutoff elements or pumps. These sensors are electrically linked with the control unit and send suitable signals as respective actual value to the control unit.
From the signals sent, the control unit itself calculates the respective amounts, volumes and/or concentrations of the conveyed materials or the mixture actually contained in the mixing chamber. 2t is known that desired concentrations of the form of administration can be securely controlled by the specific density or densities of the contrast medium compound or compounds used.
In iodized x-ray contrast media, a high density typically occurs. Here, the density can be used as a usable indicator for the determination of the concentration. In such a case, a density sensor is provided inside the mixing chamber. On the other hand, the optical rotation can also be a usable determination parameter. Of course, volumetric or grava~metric determination parameters, i.a., can also be used.
As stated above, the actual signal for the control unit is used to control the pumps or the shutoff elements as a function of a previously adjusted setpoint value; which can,be manually input in the control unit by an input unit.
The control unit sends suitable control signals to operate the shutoff elements and pi.~mps and receives the sensor signals, which pertain to the amounts of fluid which have been removed ' ~ io ~-j~-~t- ~ a from the containers and/or have been supplied to the mixing chamber.
Further, the mixing chamber can be connected by a discharge pipe with a means for administering the contrast medium, for example, hypodermic syringes, which are filled in succession with the contrast medium in the desired dosage form. Finally, the mixing chamber can be connected as an alternative with one or more containers for storage of one or more cartridges for pressure injectors or can be connected directly to a patient for a direct infusion.
Tha discharge pipe going from the mixing chamber is in this case also provided with a shutoff element, which is closed during the mixing process and is opened only for filling purposes.
According to another advantageous embodiment, the feed pipe arrangement is connected with an additional container, which exhibits a cleaning and flushing liquid. As a result, the pipes, shutoff elements, pumps, the mixing chamber, the collecting chamber, the receiving container and the like can be flushed. As liquid, every suitable cleaning medium can be suitable for this purpose, for example, sterile or nonsterile water with or~without additives. In addition, the diluent itself pan be used as flushing fluid.
The arrangement according to the invention can further be connected with a collecting chamber, in which the fluid used during the cleaning stage can be collected.
The mixing chamber can be connected with empty containers, which are closed, for example, by a septum. In such sterile ~~1 J~ .J~~~t., A
containers, the contrast medium is kept in its dosage form. Iri this case, sterile infusion or injection bottles made of plastic or glass are suitable, as also infusion bags.
According to another embodiment, the arrangement according to the invention can be connected directly to an extruder, with which suitable plastic containers are produced. Finally, the arrangement can be used for the purpose that such empty containers or a hypodermic syringe axe filled directly or else a direct infusion can be performed on the patient.
According to another advantageous embodiment, the arrangement according to the invention is connected with a sterilization unit. Such a sterilization unit can exhibit, for example, a steam generator, which is connected by a connecting pipe with the entire pipe arrangement and the shutoff element, pumps and the containers, etc. On the other hand, as a sterilization unit, a liquid disinfectant, for example, peracetic acid, can also be used, and after the sterilization process, attention must be paid that any possible disinfectant residues are removed with sterile water. Finally, the sterilization of the arrangement according to the invention is performed less often that the flushing.
The contrast medium concentrate container can exhibit any desired size, for example, 0.1-100 1, especially about 1 l, 5 1, l, 50 1 and the like. The containers can be produced from any suitable material which is suitable for storing the concentrated pharmaceutically acceptable,contrast medium and, for example, thermally stable plastic, glass or metal advantageously can be ~~y'~.~ ~
sterilized. These containers can either be reusable or else suitable only for one-time use.
Advantageously, the sterilized device is kept in sterilized state with the help of a sterile filter placed in the pipe sections. In addition, the mixing effect in the mixing zone or mixing chamber can be improved in that a stirring device is provided in the mixing zone or mixing chamber.
The contrast medium is present inside the container in high concentration. A solution with a concentration which is either equal to or higher than that of commercially available dosage forms of the contrast medium is considered as a concentrated solution and/or dispersion. As the example of an iodized x-ray contrast medium, the concentration of the contrast medium in the receiving container is in an amount of about 350-450 mg of I/ml.
In NMR contrast media, for example, in Gadopentetat dimeglumines (dimeglumines Gd-DTPA), the commercially available concentration is usually at about 0.5 moll. Consequently, concentrated solutions or dispersions of the NMR contrast medium exhibit an equal or higher concentration content, for dissolved concentrates, for example, greater than or equal to 0.5 mol/1, especially a content of 0.5-4 mol/1. , Although with the process according to the invention, a usable dosage form is preferably produced from a concentrated contrast medium, it is also possible to use the process according to the invention for reducing the concentration of commercially available dosage forms of contrast media.
According to another embodiment of the invention, a set is made available which can be used in connection with the above-described system for formulating usable dosage forms of contrast media. Such a set exhibits a first container with a specific contrast medium and a second container with a specific suitable diluent. These containers of the set preferably have means for connection with the device according to the invention to transfer predetermined amounts of fluid from each of the containers to the mixing chamber. A set can exhibit, for example, the first container with 0.1-100 liters of a concentrated x-ray contrast medium with a concentration of 350-450 mg of I/ml and a second container with 1-100 liters of diluent, which is suitable for the formulation of an x-ray contrast medium in pharmaceutically acceptable forms. On the other hand, the set can also contain a first container with 100 ml to 100 liters of an NMR contrast medium with a concentration of 0.5-4 mol per liter.
The invention is explained based on an embodiment.
Figure 1 shows a basic sketch of the mixing arrangement according to the invention.
Device 10 shown in figure 1 exhibits a container 12 for a contrast medium concentrate and a container ~.4 .for a solvent or diluent. Both containers 12 and 14 are connected by inflow pipes 16 and 18 with a mixing chamber 20. In the example, both pipes 16 and 18 are brought together in a single pipe 19 upstream from mixing chamber 20, a pipe which then ands in mixing chamber 20.
