WO1994026316A1 - Parenterally administerable oil-in-water emulsion for use as an x-ray contrasting agent which is stable under heat-sterilization conditions - Google Patents

Parenterally administerable oil-in-water emulsion for use as an x-ray contrasting agent which is stable under heat-sterilization conditions Download PDF

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Publication number
WO1994026316A1
WO1994026316A1 PCT/EP1994/001470 EP9401470W WO9426316A1 WO 1994026316 A1 WO1994026316 A1 WO 1994026316A1 EP 9401470 W EP9401470 W EP 9401470W WO 9426316 A1 WO9426316 A1 WO 9426316A1
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WO
WIPO (PCT)
Prior art keywords
emulsion
mmol
sterilization
oil
sodium
Prior art date
Application number
PCT/EP1994/001470
Other languages
German (de)
French (fr)
Inventor
Klaus Sommermeyer
Heino Foth
Bernd Eschenbach
Original Assignee
Fresenius Ag
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority to DE19934316722 priority Critical patent/DE4316722A1/en
Priority to DEP4316722.5 priority
Application filed by Fresenius Ag filed Critical Fresenius Ag
Publication of WO1994026316A1 publication Critical patent/WO1994026316A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K49/00Preparations for testing in vivo
    • A61K49/04X-ray contrast preparations
    • A61K49/0433X-ray contrast preparations containing an organic halogenated X-ray contrast-enhancing agent
    • A61K49/0447Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is a halogenated organic compound
    • A61K49/0461Dispersions, colloids, emulsions or suspensions

Abstract

The invention concerns a parenterally administerable oil-in-water emulsion for use as an X-ray contrasting agent which is stable to sterilization by heat, the emulsion having an inner phase consisting of one or more suitable oil-soluble iodinated fatty-acid esters, optionally together with one or more highly refined glyceride oils, plus one or more emulsifiers and optionally co-emulsifiers, and an outer phase consisting of distilled water plus isotonization additives and a physiologically tolerable buffer made up of 0 to 12 mMol/l of sodium hydroxide and 2 to 10 mMol/l of sodium carbonate and/or sodium hydrogen carbonate, in each case relative to the volume of the made-up emulsion. The mean droplet size in the inner phase of the emulsion can be adjusted to any value over the range 0.2 to 4.0 νm, and the emulsion exhibits very good stability on storage and to heat, thus enabling it to be sterilized in an autoclave at 121 °C for 15 to 25 minutes.

Description

Parenterally administrable, stable under heat sterilization conditions O / W emulsion of an X-ray contrast agent

The invention relates to a parenterally administrable, under Hitze¬ sterilization conditions stable O / W emulsion of a Röntgenkontrast¬ means iodinated on the basis of fatty acid ester which, upstream in a suitable concentration, if necessary after appropriate dilution geous in diagnostic radiology, for example in the Lymphogra- chromatography , can be used .

From DE 41 11 939 C2 a parenterally administrable, heat-sterilizable O / W emulsion of an X-ray contrast agent has already sawn known, wherein the internal phase comprises one or more oil-soluble organi¬ specific iodine compounds and the external phase includes distilled water with Isotonisierungszusätzen. By the addition of a physiologically acceptable buffer system the supply of sodium hydroxide solution and disodium hydrogen phosphate and / or Dinatriumglycerophosphaten is sammengesetzt, it is possible to stabilize the emulsion so that they can be sterilized for 15 to 20 minutes at 121 ° C in an autoclave, without the of the emulsion is then undesirably affected. Thereafter, the finished emulsion to an average droplet diameter of the inner phase of at least 0.6 microns. At discussed in detail in the introduction to the DE 41 11 939 C2 the prior art, reference is expressly made in the other. Although the known emulsions described above have already proven successful in diagnostic radiology, it has been found in practice that a more secure handling of the X-ray contrast agent-containing O / W emulsions, especially during the sterilization phase and thereafter is desired. This assumes that one can compared to thermal Bela¬ stung at the sterilization temperatures of 120-121 ° C make the emulsions more stable, so that operational variations in the Sterilisationsbedingun¬ gen as they occur in daily operation, not on product characteristics impact undesirable. Thus, the Her¬ would be provision of such O / W emulsions in the required quality nor less critical and more feasible.

