DE1617275C - X-ray contrast media - Google Patents

Description

ι ²

The invention relates to a contrast medium, was an anhydrous or almost anhydrous

which is stored in particular for the radiological visible emulsion, hereinafter referred to as the »basic emulsion

making of the lymphatic system (lymphography) sion ”. In the base emulsion should only

is used, but also for other purposes, when - as much water is available as according to the existing-

for example hepatography, for application according to the regulations (for example in the US Pharmacopoeia) in

long can. Glycerin is allowed. The emulsion mentioned exists

X-ray contrast media are available in a large number of the composition mentioned, in particular

Known and are for example directly from 35 to 55% of the iodized vegetable oil or

Injection into the body of the life to be examined - the iodized low molecular weight alkyl ester of a

essentially entered. The lymphography has proven itself as io vegetable oil in a mixture with 40 to 60 ° / ₀ glycerine

a valuable diagnostic aid in the ER and 4 to 8 ° / ₀ of the äthanollöslichen as lecithin

detection of disorders of the lymphatic system emulsifier.

proven. The method allows the visibility A Wasserrrienge up to about 10 ° / ₀ of the weight

making the lymph nodes and lymph channels. It is the glycerin that is normally present in it

particularly suitable for examining the pelvic 15 is permitted and does not cause any harmful or

knots and knots behind the peritoneum. Undesirable effects. Of course it's difficult

ten, which so far not accessible to an investigation to produce an absolutely anhydrous glycerine, since

was. this is strongly hygroscopic, and therefore the

Although it is known per se, iodized vegetable oils, technical production of an absolutely anhydrous for example iodized poppy seed oil, or the iodized glycerine are basically extremely expensive. Use lucky esters of vegetable oils. The oil is licherweise this is not necessary,
preferably injected directly into a lymphatic vessel. The basic emulsion is in particular prepared in the following manner, which by means of subcutaneous injection in a non-manner. The lecithin is made visible in the glycerol's toxic dye. The iodized oils have certain disadvantages; 25 yaws, for example with the help of an emulsifying machine, you can, for example, a lung-oil embolism with which rotates at a high number of revolutions. The iodized oil is then fed to the device mentioned, followed by shortness of breath, increased pulse and chest and pain and a respiratory and lecithin-glycerine dispersion are intimately mixed. Which cause or or cardiovascular collapse. To avoid these disadvantages, an attempt was made to use iodized 30 to about 0.5 μ, mainly from 0.1 to 0.5 μ, of vegetable oils in an aqueous emulsion for the droplets of the base emulsion. Will turn the base emulsion at one temperature. Supported the preparation of a suitable emulsion of about +4 ⁰ C, it remains stable and is prepared, however, considerable technical difficulties at least for 20 months for use. Nach keiten. The droplets of iodized oil tend to stand for 3 days and the mixture of substances is autosterile, as they are quite small at the beginning, to be discussed in more detail below. It has no storage to unite into larger droplets, and has satisfactory autosterility until the natural glycerine and the iodized oil or the iodized oil also present the danger of embolism after the injection of such emulsions. In addition, esters are present. . ₅

In addition, the iodized oils themselves are not stable substances, and in the presence of water the hydrolysis intended for the end use, with the formation of the free fatty acids and emulsion, produced by mixing and through-iodides, can first take place. It is known that the free fat shaking of the base emulsion with a sterile, iso-acid undesirable pharmacological side effects untonic water solution, z. B. a glucose or gene unfold and that the iodide hypersensitivity sodium chloride solution. The emulsion produced in this way can cause reactions. A further disadvantage 45 then has a degree of fineness and a stability of the emulsions of the iodinated oils of the known type, which for the purposes of the present invention lies entirely in the difficulty in making them too satisfactory in sterile form. The oil droplets get the for the end. A sterilization of the emulsion by using certain emulsions vary in their heat due to the decomposability of the iodized oil size between about 0.1 and about 0.5 μ.
and breaking the emulsion is not possible. 5 ° Even with changing conditions between

The invention is based on the object, a base emulsion and water solution remains for the

to create sterile x-ray contrast media, in the end use of which certain emulsion, if they are in a

Use pulmonary embolism and other health temperature of about +4 to +8 ⁰ C is stored,

Disturbances can be avoided. unchanged, and it remains for several weeks

The X-ray contrast medium, which is usable in the form of an im 55.

essential anhydrous emulsion is present and after the iodized oils, namely iodized vegetable oils

Dilute with sterile water for a sterile injectable or iodized low molecular weight alkyl ester of vegetable

tion is suitable, contains according to the invention borrowed oils, are produced for. B. by iodizing

20 to 65% of an iodized vegetable oil or one of vegetable oils or esters thereof, the one

iodized low molecular weight alkyl esters ^{6o have a} relatively high iodine number, which is known-

of a vegetable oil, »! ^{ch the} presence of numerous double letters n-

. durigen indicates, with iodination in itself inherently

^! ^S JL " ^yZe » 'u ",,, ·,., ·,. ·, R-. Licher way is done. The ones commonly used

3 to 10% of a athanolloslichen lecithin as emulsifier _{iodinated p} fl _an2 union oils or iodized ester

8 ^ators · 65 of these usually contain about 30 to 50,

The percentages here and in the following are preferably about 40 percent by weight iodine.

in each case based on percentages by weight. Lezethin used as an emulsifier must

The contrast agent according to the invention will naturally be nontoxic in nature, and for reasons of

For purity and non-toxicity, ethanol-soluble lecithin is used.