But such a connection is not necessary. Consequc;ntly, both pipes 16 and 18 can also be connected directly with mixing chamber 20.
~..~ ~ J~ ~ ~~.. ~
A discharge pipe 22, whose ends 24 can be connected with receiving containers (bottles, bags or syringe arrangements), not shown originates from mixing chamber 20.
A first metering element 26 is inserted in first inflow pipe 16, and a second metering element 28 is inserted in second inflow pipe 18. In addition, a third metering element 30 is inserted in discharge pipe 22.
Mixing chamber 20 is connected with a weighing device 32, which can determine the respective present weight condition of mixing chamber 20.
Metering elements 26, 28 and 30 as well as weighing device 32 are connected by signal lines 36-40 with a control unit 42.
Control unit 42 further exhibits an input unit 44, with which certain data can be input into control unit 42.
According to an advantageous embodiment, a sterile filter 46 is provided downstream from third metering element 30 in discharge pipe 22.
In addition, device 10 is advantageously provided with a sterilization unit 48, which exhibits, for example, a steam generator 50, which is connected by an inflow pipe 52 with a fresh water source, not shown. This steam generator 50 is connected by a discharge pipe 54 with inflow pipes 16, 18, and a shutoff arrangement 56 in the form of a three-way valve is placed on the junction point. This shutoff arrangement 56 is connected by a signal line 58 also with control unit 42.
i Downstream from mixing chamber 20, a collecting chamber 60, which is provided for receiving rinsing agent solutions and the 7. 5 like, goes from discharge pipe 22. This collecting chamber 60 is also connected with discharge pipe 22 by a shutoff arrangement 62 in the form of a three-way valve.
The activation of shutoff device 62 takes place in this case over a signal line 64 by control unit 42.
Further, a discharge valve 66 can be provided on the end of discharge pipe 22, which also is connected by a signal line 68 with control unit 42. Finally, steam generator 50 is connected by a signal line 51 with control unit 42.
Device 10 shown in figure 1 can exhibit in both containers 12 and 14 the above-mentioned concentrates and diluents. In this way, device 10 is nct limited to both containers 12 and 14, but it can exhibit a plurality of these containers, which each are connected with the mixing chamber by separate feed pipes, in which the respectively suitable shutoff or metering elements are inserted.
Metering elements 26, 28 and 30 used in inflow pipes 16 and 18 and in discharge pipe 22 operate because of the gravitational force principle, i.e., -in the active state, metering elements 26, 28 and 30 are open and in the opening period let the fluids respectively present upstream pass through. ,As a consequence, they act as shutoff devices. They can therefore be replaced equally by other metering devices, for example, peristaltic pumps, which work in the nonactivated state as shutoff elements and in the activated state can convey the fluid respectivel,y~
present upstream: i Device 10 shown in figure 1 is operated as follows:
16 ~ J-. ,m,,.,m,.~i ,a ~o~
i fu ~.. ~ r i ~"
The contrast medium present in container 10 exhibits --- as initially described -- a specific composition and concentration.
Both the contrast medium used and its concentrate concentration can be input by input unit 44 into control unit 42. To produce a finished usable contrast medium in mixing chamber 20, the operator has to feed the amount of the contrast medium to be mixed by feeding unit 44, whereupon the control unit calculates from the desired contrast medium concentrate and the diluent in each case the amounts to be conveyed from containers 12 and 14 into the mixing chamber. Metering elements 26 and 28 are then opened in succession, and the respective fluids flow from container 12 or 14 into mixing chamber 20. In this case the content of mixing chamber 20 is monitored by weighing machine 32, which after reaching the first amount determined by control unit 40, for example, the concentrate amount, closes metering element 26 and activates metering element 28. After reaching the second setpoint amount in mixing chamber 20, second metering element 28 is deactivated.
Then, third metering element 30 and optionally outlet valve 66 are activated, to convey either a part or the entire content of contrast medium, which is contained in mining chamber 20, to outlet 24 of discharge pipe 22. Consequently, third metering element 30 can be used not only for the production of a preparation but rather also of several preparations from mixing chamber 20.
Since a sterile filter 46 is provided downstream from metering element 30, all units which are present upstream from this sterile filter 46 remain in the sterilized state.
After emptying mixing chamber 20 or containers 12 and 14, entire device 10 is sterilized by sterilization unit 48, and steam having a sterilizing effect is conveyed by entire pipe arrangement 16, 18, 22, mixing chamber 20 and sterile filter 46 up to collecting chamber 60.
It is to be added that weighing unit 32 for determining the fluid amounts flowing into mixing chamber 20 can be replaced by a volume measuring unit.
Finally, in inflow pipe 52 for fresh water, a pyrogenic filter 70 can also be provided, which optionally effectively retains pyrogens present in inflowing water. This sterile water can also be used as the diluent in container 14 for flushing purposes in a separate flushing process.
Translator s note: The translation of °'Gadopentetat," first appearing in the first line on page 6 of the German text, was not found in available sources. The term appears in the German spelling in the translation on page 4, line 5 of second paragraph from bottom, arid on page 12, line 12 from bottom.
The invention relates to a process for the production of a contrast medium in usable dosage forms. It further relates to a device for the production of an administrable contrast medium consisting of at least one concentrate and at least one diluent.
Contrast media have become important auxiliary agents for diagnostic processes, such as ultrasonic, x-ray or nuclear resonance diagnoses. Thus, for example, the administration of a contrast medium to a patient improves the evaluation of an x-ray image, since as a result, higher--contrast images are obtained.
Because of this fact, the medical personnel can better evaluate the data made available by such an image.
Regarding the dosage, numerous factors are to be considered in the determination of the dosage amount and dosage concentration of the contrast medium to be administered, for example, the type of the diagnostic examination used, how this diagnostic examination is performed, the k~ody area of the patient to be tested as well as the age, the body weight and the state of health of the patient. In view of these numerous factors, contrast media, such as x-ray contrast media, can be obtained in a number of concentrations, for example, 120-400 mg of I/ml, and in a plurality of dosage amounts, for example, 1 ml-250 ml.