The present invention therefore has for its object to improve the stability of the X-ray contrast medium emulsions in particular in the Hi n¬ bl ick to heat sterilization at 120 to 121 ° C in the autoclave still further and to ensure that the internal phase of such an O / W emulsion iodinated Fettsäureestertröpf¬ chen with a possible for a good X-ray absorption liehst optimally adjustable center has chendurchmesser drip. In addition to be well tolerated and under appropriate conditions Aufbewah¬ approximately have a very long shelf life such parenterally administrable emulsion for the patient.

This object is achieved according to the invention by a parenterally administrable, stable under heat sterilization conditions O / W Emul¬ sion an X-ray contrast agent with an inner phase of one or more suitable oil-soluble iodinated Fettsäureestern, if appropriate oils together with one or more highly refined glyceride, or ren more emulsifiers and optionally Coemulgato- and an external phase of distilled water with additives approximately Isotonisie- and a physiologically acceptable buffer. This emulsion of the invention is characterized in that the physiologically acceptable buffer is selected from 0 to 12 m.mol / 1 sodium hydroxide solution and 2 to 10 m.mol / 1 sodium carbonate and / or sodium hydrogen carbonate is, in each case based on the volume of the final emulsion, together ¬ mensetzt and in that the iodinated fatty acid ester are present with a specifically adjustable average particle size in the range of 0, 2 to 4, 0 microns in the inner phase. __ Surprisingly, it has been found that the buffer system according to the invention proposed that at issue O / W emulsion of an

X-ray contrast agent is not only stabilizes such a way that this a

Heat sterilization can withstand at 121 ° C in an autoclave for 20 minutes without any problems, but also by a suitable choice of the ratio of carbonate to sodium hydroxide solution, Gesamtkon¬ concentration of the buffer system and the duration of heat sterilization permits the average particle size of the inner phase of the O / W to influence emulsion present iodinated fatty acid ester selectively, so that remains unchanged depending on the conditions chosen, the mean particle size of the iodinated fatty acid ester after sterilization as compared to before sterilization derjeni¬ gene or is increased in predeterminable extent. This is clearly demonstrated using the procedures described below Beispie¬ le. It has thus t is the possible answer, the X-ray contrast medium emulsions better than before or adapted to the specific needs of jeweili¬ gen examination methods. sen anzupas¬ the special requirements of a user accordingly. This is the known x-ray contrast agent emulsions not nen or only possible to a limited extent. The inventions according dung O / W X-ray contrast agent emulsion also has under a nitrogen atmosphere excellent storage stability and has a very good absorption of X-rays, so that they can advantageously be used in X-ray diagnostics.

As iodine-containing X-ray contrast agent W emulsions parenterally administrable oil-soluble organic iodine compounds are present in the inventive O / known per se, which is available commercially, are used, which provide in the radiographic imaging of organs sufficiently strong positive contrasts, namely, iodinated fatty acid ester, insbesonde- re fatty acid glycerides, before all fatty acid triglycerides such as fatty acid ethyl ester of iodized poppy se beispielswei- oil, which is under the Handels¬ name Lipiodol UF available, further iodized soybean oil, cotton seed oil, peanut oil, iodinated fish oils, etc.. The iodinated fatty acid ester are usually used in an amount of 5 to 40 parts by 7o, based on 5The finished emulsion.

