SI9400228A - Oil-water emulsion of x-ray contrast preparation for parenteral administering, stable during heat sterilisation - Google Patents

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 mu m, and the emulsion exhibits very good stability on storage and to heat, thus enabling it to be sterilized in an autoclave at 121 DEG C for 15 to 25 minutes.

Description

FRESENIUS AG

Oil-water emulsion of X-ray contrast medium for parenteral administration, stable under thermal sterilization conditions

The invention relates to a stable oil-water emulsion of an X-ray contrast medium based on iodized fatty acid esters for parenteral administration, which can be used in X-ray diagnostics, for example, after appropriate dilution, e.g. in lymphography;

From DE 41 11 939 C2, an already known thermal-sterilized oil-water emulsion of X-ray contrast medium is sterile sterilized, in which the inner phase contains one or more oil-soluble organic iodine compounds and the outer phase is from distilled water with isotonic additives . By the addition of a physiologically acceptable buffer system consisting of sodium base and disodium hydrogen phosphate and / or disodium glycerophosphates, the emulsion was stabilized so that it could be sterilized in an autoclave for 15 to 20 minutes at 121 ° C. thereby undesired formation of the emulsion. Thereafter, the finished emulsion has a mean internal phase droplet diameter of at least 0.6 μιη. We have explicitly considered the state of the art, which is exhaustively explained in the description of the instructions DE 41 11 939 C2.

Although the previously known known emulsions in X-ray diagnostics have already worked well, in practice it has been shown that even safer handling of oil-based emulsions containing X-ray contrast medium is desirable, especially during and after the sterilization phase. This assumes that the emulsions can be prepared even more stable against thermal loading at sterilization temperatures of 120-121 ° C, so that the operating fluctuations in sterilization conditions as they occur in daily operation will not unduly affect the product's characteristics. Thus, the preparation of such oil-water emulsions in the required quality would be even less critical and more easily feasible.

Therefore, it is an object of the present invention to further improve the stability of X-ray contrast media emulsions, especially with respect to thermal sterilization at 120 to 121 ° C in autoclaves, while ensuring that the internal phase of such oil-water emulsions has a drop of iodized fatty acid esters with to optimally adjustable mean droplet diameters for very good X-ray absorption. In addition, such a parenteral administration emulsion for patients should be well tolerated and have very good storage stability.

This task of the invention is solved by an oil-water emulsion of an X-ray contrast medium for parenteral administration which is stable under thermal sterilization conditions, with an internal phase of one or more oil-soluble iodized fatty acid esters, optionally together with one or more highly refined glyceride oils, one or more emulsifiers, as well as optionally co-emulsifiers and distilled water exterior phases with isotonizing additives and physiologically acceptable buffer. This emulsion of the invention is characterized in that the physiologically acceptable buffer consists of 0 to 12 mmol / l sodium base and 2 to 10 mmol / l sodium carbonate and / or sodium hydrogen carbonate, each with respect to the volume of the finished emulsion, and In the inner phase, there are iodized fatty acid esters with a target tunable mean particle size in the range of 0.2 to 4.0 μτη.

It has surprisingly been shown that the buffer system of the present invention not only stabilizes the subject oil-water emulsion of the X-ray contrast agent so that it can easily endure thermal sterilization at 121 ° C in an autoclave for 20 minutes, but also allows that by appropriately selecting the ratio of carbonate buffer to sodium base, the total concentration of the buffer system and the duration of thermal sterilization, we are targeting the mean particle size of the iodized fatty acid ester, which is in the internal phase of the oil-water emulsion, so that, depending on the selected conditions, it remains the particle size of the iodized fatty acid ester after sterilization, as compared to that before sterilization, is unchanged or increased by a predefined range. We clearly illustrate this with the help below

24059-04 / 94-D5-Re.

the examples described.

With this we have the possibility to adjust the emulsions of X-ray contrast media better than before in accordance with the specific requirements of the research methods and / or methods. tailor made to the user's specific needs. With X-ray emulsion contrast emulsions known so far, this is not possible or only to a limited extent. In addition, the oil-water emulsion of the X-ray contrast medium has an extremely storage stability under the nitrogen atmosphere and exhibits very good X-ray absorption, so that it can be usefully used in X-ray diagnostics.