Despite the numerous concentrations and dosage amounts, however, not every individual situation of the individual patient can be taken into account.
Despite this multiplicity ofidosages, which are commercially available (concentrations and sizes), it is often unavoidable r3 >~n~1r. ~i rd ~. ~ :J ?
in clinical use that only a partial amount is necessary for the test and the remaining amount is discarded. A reuse is excluded in this connection, since this would represent a contraindication.
Because of the numerous diagnostic tests and the high prices of modern contrast media, however, such a waste represents a considerable cost factor for clinical practice or medical practice. In addition, numerous forms of contrast media have to be kept in stock, by which the stand-by costs increase considerably. In the cases in which a new testing technique requires new forms of preparation, the often long time intervals for the development and approval of new bottle sizes and/or concentrations also represent a drawback.
In thelsame manner, the plurality of forms of administration of contrast media on the production side also represents a drawback, since only relatively small production batches can be produced, the storage requirement is increased, the logistics are difficult, and more expensive and extended development and approval times are the result. In addition, only little:
flexibility in the contrast media production exists for changes of the preparation forms, as they are required by the market.
These drawbacks have not been eliminated to this day.
In the pharmaceutical field, a plurality of filling devices are known, with which solutions can be mixed in portions, for' example, from WO 84/00139 or De-OS 33 15 031.
WO 84/00139 thus describes a mixing device, which exhibits suitable agents for monitoring the filling of pharmaceutical solutions. In this way, solutions ar<~ filled, which are taken from various cc>ntairm,:rs. F3ut: a spec:i fic mixture to guarantee uniform concentr:~ti~:>na in the finished, solution appropriate to use does not occur_ Also, only infusion ~;o:Lut icns E<:~r ipar~ent:eral feeding are mixed with the mixing device known cram DF-OS 33 15 031, without reference being made to the pr<obl.ems of the production of cc>ntrast medic.zm solutic>n:>.
Moreover, both known devi_c~~s are not suitable for mixing liquids with greatly di.f_ferE.mt cler~sities, single a simple bringing together ~:of such liquids does not r_ause a uniformly diluted soluti~~n, as is necessary for the mcsntioned uses .
The object. of the i:n~~~ention therefore i.s to make available a process of t:~f, above-mentr~oned type, with which patient-specific, indica L c orl-:~peci t is ~~ont cast medium compositions with appropriate dosage can be produced, without a plurality of f~.~a:ms ~;f admina. ~tration having to be kept ready for use and/o:r considerable amo~.~nts of waste occurring.
Moreover, contrast mE~ciia and opt:i.~~rlally desired "additives" can be administ.erod in one dosage by which the comfort for the patient :Ls increased.
The present invention provider a process for the production of a diagnostic contrast. medium comprising at lE:ast one contrast agent anc-1 an aqueous solution, the process comprising delive~-i.ng, under st~eri 1_e conditions, a predetermined amount of at= least: a first contrast medium concentrate containing 3'~0-45() mg of IJm:l <>f X-ray contrast accent, 0.5-4 mol of NMR c:cynt_rast agent!1_:iter, or an ultrasound contrast agent., from at least a first container by a first pipe to a mix:i_rog cr:amber, deli.vc>rinc~ a predetermined amount of c~ii_luent from a se:~c:md cJontainer by a second pipe to the mixing cruan~ber, wherein the .i 8 predetermined amounts ar~~ rni~.ed tc> form <~ phy:~iologic.ally compatible preparation, an<v d~~li..vfer::inca tloc;~ re:>ui_tant.
mixture to a di scharge :~t~~t i.c.~n .
The present invention also provides <i devic:e for production of a contrast medium, the alevic°e comprising at least one concentrate container contairoinc~ concentrated contrast media, at least c>ne dil.uerot cvonta:ainer containing a diluent suitable for use with contrast mecvl:i.a, a first feed pipe and a second feed pipc> in connect: i.orr with, respectively, the concentrate container and the diluent container, the feed pipes also being in f=lui_d communication with a mixing chamber, a delivery pipe in fluid communication with the fecad pipes, a rn:ixi.ng ch.arruber provided between the feed pipes and tr~f:a dE:livery pipe, metering elements in the feed pipes wl~:ich meter, respectively, predetermined a°.nounts of the concentrated contrast media and the diluent, means for determination of mitered amounts of the concentrated cc-_>rntrast media and the diluent, metering device iro t'~oe del.i..vrm:y pipe, which discharges contrast medium from an end of t:he delivery pipe, and control unit which _ontrols i::he metering elements.
The present invention also provides a kit for p=roduction of a contrast rnedi~.~rn, comprising a concentrate containing 350-450 mg of I/ml of X-ray contrast agent, 0.5-4 mol/liter of NMR corrt:rast agent c:~r a concentrated ultrasound contrast agent, in a first container with a volume of 0.1-100 1, and an a~~lueous di.l.uent in a second container with a content of 1-100 liters.
In the process accerciinct to the invention, one or more contrast; medium conce~nt rates <rre used in suitable containers, which are flowab.l.e and highly concentrated. These concentrates are used in the form of solutions, dispersions or as fl.owable ° ~~~aMw~~y~,~ °.'~
ac:~ ~.. ~' a a .~. .
(free-flowing) powders and are introduced in suitable concentrate containers.
In addition, one or more diluents are used fox mixing with the concentrates, for example, sterile or unsterile water. But on the other hand, pharmaceutical solutions can also be used as diluents and/or solvents or dispersing agents for the dilution of the concentrate. Finally, even diluted contrast medium solutions can be used for mixing with the contrast medium concentrates.
The contrast medium concentrates can exhibit concentrations which lie above the values which were produced previously for administration reasons (e.g., viscosity). Thus, for example, x-ray contrast medium concentrates with a content of 350-450 mg of I/ml are used or NMR contrast media in solution or dispersion with 0.5 mol/liter in the form of Gadopentetat-dimeglumines or other NMR contrast media based on paramagnetic ions. But different contrast medium concentrates can also be used for different medical techniques, for example, for x-ray, nuclear resonance or ultrasonic diagnosis.
