EP0578707A1 - Emulsions huile dans l'eau d'un agent de contraste radiographique pouvant etre administrees par voie parenterale et thermo-sterilisables - Google Patents

Emulsions huile dans l'eau d'un agent de contraste radiographique pouvant etre administrees par voie parenterale et thermo-sterilisables

Info

Publication number
EP0578707A1
EP0578707A1 EP92907897A EP92907897A EP0578707A1 EP 0578707 A1 EP0578707 A1 EP 0578707A1 EP 92907897 A EP92907897 A EP 92907897A EP 92907897 A EP92907897 A EP 92907897A EP 0578707 A1 EP0578707 A1 EP 0578707A1
Authority
EP
European Patent Office
Prior art keywords
emulsion
fatty acid
emulsions
emulsion according
iodinated
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP92907897A
Other languages
German (de)
English (en)
Inventor
Klaus Sommermeyer
Heino Foth
Bernd Eschenbach
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Fresenius SE and Co KGaA
Original Assignee
Fresenius SE and Co KGaA
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
Application filed by Fresenius SE and Co KGaA filed Critical Fresenius SE and Co KGaA
Publication of EP0578707A1 publication Critical patent/EP0578707A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K49/0447—Physical 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
    • A61K49/0461—Dispersions, colloids, emulsions or suspensions