As X-ray contrast agents containing iodine are used in the oil-aqueous emulsions of the invention known organic oil-soluble organic iodine compounds for parenteral administration which give sufficiently strong contrasts in the X-ray presentation of organs, namely iodinated fatty acid esters , especially fatty acid glycerides, especially fatty acid triglycerides, such as e.g. fatty acid ethyl ester of iodized poppy seed oil, commercially available under the trade name Lipiodol UF, further iodinated soybean oil, cottonseed oil, peanut oil, iodized fish oil, etc. The iodized fatty acid esters are typically used in an amount of 5 to 40% by weight. given the certainly emulsion.

The emulsion of the invention may optionally also contain one or more non-iodized, highly refined, parenterally stored useful glyceride oils, such as e.g. soybean oil, saffron oil, medium chain triglycerides, etc. With their addition, the density of the oil droplets as internal phases in the emulsion can be reduced, thus preventing sedimentation.

The emulsion of the invention may further comprise one or more emulsifiers which must have the required purity for parenteral use. Such emulsifiers are well known and commercially available. Preferred are naturally occurring emulsifiers used for the purpose of the invention, especially lecithins, e.g. soya beans, especially preferably egg lecithins. In this regard, suitable ratios of phospholipid fractions contained in lecithins can be adjusted by known special refining and fractionation methods. Especially preferred is the use of egg lecithins with a phosphatidylcholine content of> 75% and a cephalin content of <15%. The use of high-purity soy-gelatin fractions is also possible.

Further, the emulsion of the invention may optionally contain suitable co-emulsifiers, with alkali salts of the fatty acids of dol24059-04 / 94-D5-Re being particularly suitable.

gimi chains, such as palmitic acids, oleic acids or stearic acids.

The amounts of lecithins are generally in the range of 0.4 to 35 g / l of the finished emulsion of the invention, the amounts of co-emulsifiers, e.g. alkali salts of fatty acids are generally in the range of 0.2 to 1 g / l of the finished emulsion.

The outer phase of the emulsion according to the invention contains distilled water or. high quality purified water for injection (aqua ad injectabilia), as well as isotonizing additives, through which the external phase of the emulsion of the invention is adjusted isotonic with human blood. Particularly suitable as isotonic additives are physiologically tolerable polyols such as glycerin, sorbitol or xylitol. Glycerin is particularly preferred for this. Isotonizing additives are added to the emulsion in amounts necessary for isotonizing, e.g. in the case of glycerin 25 g / l relative to the emulsion used.

The extreme thermal and storage stability of the emulsion is achieved by the addition of a physiologically tolerated sodium carbonate and / or sodium hydrogen carbonate buffer according to the invention, to which may be added optionally to adjust the pH at a suitable concentration, e.g. 1 N sodium base. The oil-water emulsion of this invention equipped with the buffer system of the invention can be subjected to a heat sterilization process at 121 ° C over a period of 20 to 25 minutes without significant damage to the emulsion.

According to the invention, the proposed carbonate and / or hydrogen carbonate buffer system and, if appropriate, the sodium base, must naturally exist in sufficient quantity for the desired effect. We have found that the desired stabilizing effects in the emulsion and the influence of the medium droplet size of the iodized fatty acid ester in the internal phase of the emulsion occur to the extent necessary when the emulsion contains 0 to 12 mmol / l, preferably 0.5 to 10 mmol / l sodium bases and 2 up to 10 mmol / l, preferably 3 to 8 mmol / l of sodium carbonate and / or sodium hydrogen carbonate, each depending on the volume of the finished emulsion.

A particular advantage of the oil-water emulsion of the invention is that by varying the concentration of the buffer system in the emulsion and the duration of sterilization, expressed by the F _Q value (min at 121 ° C), an autoclave can be targeted to target the medium droplet size of the iodized ester fatty acids in the internal phase in the range of 0.2 to 4.0 μιη. Preferably, the internal emulsion phase of the X-ray contrast agent v

24059-04 / 94-D5-Re.

according to the invention, a medium-diameter iodized fatty acid droplet droplet in the range from 0.3 to 3.0 μτη, especially preferably 0.8 to 2.5 μτη. These emulsions are characterized by a particularly good X-ray contrast effect with exceptional thermal and storage stability.

The preparation of the emulsion according to the invention is carried out in the manner known in DE-PS 37 22 540 in a known manner, especially with respect to column 13/14, and during the entire preparation process and in the case of subsequent storage of the finished emulsion, care must be taken to ensure that the components and the resulting mixtures, as well as the resulting emulsion, are constantly maintained under a nitrogen atmosphere. The individual stages of the process can be briefly described as follows:

First, with constant stirring, the required amounts of lecithin are added to the appropriate amount of aqua ad injectabilia, which is tempered to about 55 to 60 ° C, and then stirred for a while, e.g. 15 to 20 minutes. In parallel, add, with constant stirring, an adequate amount of glycerin and sodium oleate to another appropriate amount of aqua ad injectabilia, which is also tempered at 55 to 60 ° C and dissolved. The resulting solution is then filtered through a suitable membrane filter under nitrogen pressure, e.g. with a pore size of 0.2 μιη and this filtrate is added to a pre-prepared mixture of water and lecithin, maintaining the temperature at 55 to 60 ° C.