If the contrast medium concentrates are present in,powder form, these powders can consist to 100% of the respective contrast medium or optionally contain other solid galenical auxiliary agents (which, e.g., improve the flowability of the contrast medium).
The weight ratio of contrast medium to auxiliary agent can be selected at will.
X-ray contrast media can contain, for example, iotrolan, iopromide, iohexol, iosimide, metrizamide, salts of amidoacetic dal <.. .7 .l v) .x.
acid, iotroxic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodo-isophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5-[N-{2-hydroxyethyl)-acetamido]-2,4,6-triiodo-benzoic acid-[(1RS,2SR)-2,3-dihydroxy-1-hydroxymethylpropyl]amide and dispersions of slightly soluble x-ray contrast media, such as iodipamide ethyl ester.
For example, gadolinium DTPA, gadolinium DOTA, the gadolinium complex of 10(1-hydroxymethyl-2,3-dihydroxypropyl]-1,4,7-tris-[(carboxymethyl)-1,4,7,10-tetraazacyclodecane], iron or manganese porphyrin chelates and stable magnetite dispersions belong to NMR contrast media.
For example, dispersions of galactose microparticles with or without additives in water or a galactose solution and dispersions of microbeads of enclosed air (for example, cyanacrylates or albumin microbeads) as well as other injectable microparticles belong to ultrasonic contrast media.
According to the process of the invention, a predetermined amount of contrast medium concentrate is mixed with a predetermined amount of diluent and optionally other additives to formulate the desired dosage form of the contrast medium.
Contrast media can also be mixed with ol~e another for different fields of use. In this way, two or more different tests can be performed on patients with only one dosage, which represents a marked improvement of the comfort of the patient..
Such a mixture of two or more~contrast media is usually consumed immediately after the mixings so that no stability problems occur.
s 9~.a~~~~?rv~y~J~r~
As diluent, for example, a physiologically compatible liquid vehicle is suitable which contains optionally usable additives.
Thus, for example, as diluent, sterile or unsterile water can be used, which optionally exhibits buffer substances and/or additives having an isotonic effect, as well as optionally complexing agents, such as CaNa2EDTA.
As diluent, a comparatively less concentrated contrast medium can also be used, for example, in a concentration of 0--0.5 mol/1 or 0-350 mg of I/1 or 0-100 mg of particles/ml.
Usable additives are, for example, inorganic or organic salts or buffer substances, such as sodium chloride, Iris-buffer, phosphate buffer, citrate buffer, glycine buffer, citrate phosphate buffer, maleate buffer and the like. Further, they include monosaccharides or disaccharides, such as glucose, lactose, saccharose or trehalose, sugar alcohols, such as mannitol, sorbitol, xylite or glycerol, or water-soluble polymers, such as dextrans or polyethylene glycols.
The process according to the invention can further be used for the production of dosage forms which are usable for:,a plurality of administration techniques, for example, for intravascular, subarachnoid, intraneural and. oral administration.
Further, the process according to the invention makes possible, depending on the diagnostic formulation of the problem, a concentration or volume change of the contrast medium in the course of the administration.
Thus, different concentrations or volumes automated in succession can be produced and administered in situ.
Also, it is possible to change the originally provided dosage form during the test relative to concentration or volume if the originally administered dose still was not able to produce the desired diagnostic result.
The contrast medium concentrate is present in a flowable form, for example, as solution, dispersion or powder. In the last-mentioned case, the solvent can act as solvating agent and/or dispersion medium.
The device according to the invention for performing the process according to the invention first exhibits at least one contrast medium concentrate container and at least one diluent container. A predetermined amount of fluid is removed in each case from these containers, and the removal can be performed either simultaneously or successively. The respectively removed predetermined amounts of fluid are fed to a mixing zone or a mixing chamber, in which both fluids are mixed, and a uniform contrast medium in the usable dosage farm is achieved. The concentrate container and the diluent container are each connected by pipes with the mixing zone. The conveying:of the fluids can take place either automatically because of the effect of gravity or by active pumping action by a pump, for example, a vacuum pump or a peristaltic pump.
If the conveying takes place under the effect of gravity, in each case shutoff devices, far example, valves, are provided in the inflow pipes to the mixing zone, which are activated by a control unit in a predetermin,sd way. In this way, the amount of the fluid present in the respective container and the pipe cross ~~~ r~~N'1~y ~ '~~
P~ __~ a' J ~.a~.. .s section as well as the pipe length determine the amount of inflowing fluid as well as the inflow rate of the fluid.
:If, however, pumps axe used, a peristaltic pump in the non-activated state acts as a shutoff unit, but in the activated state pumps the fluid from the respective container to the mixing zone. If the fluid is pumped into the mixing zone with the help of a vacuum, shutoff elements are again placed in the inflow pipes, which are activated together with the vacuum unit.
The inflow pipes can be connected either directly with the mixing chamber or else also can be combined in front of the mixing chamber, and a single pipe goes from the junction point to the mixing chamber, so that a Y-connection is made.
The above-described pump and shutoff devices usually do not operate precisely enough, so that for the precise determination of the amount and the concentration of the dosage form, advantageously a unit for the determination of the amounts of fluid is provided, with which the amount of fluid removed from the respective container can be determined. Such units include, for example, flow sensors in the inflow pipes, with which the amount of fluid that has flowed through per unit of time can be determined. On the other hand, weighing machines can also be used, which determine either the increase of the amounts of fluid in the mixing chamber or else the respective reduction of the amounts of fluid in the respective container. Finally, volumetrically operating units can also be placed in the mixing chamber or the output container, with which the inflowing volume or the outflowing volumes can be determined.
s~ ~'~i x ~ ~~a .bra.