The following examples are intended to explain the invention in more detail, but not to restrict it in any way.

example 1

Glycerine 52 percent by weight

Lecithin (ethanol-soluble soy

bohenlezithin) 8 percent by weight

iodized poppy seed oil 40 percent by weight

The lecithin is dispersed in the glycerin by means of the dispersing device, whereupon the iodized Poppyseed oil added and mixed with the lecithin-glycerin dispersion in the above-mentioned device will.

Example 2

Glycerine 45 percent by weight

Lecithin (ethanol-soluble egg lecithin) 10 percent by weight

Iodized ethyl ester of poppy seed oil 45 percent by weight The emulsion is made in the same way as in Example 1 described, produced.

Example 3

Glycerine 45 percent by weight

Lecithin (ethanol soluble soybean lecithin) 5 percent by weight

Iodized ethyl ester of poppy seed oil 50 percent by weight. The emulsion is prepared in the same way as in Example 1 described, produced.

B e i s ρ i e 1 4

Glycerine 50 percent by weight

Lecithin (ethanol soluble soybean lecithin) 5 percent by weight

iodized sesame oil ........'..... 45 percent by weight

The emulsion is processed in the same way as in Example 1 described, produced.

Example 5

The preparation of the substance mixtures of the preceding examples is repeated with the difference, that iodized rapeseed oil is used as iodized oil.

One of the advantages associated with the present invention is that the base emulsion is rendered essentially anhydrous, thereby reducing the risk of hydrolysis and iodide formation is turned off. It is true that anhydrous or essentially anhydrous is already available earlier Emulsions made from vegetable oils, but apparently so far none are essential anhydrous emulsions of iodized vegetable oils or of iodized low molecular weight alkyl esters made from vegetable oils. It is therefore surprising that an emulsion of this type Can be made with iodized oils that have completely different chemical and physical properties have, for example, have a higher specific weight than vegetable oils.

Another advantage of crucial importance lies in the surprising fact that an inventive Emulsion becomes sterile if left for a few days, e.g. B. 3 days or more, at room temperature is stored. It is known that iodized oils have a certain bactericidal effect, but what the For the purposes of the present invention, is completely inadequate. It is therefore extremely surprising that an emulsion according to the invention is autosterile, more surprisingly than it is known that lecithin counteracts the effects of numerous bactericidal compounds.

Sterilization test.

The sterilizing effect of the emulsions according to the invention is based on special bacteriological tests

ίο been investigated.

Broth cultures of Staphylococcus aureus, Escherichia coli, Pseudomonas pyocyaneus, Bacillus subtilis and Proteus vulgaris were diluted in the following series: 1: 100, 1: 1000,000 and 1: 100,000,000.

0.05 ml of each of these solutions were placed in test tubes which contained 2.5 ml of the basic emulsion according to the invention. The jars containing the mixture was thoroughly shaken and then stored at a temperature of +4 ⁰ C.

After IV ₂ hours and after 2, 3, 4, 5 and 14 days, 0.1 ml of the bacteria-emulsion mixture was filled into test tubes with polysorbate 80 (polyoxyethylene sorbitan monooleate) / lecithin broth. The jars were incubated at 37 ° C. After 1 and 3 days, a platinum loop was transferred full of the mixture on blood agar plates and then the plates 24 hours, incubated at +37 ⁰ C for.

A. Escherichia
coli ..

B. Proteus vulgaris .....

C. Pseudomonas pyocyaneus

D. Staphylococcus
aureus ....

E. Bacillus

subtilis ...

The base emulsion stored at +4 ^{0 C}

can be in l '/ a hours 24 hours

■ * H aSn (a) (na)

240

1600

1700

20th

42,000

400

1000! -

1 100

1.7 x 10 '2.0 x 10 ⁵

2.4 · 10 *

4.2-10 * 1.6-1O ⁸

j:

1.1 · 10 «j 4.4 · 10 *

50 A. 48 sti
a nd
n / A 72 hours
a ι na B. 1.7 · 10 ⁵
1.6 · 10 ⁶ C. 4.4 · 10 ⁴ D. 55 E. 4.4 · 10 *

These numerical values are the same for all substance mixtures of the invention that were tested were found to be correct.