Measured appropriate amount of iodized fatty acid esters, e.g. The fatty acid ethyl ester of iodized poppy seed oil is heated to 50 to 60 ° C and filtered through a nylon membrane filter with a pore size of e.g. 0.2 [mu] m and the filtrate are directly added to the previously prepared aqueous mixture of lecithin, glycerin and sodium oleate with constant stirring, e.g. using a mechanical high frequency device (Ultra-Turrax) together with a mixer to form a crude emulsion. After the complete addition of iodized oil, the resulting crude emulsion is further emulsified to obtain a suitable crude emulsion. The whole mixture is constantly maintained at 55 to 60 ° C and covered with nitrogen.

The resulting emulsion is further emulsified in a closed system in a suitable 2-stage homogenizer, in the first stage at 400 bar and in the second stage at 100 bar, maintaining the temperature between 50 and 60 ° C. After high-pressure homogenization is performed, the emulsion is transferred to a storage tank. There, the emulsion is then diluted to a suitable concentration with the addition of suitable amounts of carbonate

24059-04 / 94-D5-Re.

buffer and sodium bases. The emulsion is then cooled to approx. 10 to 15 ° C. The emulsion is then drained under a protective nitrogen atmosphere, followed by thermal sterilization in rotary autoclaves at 121 ° C for 15 to 25 minutes.

The emulsions of the invention must be protected against light and oxygen after cooling, which results in a more drained under nitrogen. After sterilization, drain the emulsions at +4 and at 21 ° C. The samples are subsequently stable over a longer period.

The invention is further explained by the following examples.

Example 1

An oil-water emulsion of an X-ray contrast medium according to the invention is prepared as follows:

231 ml of distilled water for injection is placed in a nitrogen-filled container and heated to 55 to 60 ° C and maintained at this temperature during the subsequent stages of the process. Inflate the water with nitrogen until the oxygen content slips below 0.1 mg / l. Then, with constant agitation, continuing to purge with nitrogen, in approx. Add 2 g of egg lecithin to water for 2 min and, with the high-frequency device (Ultra-Turrax) switched on, mix and crush the agitator and stir for 15 minutes. In addition, 75 ml of distilled water for injection are heated to a temperature of 55 to 60 ° C in a second nitrogen-purged container and maintained at further stages of the process. Repeatedly purge the water with nitrogen until the oxygen content has slipped below 0.1 mg / l. 25 g of glycerin (100%) and 0.3 g of sodium oleate are then added to the water and slowly dissolved with stirring. The resulting 55 to 60 ° C solution was placed under nitrogen pressure for 10 minutes, through a 0.2 μτη membrane filter, in a pre-prepared mixture of water and lecithin.

200 g of fatty acid ethyl ester of iodized poppy oil (Lipiodol UF) in a vessel, under nitrogen purging, is heated to 50 to 60 ° C and directly, with constant stirring, through a nylon membrane filter with a pore size of 0.2 μτη for 20 to 25 min. , is added to a pre-prepared aqueous mixture of lecithin, glycerin and sodium oleate, while simultaneously treating the mixture with mechanical high-frequency

24059-04 / 94-D5-Re.

device (Ultra-Turrax) with operating fine generator (G 6) and coarse generator (G 2). After the addition of the X-ray contrast medium is complete, the resulting crude emulsion is further emulsified for another 25 minutes. During the preparation of the crude emulsion, it is maintained at a temperature in the range of 55 to 65 ° C and continuously covered with nitrogen.

The crude emulsion is then immediately stirred, gently stirring, through a membrane filter with an average pore size of 40 μιη, under a nitrogen pressure of approx. 0.5 bar, in a 2 stage homogenizer suitable for the preparation of fat emulsions and there emulsified in the first stage at 400 bar and in the second stage at 100 bar. The desired homogenization pressure is achieved by hot distillation via a bypass line. Immediately thereafter, we transfer it to an emulsion.