In each case, the outflawing or inflowing amounts of fluid or fluid volumes can be determined exactly with these sensors as a function of the activation time of the shutoff elements or pumps. These sensors are electrically linked with the control unit and send suitable signals as respective actual value to the control unit.
From the signals sent, the control unit itself calculates the respective amounts, volumes and/or concentrations of the conveyed materials or the mixture actually contained in the mixing chamber. 2t is known that desired concentrations of the form of administration can be securely controlled by the specific density or densities of the contrast medium compound or compounds used.
In iodized x-ray contrast media, a high density typically occurs. Here, the density can be used as a usable indicator for the determination of the concentration. In such a case, a density sensor is provided inside the mixing chamber. On the other hand, the optical rotation can also be a usable determination parameter. Of course, volumetric or grava~metric determination parameters, i.a., can also be used.
As stated above, the actual signal for the control unit is used to control the pumps or the shutoff elements as a function of a previously adjusted setpoint value; which can,be manually input in the control unit by an input unit.
The control unit sends suitable control signals to operate the shutoff elements and pi.~mps and receives the sensor signals, which pertain to the amounts of fluid which have been removed ' ~ io ~-j~-~t- ~ a from the containers and/or have been supplied to the mixing chamber.
Further, the mixing chamber can be connected by a discharge pipe with a means for administering the contrast medium, for example, hypodermic syringes, which are filled in succession with the contrast medium in the desired dosage form. Finally, the mixing chamber can be connected as an alternative with one or more containers for storage of one or more cartridges for pressure injectors or can be connected directly to a patient for a direct infusion.
Tha discharge pipe going from the mixing chamber is in this case also provided with a shutoff element, which is closed during the mixing process and is opened only for filling purposes.
According to another advantageous embodiment, the feed pipe arrangement is connected with an additional container, which exhibits a cleaning and flushing liquid. As a result, the pipes, shutoff elements, pumps, the mixing chamber, the collecting chamber, the receiving container and the like can be flushed. As liquid, every suitable cleaning medium can be suitable for this purpose, for example, sterile or nonsterile water with or~without additives. In addition, the diluent itself pan be used as flushing fluid.
The arrangement according to the invention can further be connected with a collecting chamber, in which the fluid used during the cleaning stage can be collected.
The mixing chamber can be connected with empty containers, which are closed, for example, by a septum. In such sterile ~~1 J~ .J~~~t., A
containers, the contrast medium is kept in its dosage form. Iri this case, sterile infusion or injection bottles made of plastic or glass are suitable, as also infusion bags.
According to another embodiment, the arrangement according to the invention can be connected directly to an extruder, with which suitable plastic containers are produced. Finally, the arrangement can be used for the purpose that such empty containers or a hypodermic syringe axe filled directly or else a direct infusion can be performed on the patient.
According to another advantageous embodiment, the arrangement according to the invention is connected with a sterilization unit. Such a sterilization unit can exhibit, for example, a steam generator, which is connected by a connecting pipe with the entire pipe arrangement and the shutoff element, pumps and the containers, etc. On the other hand, as a sterilization unit, a liquid disinfectant, for example, peracetic acid, can also be used, and after the sterilization process, attention must be paid that any possible disinfectant residues are removed with sterile water. Finally, the sterilization of the arrangement according to the invention is performed less often that the flushing.
The contrast medium concentrate container can exhibit any desired size, for example, 0.1-100 1, especially about 1 l, 5 1, l, 50 1 and the like. The containers can be produced from any suitable material which is suitable for storing the concentrated pharmaceutically acceptable,contrast medium and, for example, thermally stable plastic, glass or metal advantageously can be ~~y'~.~ ~
sterilized. These containers can either be reusable or else suitable only for one-time use.
Advantageously, the sterilized device is kept in sterilized state with the help of a sterile filter placed in the pipe sections. In addition, the mixing effect in the mixing zone or mixing chamber can be improved in that a stirring device is provided in the mixing zone or mixing chamber.
The contrast medium is present inside the container in high concentration. A solution with a concentration which is either equal to or higher than that of commercially available dosage forms of the contrast medium is considered as a concentrated solution and/or dispersion. As the example of an iodized x-ray contrast medium, the concentration of the contrast medium in the receiving container is in an amount of about 350-450 mg of I/ml.
In NMR contrast media, for example, in Gadopentetat dimeglumines (dimeglumines Gd-DTPA), the commercially available concentration is usually at about 0.5 moll. Consequently, concentrated solutions or dispersions of the NMR contrast medium exhibit an equal or higher concentration content, for dissolved concentrates, for example, greater than or equal to 0.5 mol/1, especially a content of 0.5-4 mol/1. , Although with the process according to the invention, a usable dosage form is preferably produced from a concentrated contrast medium, it is also possible to use the process according to the invention for reducing the concentration of commercially available dosage forms of contrast media.
According to another embodiment of the invention, a set is made available which can be used in connection with the above-described system for formulating usable dosage forms of contrast media. Such a set exhibits a first container with a specific contrast medium and a second container with a specific suitable diluent. These containers of the set preferably have means for connection with the device according to the invention to transfer predetermined amounts of fluid from each of the containers to the mixing chamber. A set can exhibit, for example, the first container with 0.1-100 liters of a concentrated x-ray contrast medium with a concentration of 350-450 mg of I/ml and a second container with 1-100 liters of diluent, which is suitable for the formulation of an x-ray contrast medium in pharmaceutically acceptable forms. On the other hand, the set can also contain a first container with 100 ml to 100 liters of an NMR contrast medium with a concentration of 0.5-4 mol per liter.
The invention is explained based on an embodiment.
Figure 1 shows a basic sketch of the mixing arrangement according to the invention.
Device 10 shown in figure 1 exhibits a container 12 for a contrast medium concentrate and a container ~.4 .for a solvent or diluent. Both containers 12 and 14 are connected by inflow pipes 16 and 18 with a mixing chamber 20. In the example, both pipes 16 and 18 are brought together in a single pipe 19 upstream from mixing chamber 20, a pipe which then ands in mixing chamber 20.