The emulsion of the invention may include one or more non-iodinated, highly refined optionally also contain regions which can be used in parenteral Ernährungs¬ glyceride oils such as soybean oil, safflower oil, triglycerides, etc. lOmittelkettige. By their addition, the density of the oil droplets can be decreased as the internal phase in the emulsion and thereby be prevented from sedimenting.

furthermore contain one or more emulsifying agents 15, which have to have the derliche erfor¬ purity for parenteral use in the inventive emulsion. Such emulsifiers are known and commercially available. naturally occurring emulsifiers are preferably used for the inventive purpose, insbesonde¬ re lecithin, eg soybean, particularly preferably egg lecithins. 2θDabei, appropriate proportions of vorliegen¬ in the lecithins TION the phospholipid fractions by known per se special Raffina¬ and fractionation are set. Very particularly preferred to use Eilecithinen is dylcholingehalt with a phosphatidylcholine _> * 757 0 and a Kephalingehalt - * 157o. 25auch is possible the use of highly pure fractions of soy lecithin.

Further, the emulsion of the invention can optionally contain appropriate co-emulsifiers, in particular the alkali metal salts are of long-chain fatty acids such as palmitic acid, oleic acid or stearic 30säure suitable.

The amounts of lecithins are generally in the range of 0.4 to 35 g / 1 final emulsion according to the invention, the amounts of Gators Coemul¬, for example alkali metal salts of fatty acids, generally in the 5 range of 0.2 to 1 g / 1 final emulsion. The outer phase of the emulsion according to the invention contains water or destillier¬ tes. with the aid of the external phase of the emulsion according to the invention is isotonic with the human blood 5 highly purified water inj izierbarer quality (water for injection) and isotonization. As isotonization particularly physiologically acceptable polyols such as glycerol, sorbitol or xylitol are suitable. Glycerin is particularly preferred sets einge¬ this. The isotonization additives are added to the emulsion in the necessary quantities for the isotonicity, for example, in the case 10 of glycerol 25 g / 1, based on the finished emulsion.

The excellent heat and storage stability of the emulsion is prepared by the present invention proposed the addition of a physiologically acceptable buffer of sodium carbonate and / or sodium

15 hydrogen carbonate causes the optionally adjusting the pH of sodium hydroxide in an appropriate concentration, for. B. a 1-normal sodium hydroxide solution, may be added. The provided with this buffer system according to the invention O / W emulsion can be a heat sterilization process at 121 ° C over a period of 20 to

20 25 minutes without undergoing significant damage to the emulsion.

The proposed inventions buffer system of carbonate and / or bicarbonate, and optionally sodium hydroxide solution must

25, of course, be present in an amount sufficient for the desired effect in the emulsion. It has been found that the desired effects in stability of the emulsion and the solution Beeinflus¬ the average particle size of the iodinated Fettsäureestertröpfchen in the inner phase of the emulsion to the extent necessary

30 occur when the emulsion is 0 to 12 mmol / 1, preferably 0, 5 to 10 mmol / 1 sodium hydroxide solution and 2 to 10 mmol / 1, preferably 3 to 8 mmol / 1 sodium carbonate and / or sodium bicarbonate, respectively be¬ attracted to the volume of the finished emulsion contains. A particular advantage of the O / W emulsion according to the invention is that the by varying the concentration of the buffer system in the emulsion and the sterilization time is expressed by

F value (in min. At 121 ° C) in an autoclave targeted to a particular o mean particle size of iodinated Fettsäureestertröpfchen in the range of 0, 2 to 4, 0 microns can set in the internal phase. Vorzugswei¬ se has iodinated Fettsäureestertröpfchen having an average diameter in the range of 0, 3 to 3, 0 .mu.m, particularly preferably from 0 8 to 2, 5 .mu.m to the internal phase of the X-ray contrast medium erfindungsg.emäßen emulsion. These emulsions are characterized by a particularly good radiopaque with excellent heat and storage stability.