Definitions

  • the invention relates to a parenterally administrable, heat-sterilizable O / W emulsion of an X-ray contrast agent based on iodinated fatty acid esters, which can be used advantageously in X-ray diagnostics, for example in lymphography, in a suitable concentration, if appropriate after appropriate dilution.
  • X-ray contrast agent emulsions in particular those based on iodinated fatty acid esters, have already been proposed and recommended for use in X-ray diagnostics because it has been found that they are suitable for parenteral, in particular intravenous, administration.
  • the emulsions which have become known do not meet all the requirements to the required or desired extent, for example they often do not have a sufficiently high absorption capacity for X-rays.
  • a particular problem with their use has been their low stability, with the disadvantageous consequence that they are difficult or impossible to sterilize or cannot be stored for a sufficiently long time.
  • DE-PS 26 02 907 describes aqueous emulsions of iodinated glycerol fatty acid esters with a content of 50 to 60% by weight of an iodinated glycerol fatty acid ester with an alkyl chain length of the fatty acids of at least 10 C atoms, 2 to 10% by weight % of a polyoxyethylene sorbitan fatty acid ester as an emulsifier and the rest of bidistilled water, the emulsion obtained being able to be sterilized only with ⁇ rays because of its instability at higher temperatures.
  • EOE 13 contained 53% by volume of an iodinated fatty acid ethyl ester of poppy oil (commercially available as Ethiodol), 10% alcohol, 0.45% soy lecithin and a phosphate buffer to adjust to pH 7. Approx. 55% of the oil were present as particles with a diameter of 1 to 3 ⁇ m.
  • the particle sizes in the emulsion must be within a range of 2 to 4 ⁇ m if the emulsions are to have a sufficiently high absorption capacity for X-rays in the liver.
  • the emulsion EOE 13 is not stable and is difficult to prepare in large amounts.
  • this emulsion causes undesirable side effects such as fever, so that the patients had to be pretreated with steroids. From US Pat. No.
  • EP-A-0294534 describes an iodine-containing emulsion for use as an X-ray contrast agent.
  • iodinated lipids e.g. iodinated fatty acid esters of poppy oil, cottonseed oil, soybean oil and the like, which are emulsified in an aqueous phase by means of emulsifiers
  • this emulsion is characterized by a content of 0.1 to 5% by weight of one or more amino acids, fatty acids Ren or their salts and / or fat-soluble vitamins and / or urea and optionally one or more pharmacologically acceptable oils or fats, these additives should contribute to the improved stability of the emulsion.
  • the emulsion should contain the iodinated lipids in an amount of 2.5 to 65% by volume and with a particle diameter of less than 0.5 ⁇ m.
  • the emulsions described are so stable that they can be sterilized in an autoclave.
  • emulsions in which a substantial part of the dispersed phase has a particle size in the range from 2 to 4 ⁇ m have a significantly better X-ray absorption, for example in the liver and spleen, and thus do their job as X-ray contrast agents perform better than corresponding emulsions with considerably smaller particle sizes, for example below 0.75 ⁇ m, such as E. Grimes et al. in Journal of Pharmaceutical Science 68 (1979), pages 52 to 56.
  • EP-A-0294534, column 4, lines 45 to 47 shows that in order to achieve stable, heat-sterilizable X-ray contrast medium emulsions, the particle size of the dispersed iodinated fatty acid esters is less than
  • the O / W emulsion according to the invention is given excellent stability by a small but defined addition of the proposed physiologically compatible buffer system, so that it can be sterilized in an autoclave at 121 ° C. for about 15 to 20 minutes. and that after the sterilization process, through a suitable choice of the ratio of phosphate buffer to sodium hydroxide solution and the total amount of the buffer, a suitable average particle size is achieved without the structure of the emulsion being appreciably impaired, and that it is filled under nitrogen and has an excellent storage capacity - Has stability, whereby the safe handling of these contrast medium emulsions in parenteral applications is considerably easier.
  • the X-ray contrast medium emulsion according to the invention has very good absorption of X-rays, so that it can be used advantageously in X-ray diagnostics.
  • X-ray contrast media containing iodine can be used in the O / W emulsion according to the invention, generally known, commercially available, parenterally.
  • administrable oil-soluble organic iodine compounds are used which provide sufficiently strong positive contrasts in the X-ray imaging of organs.
  • Iodized fatty acid esters in particular fatty acid glycerides, especially fatty acid triglycerides, are preferably used, such as, for example, fatty acid ethyl ester of iodinated poppy oil, which is sold under the Name Lipiodol UF is available, also iodized soybean oil, cottonseed oil, peanut oil, iodized fish oils and the like.
  • the combined fatty acid esters are usually used in an amount of 5 to 40% by weight, based on the finished emulsion.
  • the emulsion according to the invention can optionally also contain one or more non-iodinated, highly refined glyceride oils which can be used in the parenteral nutritional field, such as e.g. Soybean oil, safflower oil, medium-chain triglycerides and the like. By adding them, the density of the oil droplets as the inner phase in the emulsion can be reduced, thereby preventing sedimentation.
  • one or more non-iodinated, highly refined glyceride oils which can be used in the parenteral nutritional field, such as e.g. Soybean oil, safflower oil, medium-chain triglycerides and the like.