But such a connection is not necessary. Consequc;ntly, both pipes 16 and 18 can also be connected directly with mixing chamber 20.
~..~ ~ J~ ~ ~~.. ~
A discharge pipe 22, whose ends 24 can be connected with receiving containers (bottles, bags or syringe arrangements), not shown originates from mixing chamber 20.
A first metering element 26 is inserted in first inflow pipe 16, and a second metering element 28 is inserted in second inflow pipe 18. In addition, a third metering element 30 is inserted in discharge pipe 22.
Mixing chamber 20 is connected with a weighing device 32, which can determine the respective present weight condition of mixing chamber 20.
Metering elements 26, 28 and 30 as well as weighing device 32 are connected by signal lines 36-40 with a control unit 42.
Control unit 42 further exhibits an input unit 44, with which certain data can be input into control unit 42.
According to an advantageous embodiment, a sterile filter 46 is provided downstream from third metering element 30 in discharge pipe 22.
In addition, device 10 is advantageously provided with a sterilization unit 48, which exhibits, for example, a steam generator 50, which is connected by an inflow pipe 52 with a fresh water source, not shown. This steam generator 50 is connected by a discharge pipe 54 with inflow pipes 16, 18, and a shutoff arrangement 56 in the form of a three-way valve is placed on the junction point. This shutoff arrangement 56 is connected by a signal line 58 also with control unit 42.
i Downstream from mixing chamber 20, a collecting chamber 60, which is provided for receiving rinsing agent solutions and the 7. 5 like, goes from discharge pipe 22. This collecting chamber 60 is also connected with discharge pipe 22 by a shutoff arrangement 62 in the form of a three-way valve.
The activation of shutoff device 62 takes place in this case over a signal line 64 by control unit 42.
Further, a discharge valve 66 can be provided on the end of discharge pipe 22, which also is connected by a signal line 68 with control unit 42. Finally, steam generator 50 is connected by a signal line 51 with control unit 42.
Device 10 shown in figure 1 can exhibit in both containers 12 and 14 the above-mentioned concentrates and diluents. In this way, device 10 is nct limited to both containers 12 and 14, but it can exhibit a plurality of these containers, which each are connected with the mixing chamber by separate feed pipes, in which the respectively suitable shutoff or metering elements are inserted.
Metering elements 26, 28 and 30 used in inflow pipes 16 and 18 and in discharge pipe 22 operate because of the gravitational force principle, i.e., -in the active state, metering elements 26, 28 and 30 are open and in the opening period let the fluids respectively present upstream pass through. ,As a consequence, they act as shutoff devices. They can therefore be replaced equally by other metering devices, for example, peristaltic pumps, which work in the nonactivated state as shutoff elements and in the activated state can convey the fluid respectivel,y~
present upstream: i Device 10 shown in figure 1 is operated as follows:
16 ~ J-. ,m,,.,m,.~i ,a ~o~
i fu ~.. ~ r i ~"
The contrast medium present in container 10 exhibits --- as initially described -- a specific composition and concentration.
Both the contrast medium used and its concentrate concentration can be input by input unit 44 into control unit 42. To produce a finished usable contrast medium in mixing chamber 20, the operator has to feed the amount of the contrast medium to be mixed by feeding unit 44, whereupon the control unit calculates from the desired contrast medium concentrate and the diluent in each case the amounts to be conveyed from containers 12 and 14 into the mixing chamber. Metering elements 26 and 28 are then opened in succession, and the respective fluids flow from container 12 or 14 into mixing chamber 20. In this case the content of mixing chamber 20 is monitored by weighing machine 32, which after reaching the first amount determined by control unit 40, for example, the concentrate amount, closes metering element 26 and activates metering element 28. After reaching the second setpoint amount in mixing chamber 20, second metering element 28 is deactivated.
Then, third metering element 30 and optionally outlet valve 66 are activated, to convey either a part or the entire content of contrast medium, which is contained in mining chamber 20, to outlet 24 of discharge pipe 22. Consequently, third metering element 30 can be used not only for the production of a preparation but rather also of several preparations from mixing chamber 20.
Since a sterile filter 46 is provided downstream from metering element 30, all units which are present upstream from this sterile filter 46 remain in the sterilized state.
After emptying mixing chamber 20 or containers 12 and 14, entire device 10 is sterilized by sterilization unit 48, and steam having a sterilizing effect is conveyed by entire pipe arrangement 16, 18, 22, mixing chamber 20 and sterile filter 46 up to collecting chamber 60.
It is to be added that weighing unit 32 for determining the fluid amounts flowing into mixing chamber 20 can be replaced by a volume measuring unit.
Finally, in inflow pipe 52 for fresh water, a pyrogenic filter 70 can also be provided, which optionally effectively retains pyrogens present in inflowing water. This sterile water can also be used as the diluent in container 14 for flushing purposes in a separate flushing process.
Translator s note: The translation of °'Gadopentetat," first appearing in the first line on page 6 of the German text, was not found in available sources. The term appears in the German spelling in the translation on page 4, line 5 of second paragraph from bottom, arid on page 12, line 12 from bottom.
Claims (22)
1. A process for the production of a diagnostic contrast medium comprising at least one contrast agent and an aqueous solution, said process comprising:
delivering, under sterile conditions, a predetermined amount of at least a first contrast medium concentrate containing 350-450 mg of I/ml of X-ray contrast agent, 0.5-4 mol of NMR contrast agent/liter, or an ultrasound contrast agent, from at least a first container by a first pipe to a mixing chamber;
delivering a predetermined amount of diluent from a second container by a second pipe to the mixing chamber, wherein said predetermined amounts are mixed to form a physiologically compatible preparation; and delivering the resultant mixture to a discharge station.
delivering, under sterile conditions, a predetermined amount of at least a first contrast medium concentrate containing 350-450 mg of I/ml of X-ray contrast agent, 0.5-4 mol of NMR contrast agent/liter, or an ultrasound contrast agent, from at least a first container by a first pipe to a mixing chamber;
delivering a predetermined amount of diluent from a second container by a second pipe to the mixing chamber, wherein said predetermined amounts are mixed to form a physiologically compatible preparation; and delivering the resultant mixture to a discharge station.