The preparation of the emulsion according to the invention is carried out in the manner known from DE-PS 37 22 540, in principle manner, see in particular column 13/14, wherein sion during the entire manufacturing process and, where appropriate, the subsequent storage of the finished Emul¬ it is ensured that the components and Mi¬ mixtures obtained and the finished emulsion are constantly kept under Stickstoffatmosphä- re. The individual process steps can be briefly described as follows:

There are first the required amounts of lecithin under ständi¬ according stirring in an appropriate amount of water for injection, which at approx. 55 to 60 ° C is heated, entered and then the mixture for a time such. B. Further stirred for 15 to 20 minutes. In parallel, are input and dissolved appropriate quantities of glycerol and sodium oleate while stirring continuously in a second appropriate amount of water for injection, which is also heated to 55 to 60 ° C. The resulting solution is then pressure under a nitrogen through an appropriate membrane filter, for example having a pore size of 0, 2 microns, filtered and the filtrate is added into the prepared water / lecithin mixture, the temperature being still kept at 55 to 60 ° C , A measured appropriate amount of iodinated Fettsäureestern, spielsweise Fettsäureethy esters of iodized poppy seed oil, is heated to 50 to 60 ° C and passed through a nylon Membrane filters with a pore size of z. B. 0, 2 .mu.m filtered and the filtrate directly oleate in the prepared aqueous mixture of lecithin, glycerol and sodium with continuous stirring, for example using a mechanical high-frequency device (Ultra-Turrax), together with a stirrer, optionally, forming a crude emulsion. After voll¬ constant addition of iodinated oil, the crude emulsion formed was further emulsified for some time in order to receive a crude emulsion. The entire mixture is kept at 55 to 60 ° C and blanketed with nitrogen.

The emulsion obtained is further emulsified bar and bar in a second stage at 100 in a closed system in a suitable 2-stage homogenizer at a first stage at 400, where the temperature is kept between 50 and 60 ° C. After Durchfüh¬ the high-pressure homogenization tion, the emulsion is transferred into a tank Lager¬ '. then there is effected the dilution of the emulsion to an appropriate concentration with the addition of appropriate amounts of carbonate and sodium hydroxide. The emulsion is approx. cooled 10 to 15 ° C. Thereafter, the filling of the emulsion under nitrogen blanket, to which then the heat sterilization in rotary autoclave at 121 ° C followed 15 to 25 minutes is done.

The emulsions of the invention must be protected from light and, after cooling, the action of oxygen, which is why the Abfül¬ development is carried out under nitrogen. After sterilization, the advertising stored the filled quantities of emulsion at 4 and at 21 ° C. The samples are then stable in storage for long periods.

The invention is further tert erläu¬ by the following examples: Example 1

An O / W emulsion of an X-ray contrast agent of the present invention was prepared as follows:

231 ml of distilled water for injection were placed in a gassed with 5 nitrogen vessel and heated to 55 to 60 ° C and during the following process stages maintained at this temperature. The water was sparged with nitrogen for so long, until the oxygen content below 0, was dropped 1 mg /. 1 Then, 16 g egg lecithin in about while continuing the nitrogen purge. 2 minutes

10 inputted with constant stirring in the water, and is running high frequency device (Ultra-Turrax) and stirrer comminuted and 15 th Minu¬ further stirred. In parallel, 75 ml of warmed distilled water for injection in a second, gassed with nitrogen vessel to a temperature of 55 to 60 ° C and during

15 of the further process stages maintained at this temperature. The water was in turn gassed so long with nitrogen until the oxygen content below 0, was dropped 1 mg / first Subsequently, 25 g of glycerol (1007oig) and 0, 3 g of sodium oleate was added to the water and slowly dissolved with stirring. The resulting 55 to

20 60 ° C warm solution was added under nitrogen pressure over 10 minutes through a 0.2 micron membrane filter into the prepared water / read cithin mixture.