During homogenization, the temperature is approximately 60 ° C. The resulting emulsion is placed in a nitrogen-lined storage tank. Leave the emulsion here with occasional slow stirring. The emulsion is then subjected to two further homogenization steps, maintaining the temperature at about 60 ° C. Cool about 500 ml of this emulsion to 12 ° C and add a solution of 10 mmol / 1 Na ₂ CO ₃ in distilled water to oxygen in a 500 ml cartridge containing a diluted emulsion of 5 mmol / 1 Na ₂ CO ₃ in a 1: 1 ratio. During the introduction of the homogenized emulsion, we no longer inflate the template with nitrogen, but only flush it with nitrogen. With occasional slow stirring, the emulsion is further cooled to 8 to 9 ° C. When this temperature is reached, the mixer is switched off.

Check the pH value of the emulsion. At a pH lower than the predicted value of at least pH 10.0, in the following cases the pH is corrected by adding an appropriate amount of 1 N sodium base. In the previous case, such an additive was not necessary because the emulsion had a pH value of 10.2 after the addition of carbonate buffer before sterilization.

The resulting emulsion is stored in a cooling tank under a nitrogen atmosphere and filtered through a membrane filter with a pore size of 2 to 8 μτη before draining, with a leakage pressure of not more than 0.5 bar. Drainage into infusion bottles is carried out under a protective atmosphere of nitrogen, whereby nitrogen is purged during the flow to ensure that the oxygen content of the bottles is less than 0.1 mg / l. After flowing, close the bottle with rubber stoppers and fins.

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

24059-04 / 94-D5-Re.

Immediately afterwards, the infused emulsion filled bottles were heat sterilized for 15 min in rotary autoclaves at 121 ° C. Since, in addition to the retention time at which the temperature in the sample is constantly maintained at 121 ° C (the sterilization phase itself), some contribution is also made to the sterilization of the sample, which is covered by the so-called F _Q value (in minutes), the time until the prescribed sterilization temperature and cooling time are reached, i.e. the cooling phase, is given in the following cases instead of the holding times of the F _Q values. In the previous example, the F _Q value is 17.5 minutes.

After sterilization, the emulsion has a pH value of 7.68. An optical test showed that the emulsion obtained before and after sterilization met the usual criteria of an oil-water emulsion for parenteral administration. With Autosizer 2c, the measured mean particle size of the emulsion after sterilization is 239.8 nm.

After sterilization, the drained emulsion is stored protected from light at + 4 ° and at 21 ° C. Random samples showed that the emulsion was still fine after a long storage time.

It is not only noteworthy that the carbonate-buffered emulsion has very good stability under the conditions of thermal sterilization used, but that the mean size of the emulsion droplets after sterilization at 239.8 nm only slightly deviates from the average size of the pre-sterilization droplets, which is 234.8 nm. This opens up the possibility of sterilizing the oil-water emulsions of X-ray contrast media under suitable conditions without having to take into account that the droplets of the iodized fatty acid ester become significantly coarser.

Examples 2 to 6

In the following cases, the use of oil-water emulsions of X-ray contrast media of the same composition and preparation as described in Example 1, with the exception that in Example 2 an emulsion without buffer system is used for comparative purposes and in cases 3 to 6 emulsions with different amounts the buffer system. Carbonate buffers are added to the emulsions after the homogenisation step 4 and the subsequent cooling of the emulsion to 12 ° C in the following amounts:

24059-04 / 94-D5-Re.

Example 2: no buffer system

Example 3: 2.5 mmol / l sodium carbonate + 1.28 mmol / l NaOH

Example 4: 2.5 mmol / l sodium carbonate + 0.53 mmol / l NaOH

Example 5: 5.0 mmol / l sodium carbonate

Example 6: 8.0 mmol / l sodium carbonate.

The resulting emulsions appear to be perfectly fine before being sterilized on scanning. The following table gives the F _Q values as a measure of the duration of thermal sterilization, the average particle sizes once measured by dynamic light dispersion (Autosizer 2c, Malvern) and once determined as the arithmetic mean by the Coulter method of determining the number distribution particles, as well as for examples 3 to 6 of the particle size distribution after sterilization, measured by the Coulter method.

The results in the table show very clearly that the bufferless emulsions (Example 2) cannot be thermally sterilized at 121 ° C. The emulsion is broken after sterilization. In contrast, the emulsions are provided with a buffer system of the invention (Examples 3 to 6), after sterilization, completely intact. Particularly noteworthy is the result of Example 6, in which both the average particle size and the particle size distribution in comparison with Example 2 show that the internal phase has hardly changed with respect to the size of the droplets after sterilization compared to the pre-sterilization state. The F _Q values of Examples 4 to 6 further indicate that these emulsions are extremely stable due to the addition of the buffer of the invention under thermal sterilization conditions. In addition, we see that with a relatively small addition of buffer, as in Examples 3 and 4, after sterilization in the internal phase of the emulsion, there is a clear tendency for particle swelling, that is, for the deepening of the emulsion, whereas this tendency with increasing concentration of the buffer in the emulsion otherwise equal conditions, notion.