As can be seen from Table 1, the base emulsion can all bacteria of the species Bacillus subtilis within l '/ kill ₂ hours. After 24 hours, all bacteria of the Proteus vulgaris type have been killed, and after 48 hours all bacteria of the Escherichia coli and Pseudomonas pyocyaneus types have been killed. After 72 hours, all bacteria of the Staphyl-

I 617 275

ococcus aureus also killed. The inventive The base emulsion therefore has a clear auto-sterilizing effect.

To the effect of a known emulsion of an iodized oil with an emulsion according to the invention To compare, the following experiments were carried out.

For further bactericidal and fungicidal comparative tests, the following emulsions were used, where the amounts of bacteria, the amounts of emulsion and all other conditions in each experiment were the same.

A = basic emulsion according to the invention diluted with distilled water in a ratio of 1: 1;

B = iodized oil, lecithin (according to the invention Base emulsion), but distilled water instead of glycerine, and also with distilled water diluted in a ratio of 1: 1;

C '== control test ;.

D = lecithin, glycerine and peanut oil diluted with distilled water in a ratio of 1: 1.

Various types of bacteria and Candida albicans were added to the emulsions mentioned.

Tables 7th
A. 2 sti
B. young people
C. η
D. 168St
A j B a
a
n / A and c
C. η
D. a
a
a a
a
n / A n / A
n / A
n / A a
a
n / A PPP ' n / A
n / A
n / A a
a
n / A Staphylococcus aureus
Pseudomonas aeruginosa
Candida albicans .....

From the results of these comparative tests it can be seen that the emulsion B and the substance mixture D a bactericidal effect on some of the selected Exercise test bacteria after 72 hours. The only emulsion, which against the resistant kind Candida albicans is effective, Emulsion A is according to the present invention. With this effect acts it is a synergistic effect, as neither the substance mixture B and D, which iodized oil or Contains glycerine against the resistant type Candida albicans are effective.

Clinical tests

With the new X-ray contrast media according to the invention Both animal and clinical trials have been carried out with the greatest success. The following dilutions of the base emulsion were used:

Base emulsion

Glucose solution (5.5%)

Part 1

The sterile water used for final dilution of the emulsion immediately prior to use was usually added in the form of an isotonic solution, ie a glucose or sodium chloride solution, and the water content of the final aqueous emulsion was preferably about 15 to 60 ° / ₀ of the weight of the particular end use for the emulsion.

There were also other proportions between the base emulsion and the sterile isotonic Solution In-vitro test carried out. Microscopic examinations of the said, for the End-use emulsions mixed with scrum and blood gave good compatibility and good stability to red blood cells.

In these mixtures of substances, oil-soluble chlorophyll can also be present as a further component, namely generally up to about 2 ⁰ _{I 0} , preferably 1%, based on the weight of the base emulsion. The presence of chlorophyll has proven to be of great value due to the fact that the lymph nodes and. Lymph channels can be made more visible because of their characteristic green color.

The clinical trials relate to the Radiological visualization of the lymphatic system (Lymphography) in about 40 patients. The results were extremely satisfactory; the radiological The visualization was excellent and any side effects were negligible. As can be seen from the test protocols, the dye was first administered subcutaneously in order to remove the Allow visualization of the lymphatic vessels, and shortly afterwards the emulsion was poured directly into the Lymph vessels to be made visible are injected.

Lung X-ray examinations carried out for control purposes were in no case positive, which

Essence of dangerous lung oil embolism under Proof provided.

The application of the emulsions according to the invention is not, however, to the actual lymphography limited. Another area of application is radiographic visualization of the liver (hepatography), for which one already has emulsions of iodized oils or suspensions of iodized oils has used, but has abandoned it again due to the instability and other causes.

In such uses, chlorophyll is said to be preferably not to be present.

The high practical value and suitability. the substance mixtures according to the invention extend, as shown by animal studies, for use in both humans and lower animals; leave that recognize the experiments listed above. The clinical review on humans is, however not yet fully completed.

Claims (3)

Patent claims: 1. In the form of an essentially anhydrous emulsion, autosterile X-ray contrast medium which is suitable for sterile injection after dilution with sterile water _r characterized in that it 20 to 65% of an iodized vegetable oil or an iodized low molecular weight alkyl ester of a vegetable oil, 30 to 75% glycerin and 3 to 10% of an ethanol-soluble lecithin as Emulsifier
contains. 2. X-ray contrast medium according to claim 1, characterized in that it 35 to 55% of the iodized vegetable oil or Alk.ylesters,
40 to 60% glycerin and 4 to 8% of the ethanol soluble lecithin
contains. 3. X-ray contrast medium according to claim 1 or 2, characterized in that it is additionally up to contains about 2% oil-soluble chlorophyll.