2. A process according to claim 1, wherein said concentrate is in liquid, dispersion or powder form.
3. A process according to claim 1 or 2, wherein said contrast agent is iotrolan, iopromide, iohexol, iosimide, metrizamide, a salt of amidoacetic acid, iotroxic acid, iopamidol, 5-hydroxyacetamido-2,4,6-triiodoisopththalic acid- (2, 3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5-[N-(2-hydroxyethyl)-acetamido]
-2,4,6-triiodobenzoic acid-[(]RS, 2RS)-2,3, -dihydroxy-1-hydroxymethylpropyl]-amide, dispersions of iodipamide ethyl ester, gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10 [1-hydroxymethyl-2, 3-dihydroxypropyl]-1,4,7-tris [(carboxymethyl) -1,4,7,10-tetrazayclodecane], an iron porphyrin chelate, a manganese porphyrin chelate, a stable magnetite dispersion, an aqueous dispersion of clalactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.
-2,4,6-triiodobenzoic acid-[(]RS, 2RS)-2,3, -dihydroxy-1-hydroxymethylpropyl]-amide, dispersions of iodipamide ethyl ester, gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10 [1-hydroxymethyl-2, 3-dihydroxypropyl]-1,4,7-tris [(carboxymethyl) -1,4,7,10-tetrazayclodecane], an iron porphyrin chelate, a manganese porphyrin chelate, a stable magnetite dispersion, an aqueous dispersion of clalactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.
4. A process according to claim 3, wherein the microspheres are cyanoacrylate microspheres or albumin microspheres, or both.
5. A process according to any of of claims 1 to 4, wherein said diluent is water or an aqueous solution.
6. A process according t.o any one of claims 1 to 4, wherein said diluent is an aqueous medium containing at least one substance selected from the group consisting of 0-0.5 mol/1 of NMR contrast agent, 0-350 mg of I/ml of X-ray contrast agent, a medicinally active substance, a buffer substance, an isotonically active additive, and a complexing agent.
7. A process according to any one of claims 1 to 6, wherein said first contrast medium concentrate and said diluent are conveyed to said mixing chamber by gravity.
8. A process according to any one of claims 1 to 6, wherein said first contrast medium concentrate and said diluent are conveyed to said mixing chamber by pump.
9. A process according to any one of claims 1 to 8, wherein said first pipe and said second pipe are joined together upstream of the mixing chamber at a junction point and a single pipe connects said junction point to said mixing chamber.
10. A device for production of a contrast medium, the device comprising:
at least one concentrate container containing concentrated contrast media;
at least one diluent container containing a diluent suitable for use with contrast media;
a first feed pipe and a second feed pipe in connection with, respectively, said concentrate container and said diluent container, said feed pipes also being in fluid communication with a mixing chamber;
a delivery pipe in fluid communication with said feed pipes;
a mixing chamber provided between said feed pipes and said delivery pipe;
metering elements in said feed pipes which meter, respectively, predetermined amounts of said concentrated contrast media and said diluent;
means for determination of metered amounts of said concentrated contrast media and said diluent;
metering device in said delivery pipe, which discharges contrast medium from an end of said delivery pipe; and control unit which controls said metering elements.
at least one concentrate container containing concentrated contrast media;
at least one diluent container containing a diluent suitable for use with contrast media;
a first feed pipe and a second feed pipe in connection with, respectively, said concentrate container and said diluent container, said feed pipes also being in fluid communication with a mixing chamber;
a delivery pipe in fluid communication with said feed pipes;
a mixing chamber provided between said feed pipes and said delivery pipe;
metering elements in said feed pipes which meter, respectively, predetermined amounts of said concentrated contrast media and said diluent;
means for determination of metered amounts of said concentrated contrast media and said diluent;
metering device in said delivery pipe, which discharges contrast medium from an end of said delivery pipe; and control unit which controls said metering elements.
11. A device according to claim 10, wherein the end of said delivery pipe is connected to a container or a syringe for receiving the resultant contrast medium.
12. A device according to claim 10 of 11, wherein said device further comprises shut-off elements in said first feed pipe, said second feed pipe and said delivery pipe, and wherein said control unit also controls said shut-off elements.
13. A device according to claim 10, 11 or 12, wherein said means for determination is a weighing device connected to said mixing chamber and to said control unit.
14. A device according to any one of claims 10 to 13, wherein said first feed pipe and said second feed pipe are provided with flow sensors.
15. A device according to any one of claims 10 to 14, further comprising a density sensing means within said mixing chamber.
16. A device according to any one of claims 10 to 14, further comprising at least one temperature control means for controlling fluid temperature.
17. A kit for production of a contrast medium, comprising:
a concentrate containing 350-950 mg of I/ml of X-ray contrast agent, 0.5-4 mol/liter of NMR contrast agent or a concentrated ultrasound contrast. agent, in a first container with a volume of 0.1-100 l; and an aqueous diluent in a second container with a content of 1-100 liters.
a concentrate containing 350-950 mg of I/ml of X-ray contrast agent, 0.5-4 mol/liter of NMR contrast agent or a concentrated ultrasound contrast. agent, in a first container with a volume of 0.1-100 l; and an aqueous diluent in a second container with a content of 1-100 liters.
18. A kit according to claim 17, wherein the agent of said concentrate contains as compound iotrolan, iopromide, iohexol, iosimide, metrizamide, a salt of amidoacetic acid, iotroxic acid, iopamidol, 5-hydroxyacetamido-2,4, 6-triiodoisophthalic acid-(2,3-dihydroxy-N-methylpropyl)-(2-hydroxyethyl)-diamide, 3-carbamoyl-5[N-(2-hydroxyethyl) -acetamido]-2,4,6-triiodobenzoic acid[(1RS,2SR)-2, 3-dihydroxy-1-hydroxymethylpropyl]-amide, dispersions of iodipamide ethyl ester, gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10[1-hydroxymethyl-2, 3-dihydroxypropyl]-1,4,7-tris[(carboxymethyl)-1,4,7, 10-tetraazacyclodecane], an iron porphyrin chelate, a manganese porphyrin chelate, a stable magnetite dispersion, an aqueous dispersion of galactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.