200 g of a fatty acid ethyl ester of iodized poppy seed oil (Lipiodol UF) 25 were heated in a container under a stream of nitrogen at 50 to 60 ° C and filtered through a nylon membrane filter with a pore size of 0, 2 microns within 20 to 25 minutes directly into the prepared aqueous mixture of lecithin, glycerin and sodium oleate added with constant stirring, and the mixture was simultaneously treated by a mechanical high-frequency device 30 (Ultra-Turrax) with running fei¬ NEN generator (G 6) and coarse generator (G 2). After all of the X-ray contrast agent, the gebil¬ finished crude emulsion was further emulsified 25 minutes. During the Herstel¬ the crude emulsion was lung these maintained at a temperature in the range 35 from 55 to 65 ° C and continuously overlaid with nitrogen. Subsequently, the crude emulsion was under gentle stirring through a membrane filter having an average pore size of 40 microns under a nitrogen pressure of approx. 0, 5 bar placed in a suitable for the preparation of fat emulsions 2-stage homogenizer and homogenized where in the first stage at 400 bar and in the second stage at 100 bar. The required homogenizing sierdruck was achieved with hot distillate through a by-pass. It was then switched to the emulsion.

During homogenization, the temperature was approx. 60 ° C. The emulsion formed was placed in a storage tank, which was covered with nitrogen. Here was allowed to rest for the emulsion with occasional slow stirring. Thereafter, the Emul¬ was further subjected to two more homogenization steps sion, the temperature was again maintained at about 60 ° C. Approximately 500 ml of this emulsion was cooled to 12 ° C and placed in a template from 500 ml of a likewise cooled to 12 ° C solution of 10 mmol / 1 Na 2 CO "in oxygen-free distilled water so that the ratio of 1: diluted 1 emulsion 5 mmol / 1 Na ^ CO "contained. During the running of the homogenised emulsion in the submission was not further exposed to nitrogen gas, but overlaid with nitrogen. With occasional stirring, the slow Emul¬ sion was continued at 8 to 9 ° C chilled. After reaching this temperature, the stirrer was switched off.

The pH of the emulsion was checked. At a pH value lower than the target value of at least pH 10, 0 has the following

Examples of the pH by adding an appropriate amount

1N sodium hydroxide solution corrected. In the present example, such addition was not required because the emulsion having a pH of 10, 2, after the addition of the carbonate prior to sterilization.

The emulsion was stored in a cooling tank under a nitrogen atmosphere and filtered with a pore size of 2 to 8 microns through a membrane filter before filling, wherein the filling pressure was not more than 0.5 bar. The filling was carried out under Stickstoffschutz¬ gas into glass infusion bottles, which has been gassed during the filling with Stick¬ material, so that the oxygen content was less than 0.1 mg / 1 in the glass bottles. After filling, the bottles were sealed with wooden stoppers and crimped.

The emulsions of the invention were protected during the preparation and storage from light and oxygen exposure.

The filled into the glass infusion bottles emulsion was anschlie¬ ßend in rotary autoclave at 121 ° C for 15 minutes Siert hitzesterili¬. Since other than this hold time, wherein the temperature of 12l ° C in the sample is kept constant (actual sterilization phase), and the heating time siertemperatur until reaching the prescribed sterilization and the fall time, that is, the cooling phase, still a certain contribution to the sterilization of the afford sample, known by the. F value is also detected (in minutes) be given here and the F values ​​in the following examples, instead of the holding times. In this example, the F value was 17.5 minutes.

After sterilization, the emulsion had a pH of 7.68. The optical examination showed that the emulsion obtained both before and after sterilization fulfilled the usual criteria for a parenterally administrable O / W emulsion. The sizer with a car 2c determined average particle size of the emulsion after sterilization was 239.8 nm.

After sterilization, the filled emulsion was protected from light at + 4 ° and stored at 21 ° C. Sampling showed that the emulsion even after prolonged storage time unchanged fine ar. Remarkable in this result is not only that provided with the carbonate emulsion under the applied Hitzesterili¬ sationsbedingungen has a very good stability, but that the average particle size of the emulsion droplets after the sterilization with 239, 8 nm on the average particle size of the Emulsionströpf ¬ surfaces before sterilization, only slightly deviates was 234, 8 nm. Thus, the ability of the invention to sterilize O / W emulsions Röntenkontrastmittel under appropriate conditions, without causing a significant coarsening of iodinated Fettsäureestertröpfchen must be taken into account opened.