  • the emulsion according to the invention also contains one or more emulsifiers which must have the purity required for parenteral use.
  • emulsifiers are known and commercially available.
  • Naturally occurring emulsifiers in particular lecithin, for example from soybeans, particularly preferably egg lecithins, are preferably used for the purpose according to the invention.
  • Suitable ratios of the phospholipid fractions present in the lecithins can be set by special refining and fractionation processes known per se.
  • the use of egg lecithins with a phosphatidylcholine content> 75% and a cephaline content " 15% is very particularly preferred. It is also possible to use high-purity fractions of soy lecithin.
  • the emulsion according to the invention can optionally contain suitable co-emulsifiers, the alkali metal salts of long-chain fatty acids such as palmitic acid, oleic acid or stearic acid being particularly suitable.
  • suitable co-emulsifiers the alkali metal salts of long-chain fatty acids such as palmitic acid, oleic acid or stearic acid being particularly suitable.
  • the amounts of lecithins are generally in the range from 0.4 to 35 g / 1 finished emulsion according to the invention
  • the amounts of co-emulsifiers, for example alkali metal salts of fatty acids generally in the range from 0.2 to 1 g / 1 finished emulsion.
  • the outer phase of the emulsion according to the invention contains distilled water or highly purified water of injectable quality (aqua ad injectabilia) as well as isotonizing additives with the aid of which the outer phase of the emulsion according to the invention is adjusted isotonic with human blood.
  • Physiologically compatible polyols such as glycerol, sorbitol or xylitol are particularly suitable as isotonizing additives. Glycerol is particularly preferably used for this.
  • the isotonization additives are added to the emulsion in the amounts necessary for the isotonization, for example 25 g / l in the case of gl.ycerol, based on the finished emulsion.
  • the excellent heat and storage stability of the emulsion is brought about by the addition according to the invention of a physiologically compatible buffer made of sodium hydroxide solution in a suitable concentration, for example a 1N sodium hydroxide solution, and one or more suitable inorganic and / or organic phosphates.
  • the emulsion according to the invention preferably contains disodium hydrogen phosphate as the inorganic phosphate.
  • Suitable organic phosphates are, in particular, physiologically compatible organic phosphoric acid esters which can be subjected to a heat sterilization process at 121 ° C. over a period of 15 to 20 minutes without substantial decomposition. Good results were achieved in particular with glycerophosphates, as are currently used in commercial parenteral infusion solutions.
  • the emulsion according to the invention preferably contains disodium glycerophosphates as organic phosphates.
  • the proposed buffer system consisting of 5 sodium hydroxide solution and phosphate must be present in the emulsion in an amount sufficient for the desired effect. It has been found that the desired stability effects occur in the emulsion when the emulsion contains 2 to 10 ⁇ mol / 1, preferably 3 to 8 ⁇ mol / 1, inorganic and / or organic phosphate and 0.2 to 5 mmol / 1. preferably contains 0.5 to 3 ⁇ mol / 1 sodium hydroxide solution, in each case based on the volume of the finished emulsion.
  • An emulsion in which the iodinated fatty acid ester droplets have an average diameter in the range from 0.8 to 3.0 ⁇ m is particularly preferred, and very particularly preferred is an emulsion with iodinated fatty acid ester droplets which have an average diameter in the range from 0.8 to 3.0 2.5 ⁇ m because they are characterized by a particularly good X-ray contrast effect with excellent heat and storage stability.
  • the emulsion according to the invention is prepared in the manner known in principle from DE-PS 37 22 540, see in particular column 13/14, care being taken during the entire production process and, if appropriate, the subsequent storage of the finished emulsion that the components and obtained mixtures and the finished emulsion are kept constantly under a nitrogen atmosphere.
  • the individual process steps can be briefly described as follows:
  • the required amounts of lecithin are first introduced into a corresponding amount of aqua ad injecta- bilia, which is heated to approx. 55 to 60 ° C, with constant stirring and then the mixture is left for a while, e.g. 15 to 20 minutes, stirring continued.
  • glycerol and sodium oleate are added and dissolved in a second corresponding amount of aqua ad injectabilia, which is also heated to 55-60 ° C., with constant stirring.
  • the solution obtained is then filtered under nitrogen pressure through a suitable membrane filter, for example with a pore size of 0.2 ⁇ m, and the filtrate is added to the prepared water / lecithin mixture, the temperature being kept at 55 to 60 ° C. is held.
  • a measured suitable amount of iodinated fatty acid esters for example fatty acid ethyl ester of iodized poppy oil, is heated to 50 to 60 ° C. and filtered through a nylon membrane filter with a pore size of 0.2 ⁇ m, for example, and the filtrate is passed directly into the prepared aqueous solution
  • Mixture of lecithin, glycerol and sodium oleate is added with constant stirring, for example using a mechanical high-frequency device (Ultra-Turrax) together with a stirrer, a crude emulsion being formed.
  • the raw emulsion formed is further emulsified for a time in order to obtain a corresponding pre-emulsion.
  • the entire mixture is kept constantly at 55 to 65 ° C. and blanketed with nitrogen.