24059-04 / 94 D5-Re.

Table

E £

d

ΛΙ

O O O O o o o o o o o o o d θ 'd θ'>

<U ϋ

T)

Rt • rrt

4- * ζΛ

Oh

ES>

>

ω u

N rt tl

Oh

Pa &

o o

. E

o d ΛΙ E cg: iS d υ M co N s s £ G. * »« o §d

N rt C ω

XJ • w O c / 3 45 o o M Ό LG

U: =? > O rt e .H> O r = 2 <u C o

C / 3

Oh

CA

E 'g

T t—, υ

Έ o

U

S <U ”P

R «D

N •

CZ3 o

& o 3 Pa CL <

c / 3

About c

-a <o

Z

CA

Oh

CA O CO., LTD

N

T3 5 E |

Ca (λ

Well, t-l

Oh

E 'o'

A: g? d rt

M «n S θ 'M' j. Ό O <U

CA

O rt- O O O O O T-l O O O O <d o d d

O MO 00 rA O V) O O O O O O θ 'd d d

Oh

MO θ '

Ol

E g

rt co

OJ .rt

S

Έ

E ω

OJ mo d

mo d

OJ

Oh

Mr

Ό

O s

co 'g

4->

m

Ό

O r

Uh ad

4- »

S rt co

Li

Mr

CA

N

1)

I-,

XJ mo oi o o

MO νγ OJ ~ rA d d rf rf CO 00 CO rA

E E E E

3. 4. d. i are co Γ- OJ 00 CA ό- MO MO OS μο O- d <d d d

E

E E

U Mr Mr 1 <γ oo d ! d d T-H ! CA OJ Tt co Ol

rt- co mo CA 03 rt CA t> d d d d

CA CA Ol Ol cO X) dodd ^- <zy -rt ~ -rt -rt i> ddd TA OJ Ol OJ * * * * * * co rt- mo lo

K

O rt

Z +

cc

O υ

Co4 co

With gos ^υ „cfl

Z

ΙΛ *. t-l t-l O, <D A-ι A — i G G CA CA

Because sodium carbonate in water in a known way dissociates into Na ⁺ - and CO ₃ - ions and because carbonate ions react with water until chemical equilibrium is reached to hydrogen carbonate ions and hydroxyl ions, which results in an extraordinary alkaline reaction of sodium carbonate at a solution in water, they also exist with the explicit use of sodium carbonate in the resulting buffered solution of hydrogen carbonate ions. For this reason, it is hypothesized that sodium hydrogen carbonate, instead of sodium carbonate, could also have a stabilizing effect on oil-water emulsions of X-ray contrast agents. Relevant experiments confirmed this assumption and showed that the same stabilizing effect as that given by the carbonate buffer system is also achieved by the addition of sodium hydrogen carbonate instead of sodium carbonate.

Claims (4)

1. An oil-water emulsion of an X-ray contrast agent for parenteral administration which is stable under thermal sterilization conditions, with an internal phase of one or more oil-soluble, iodized fatty acid esters, optionally together with one or more highly refined glyceride oils, one or more emulsifiers, as well as optionally co-emulsifiers and an external phase of distilled water with isotonic additives, and a physiologically acceptable buffer, characterized in that the physiologically acceptable buffer consists of 0 to 12 mmol / 1 sodium base and 2 to 10 mmol / l sodium carbonate and / or sodium hydrogen carbonate, each with respect to the volume of the finished emulsion, and that there are iodinated fatty acid esters in the inner phase with a target adjustable mean particle size in the range of 0.2 to 4.0 μιη. Emulsion according to claim 1, characterized in that it contains 0.5 to 10 mmol / l of sodium base and 3 to 8 mmol / l of sodium carbonate and / or sodium bicarbonate, each with respect to the volume of the finished emulsion. Emulsion according to claim 1 or 2, characterized in that the inner phase of the droplet has a medium diameter in the range from 0.3 to 3.0 μιη. Emulsion according to any one of claims 1 to 3, characterized in that the droplets have a mean diameter in the range of 0.8 to 2.5 μιη.