Examples 2 to 6

In the following examples O were / W X-ray contrast media emulsions NEN the same composition and the same kind their manufacture as described in Example 1 was used with the difference that in Example 2 for comparative purposes, an emulsion without Puffer¬ system and 3 to 6 were used with emulsions unterschiedli¬ chen amounts of the buffer system in the examples. The carbonate were added to the emulsion after homogenization fourth and carried out cooling the emulsions to approx. 12 ° C added in the amounts indicated below:

Example 2: no buffer system

Example 3: 2, 5 mmol / 1 sodium carbonate + 1, 28 mmol / 1 NaOH Example 4: 2, 5 mmol / 1 sodium carbonate + 0, 53 mmol / 1 NaOH

Example 5: 5.0 mmol / 1 sodium carbonate

Example 6: 8, 0 mmol / 1 sodium carbonate.

The resulting emulsions were found to all be in order before sterilization in optical testing. The following tabular compilation of the F o values ​​as a measure of

Duration of the heat sterilization, the average particle size, measured once via dynamic light scattering (Autosizer 2c company Malver.n) and once sizes determined as the arithmetic mean of the determined by the Coulter method number distribution of Teilchen¬, as well as for Examples 3 to 6 to give the particle size distribution after sterilization, as measured by the Coulter method ange¬.

The results in the table show very clearly that the emulsion is not heat-sterilized at 121 ° C without a buffer (Example 2). The emulsion is broken after sterilization. In contrast, the present invention equipped with the buffer system are emulsions (Beispie- le 3 to 6) are all fully intact after sterilization. Of particular note the result of Example 6, in which both the average particle size and the Teilchen¬ size distribution compared to Example 2 is in this case shows that the inner phase with respect to the droplet size after sterilization as compared with the state before sterilization hardly changed Has . The F values ​​of the examples 4 to 6 further show that these emulsions conditions by the inventive addition of a buffer among the Be¬ heat sterilization are extremely stable. Außer¬ the one recognizes that by a relatively small addition of buffer, as in Examples 3 and 4, after sterilization in the inner phase of the emulsion is a clear trend towards an increase in particle size, i .e. to a coarsening of the emulsion, results while this tendency with increasing concentration of buffer in the emulsion at the same conditions decreases.

As is well known, sodium carbonate in water to Na - "dissociated ions and CO and the carbonate ions react with water to achieve a chemical equilibrium to hydrogen ions and hydroxyl ions, resulting in the highly alkaline reaction tion of the sodium carbonate in the solution in water results, are also present in the exclusive use of sodium carbonate in the solution forming buffer bicarbonate ions. It wur¬ de therefore suggested that also a stabilizing effect on the O / W X-ray contrast media emulsions can be accomplished with sodium bicarbonate in place of sodium carbonate. corresponding table

Example pH avg. Particle size particle size distribution after sterilization o (%) No. (Min.) Determined prior to over after sterilization the sterilization Autosizer Coulter Ed. > 0.6 microns> _3,0 microns microns ≥5,0 "≥7,0 microns

2 (without 17.5 7.52 234.8 nm emulsion 20.60 0.175 0.000 0.000

Buffer) broken ((before sterilization) values ​​before sterilization)

17.5 10.2 6.84 412.4 nm 0.586 microns 33.56 0.000 0.000 0.000

25.4 10.2 6.43 0.993 0.055 0.004 0.000 microns 87.52

* *

25.4 10.39 6.95 395.5 nm 0.547 0.008 0.000 microns 34,20 0 000

, ,

25.4 10.59 7.79 226.8 nm 0.572 microns 14.10 0.001 0.010 0.000

Buffer system: a 2 C0 3 + NaOH

* *)

Buffer: a 2 C0 3

Experiments have confirmed this suspicion and revealed that the same advantageous effect stable lisierende which system the carbonate buffer has on the O / W X-ray contrast agent emulsions, including the use of sodium bicarbonate in place of sodium carbonate is effected.