19. A kit according to claim 17, wherein said first container contains 1-100 liters of concentrated X-ray contrast agent at a concentration of 350-450 mgI/ml, and said second container contains 1-100 liters of said diluent.
20. A kit according to claim 17, wherein said NMR contrast agent is gadolinium DTPA, gadolinium DOTA, gadolinium complex of 10[1-hydroxymethyl-2,3-dihydroxypropyl]1,4, 7-tris[(carboxymethyl)-1,4,7,10-tetraaracyclododecane], or an iron porphyrin chelate, a manganese poxphyrin chelate, or a stable magnetite dispersion.
21. A kit according to claim 17, wherein said ultrasound contrast agent is an aquepous dispersion of galactose microparticles, a galactose solution, or a dispersion of microspheres containing trapped air.
22. A kit according to claim 21, wherein the microspheres are cyanoacrylate microspheres or albumin microspheres, or both.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US68892291A | 1991-04-22 | 1991-04-22 | |
| EP92250170.5 | 1992-06-29 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CA2077712A1 CA2077712A1 (en) | 1993-12-30 |
| CA2077712C true CA2077712C (en) | 2003-06-17 |
Family
ID=24766346
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002077712A Expired - Fee Related CA2077712C (en) | 1991-04-22 | 1992-09-08 | Process and device for the production of a contrast medium from a concentrate |
Country Status (7)
| Country | Link |
|---|---|
| EP (1) | EP0576740B1 (en) |
| JP (1) | JPH069435A (en) |
| AT (1) | ATE168888T1 (en) |
| CA (1) | CA2077712C (en) |
| DE (1) | DE4121568C2 (en) |
| DK (1) | DK0576740T3 (en) |
| ES (1) | ES2121816T3 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11724022B2 (en) | 2017-12-20 | 2023-08-15 | Ge Healthcare As | Tailored dose of contrast agent |
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| US5827219A (en) * | 1993-10-28 | 1998-10-27 | Medrad, Inc. | Injection system and pumping system for use therein |
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| EP0692766B1 (en) * | 1994-07-12 | 2002-05-08 | Medrad, Inc. | Closed loop information path for medical fluid delivery systems |
| US5840026A (en) * | 1994-09-21 | 1998-11-24 | Medrad, Inc. | Patient specific dosing contrast delivery systems and methods |
| DE19648650C2 (en) * | 1996-01-29 | 1998-07-02 | Schering Ag | Buffer systems and their use to stabilize pharmaceutical preparations |
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| JP2008500119A (en) * | 2004-05-27 | 2008-01-10 | イー‐ゼット‐イーエム，インコーポレイテッド | Systems, methods and computer program products for handling, mixing, dispensing and injecting radiopharmaceuticals |
| EP1812101A4 (en) | 2004-11-16 | 2014-04-23 | Medrad Inc | Modeling of pharmaceutical propagation |
| DK2990073T3 (en) | 2004-11-24 | 2018-08-13 | Bayer Healthcare Llc | DEVICES AND SYSTEMS FOR DELIVERING FLUIDS |
| JP5486315B2 (en) | 2006-12-29 | 2014-05-07 | メドラッド インコーポレーテッド | System for generating patient-based parameters for medical infusion procedures |
| CN103976736B (en) | 2007-07-17 | 2017-01-11 | 拜耳医药保健有限责任公司 | Devices and systems for determination of parameters for a procedure, for estimation of cardiopulmonary function and for fluid delivery |
| ITFI20080186A1 (en) * | 2008-09-30 | 2010-04-01 | Maspres Di Alfredo Speranzi | MSA MIXER 206 |
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| JP6516584B2 (en) * | 2015-06-22 | 2019-05-22 | 大陽日酸株式会社 | Contrast agent supply device |
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| US11478581B2 (en) | 2017-08-31 | 2022-10-25 | Bayer Healthcare Llc | Fluid injector system volume compensation system and method |
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| US4467844A (en) * | 1982-06-24 | 1984-08-28 | Baxter Travenol Laboratories, Inc. | Flow monitoring method and apparatus |
| DE3315031C2 (en) * | 1983-04-26 | 1985-09-05 | Pfrimmer-Viggo GmbH & Co KG, 8520 Erlangen | Method and device for producing mixtures of pharmaceutical liquids |
-
1991
- 1991-06-29 DE DE4121568A patent/DE4121568C2/en not_active Expired - Fee Related
-
1992
- 1992-06-29 EP EP92250170A patent/EP0576740B1/en not_active Expired - Lifetime
- 1992-06-29 AT AT92250170T patent/ATE168888T1/en not_active IP Right Cessation
- 1992-06-29 ES ES92250170T patent/ES2121816T3/en not_active Expired - Lifetime
- 1992-06-29 DK DK92250170T patent/DK0576740T3/en active
- 1992-09-07 JP JP4237869A patent/JPH069435A/en active Pending
- 1992-09-08 CA CA002077712A patent/CA2077712C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11724022B2 (en) | 2017-12-20 | 2023-08-15 | Ge Healthcare As | Tailored dose of contrast agent |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2121816T3 (en) | 1998-12-16 |
| JPH069435A (en) | 1994-01-18 |
| EP0576740B1 (en) | 1998-07-29 |
| DE4121568A1 (en) | 1992-10-29 |
| DK0576740T3 (en) | 1999-04-26 |
| DE4121568C2 (en) | 1997-07-03 |
| EP0576740A1 (en) | 1994-01-05 |
| ATE168888T1 (en) | 1998-08-15 |
| CA2077712A1 (en) | 1993-12-30 |
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