  • the pre-emulsion obtained is further emulsified in a closed system in a suitable 2-stage homogenizer in a first stage at 400 bar and in a second stage at 100 bar, the temperature being kept between 50 and 60 ° C.
  • the emulsion is transferred to a storage tank. There, the emulsion is then diluted to a suitable concentration with the addition of the appropriate amounts of phosphate buffer and sodium hydroxide solution.
  • the emulsion is cooled to approx. 10 to 15 ° C.
  • the emulsion is then filled under a protective nitrogen atmosphere, followed by heat sterilization in a rotary autoclave at 121 ° C for 15 minutes.
  • the emulsions according to the invention must be protected from light and oxygen after the filling, which is why the filling is carried out under nitrogen. After sterilization, the filled emulsion quantities are stored at +4 and at 21 ° C. After a storage period of 14 and 35 days, corresponding investigations showed that the emulsion had not changed during this time.
  • Fatty acid ethyl esters of iodized poppy oil (trade name: Lipiodol UF) were heated to 50 to 60 ° C. in a container under nitrogen gas and passed directly through a nylon membrane filter with a pore size of 0.2 ⁇ m within 20 to 25 minutes the prepared aqueous mixture of lecithin, glycerol and sodium oleate was added with constant stirring, the mixture being treated simultaneously by a mechanical high-frequency device (Ultra-Turrax) while the fine generator (G6) and coarse generator (G2) were running. After the X-ray contrast medium had been completely added, the crude emulsion formed was further emulsified for 25 minutes. During the preparation of the raw emulsion, this was kept at a temperature in the range of 55 to 65 ° C and constantly blanketed with nitrogen.
  • the raw emulsion was passed through a membrane filter with an average pore size of 40 ⁇ m (trade name HDC H 400) under a nitrogen pressure of approx. 0.5 bar into a suitable 2 for the production of fat emulsions with gentle stirring -stage homogenizer (Gaulin two-stage homogenizer) and homogenized there in the first stage at 400 bar and in the second stage at 100 bar.
  • the required homogenization pressure was achieved with a hot distillate through a by-pass. It was then switched to the emulsion.
  • the temperature was approx. 60 ° C.
  • the emulsion formed was placed in a storage tank overlaid with nitrogen. Here the emulsion was allowed to rest with occasional slow stirring.
  • the emulsion was then subjected to 2 further homogenization steps, the temperature again being kept at about 60.degree.
  • the emulsion was cooled as much as possible and placed in a template which contained 500 ml of oxygen-free distilled water cooled to 12 ° C. and 0.89 g of disodium hydrogen phosphate ⁇ 2 H. 0.
  • nitrogen was no longer gassed, but only an overlay.
  • the stirrer was switched off. The pH of the emulsion was checked.
  • Deviations from the specified target value were corrected by adding 2.2 ml of 1N sodium hydroxide solution.
  • the emulsion obtained was stored in a cooling tank under a nitrogen atmosphere and, before filling, was filtered through a membrane filter with a pore size of 2 to 8 ⁇ m, the filling pressure being a maximum of 0.5 bar.
  • the filling was carried out under nitrogen protective gas in glass infusion bottles (quality class II), with nitrogen being gassed during the filling so that the oxygen content in the glass bottles was less than 0.1 mg / l. After filling, the bottles were closed and crimped with hollow stoppers.
  • the emulsions according to the invention must be protected from light and oxygen during production and storage.
  • the emulsion filled into the glass infusion bottles was then heat sterilized in a rotary autoclave at 121 ° C. for 15 minutes.
  • the emulsion had a pH of 10.0 before sterilization and a pH of 7.1 after sterilization.
  • the density of the emulsion was 1.046 before and after sterilization.
  • the osmolality of the emulsion was 278 mosm / 1.
  • the optical test showed that the emulsion obtained met the usual criteria of a parenterally applicable O / W emulsion both before and after the sterilization.
  • the particle size distribution in the emulsion was determined before the sterilization by dynamic light scattering (Automizer 2c, Malvern) and after the sterilization using the Coulter method. These measurements were carried out using an "Elzone” measuring device from Particle Data. The following results were obtained:
  • the filled emulsion was stored protected from light at + 4 ° and 21 ° C. Random samples showed that after a storage period of 14 and 35 days the emulsion was still in order and that the partially sedimented droplets could be redispersed unchanged by shaking the bottles gently.
  • Example 2 Further O / W emulsions of an X-ray contrast medium were produced in the manner described in detail in Example 1, which have the composition described below and differ only in the type and amount of the buffer system specified below.
  • an emulsion without a buffer system was produced as example 2, which of course could not be heat-sterilized, and its particle size distribution was determined in the non-sterilized state, while in the emulsions of examples 3 to 9 after sterilization in a rotary autoclave, 15 minutes at 121 ° C the particle size distribution was measured.
  • Example 2 no buffer system
  • Example 3 5 mmol / 1 Na 2 HP0 4 x 2 H 2 0 + 0.68 mmol / 1 NaOH
  • Example 4 5 mmol / 1 Na 2 HP0 4 x 2 H 2 0 + 1.2 mmol / 1 NaOH
  • Example 5 5 mmol / 1 Na-, HP0 4 x 2 H., 0 + 1.5 mmol / 1 NaOH
  • Example 6 5 mmol / 1 Na 2 HP0 4 x 2 H 2 0 + 2.2 mmol / 1 NaOH
  • Example 7 5 mmol / 1 sodium glycerophosphate + 1.1 mmol / 1 NaOH
  • Example 8 5 mmol / 1 sodium glycerophosphate +
  • Average particle size measured via dynamic light scattering (Autosizer 2c, Maemper company) 264 nm
  • Buffer system sodium glycerophosphate + NaOH