Claims

claims
1. Parenterally administrable, stable under heat sterilization conditions O / W emulsion of an X-ray contrast agent having a inne¬ ren phase of one or more suitable oil-soluble iodinated Fettsäureestern, optionally together with one or more
5 highly refined glyceride oils, one or more emulsifiers and optionally co-emulsifiers and an outer phase of destil¬ of water required with Isotonisierungszusätzen and a physiologically compatible buffer, characterized in that the physiologically acceptable buffer is selected from 0 to 12 mmol / 1 sodium hydroxide solution and 10 2 nat to 10 mmol / 1 sodium carbonate and / or Natriumhydrogencarbo¬, each based on the volume of the final emulsion, composed and in that the iodinated fatty acid ester with a specifically adjustable average particle size in the range of 0 2 to 4.0 microns are present in the inner phase ,
15
2. Emulsion according to claim 1, characterized in that it contains 0, 5 to 10 mmol / 1 sodium hydroxide solution and 3 to 8 mmol / 1 sodium carbonate and / or sodium hydrogen carbonate, each based on the Volu¬ men of the final emulsion.
20
3. The emulsion of claim 1 or 2, characterized in that the internal phase droplets having a mean diameter in the range of 0, 3 to 3, 0 microns.
254. Emulsion according to one of claims 1 to 3, characterized gekennzeich¬ net, that the droplets have a mean diameter in the range of 0, 8 to 2, 5 .mu.m.
PCT/EP1994/001470 1993-05-19 1994-05-07 Parenterally administerable oil-in-water emulsion for use as an x-ray contrasting agent which is stable under heat-sterilization conditions WO1994026316A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
DE19934316722 DE4316722A1 (en) 1993-05-19 1993-05-19 Parenterally administrable, stable under heat sterilization conditions O / W emulsion of an X-ray contrast agent
DEP4316722.5 1993-05-19

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
AU67968/94A AU6796894A (en) 1993-05-19 1994-05-07 Parenterally administerable oil-in-water emulsion for use as an x-ray contrasting agent which is stable under heat-sterilization conditions

Publications (1)

Publication Number Publication Date
WO1994026316A1 true WO1994026316A1 (en) 1994-11-24

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Country Link
AU (1) AU6796894A (en)
DE (1) DE4316722A1 (en)
IL (1) IL109567D0 (en)
SI (1) SI9400228A (en)
WO (1) WO1994026316A1 (en)
YU (1) YU28194A (en)
ZA (1) ZA9403196B (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE19730901C2 (en) * 1997-07-18 1999-05-06 Fresenius Ag A method of sterilizing is currency in flexible film packaging material to be sterilized and apparatus for carrying out the method

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2299854A1 (en) * 1975-02-05 1976-09-03 Schering Ag X-ray contrast agents administered orally
DE4111939A1 (en) * 1991-04-12 1992-10-22 Fresenius Ag Parenterally administrable, heat sterilizable O / W emulsion of a roentgenkontrastmittels

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK155714C (en) * 1978-07-04 1989-10-30 Nyegaard & Co As A process for preparing a sterile, injectable, physiologically acceptable solution of a roentgenkontrastmiddel, and a solution of roentgenkontrastmidlet for use in the method
DE3722540C2 (en) * 1987-07-08 1990-06-13 Fresenius Ag, 6370 Oberursel, De

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2299854A1 (en) * 1975-02-05 1976-09-03 Schering Ag X-ray contrast agents administered orally
DE4111939A1 (en) * 1991-04-12 1992-10-22 Fresenius Ag Parenterally administrable, heat sterilizable O / W emulsion of a roentgenkontrastmittels
WO1992018168A1 (en) * 1991-04-12 1992-10-29 Fresenius Ag Parenterally administrable, heat sterilisable o/w emulsions of an x-ray contrast agent

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IL109567D0 (en) 1994-08-26
AU6796894A (en) 1994-12-12
DE4316722A1 (en) 1994-11-24
YU28194A (en) 1996-10-18
SI9400228A (en) 1994-12-31

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