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Dispersion Chemistry (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une émulsion huile dans l'eau d'un agent de contraste radiographique, pouvant être administrée par voie parentérale et thermostérilisable, comprenant une phase intérieure constituée d'un ou de plusieurs composés d'iode organique, solubles dans l'eau, adéquats, en particulier des esters d'acide gras iodés, un ou plusieurs émulsifiants et, le cas échéant, des co-émulsifiants, ainsi qu'une phase extérieure d'eau distillée contenant des additifs isotonisants, ladite émulsion étant caractérisée par une teneur en un tampon physiologiquement acceptable de soude caustique et un ou plusieurs phosphates adéquats inorganiques et/ou organiques. Les émulsions obtenues se distinguent par une très bonne stabilité au stockage et à la chaleur, ce qui leur permet de pouvoir être stabilisées en autoclave à 121°C.
EP92907897A 1991-04-12 1992-04-08 Emulsions huile dans l'eau d'un agent de contraste radiographique pouvant etre administrees par voie parenterale et thermo-sterilisables Withdrawn EP0578707A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4111939 1991-04-12
DE4111939A DE4111939A1 (de) 1991-04-12 1991-04-12 Parenteral verabreichbare, hitzesterilisierbare o/w-emulsion eines roentgenkontrastmittels

Publications (1)

Publication Number Publication Date
EP0578707A1 true EP0578707A1 (fr) 1994-01-19

Family

ID=6429433

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92907897A Withdrawn EP0578707A1 (fr) 1991-04-12 1992-04-08 Emulsions huile dans l'eau d'un agent de contraste radiographique pouvant etre administrees par voie parenterale et thermo-sterilisables

Country Status (19)

Country Link
EP (1) EP0578707A1 (fr)
JP (1) JPH06506453A (fr)
CN (1) CN1065595A (fr)
AU (1) AU1536292A (fr)
BR (1) BR9205944A (fr)
CA (1) CA2101430A1 (fr)
CZ (1) CZ193993A3 (fr)
DE (1) DE4111939A1 (fr)
FI (1) FI934478A (fr)
HU (1) HUT65238A (fr)
IE (1) IE921027A1 (fr)
IL (1) IL101231A0 (fr)
MX (1) MX9201589A (fr)
NO (1) NO933672L (fr)
NZ (1) NZ242237A (fr)
PT (1) PT100378A (fr)
SK (1) SK109793A3 (fr)
WO (1) WO1992018168A1 (fr)
ZA (1) ZA922580B (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
SE470086B (sv) * 1991-04-23 1993-11-08 Kabi Pharmacia Ab Organspecifik emulsion
DE4316722A1 (de) * 1993-05-19 1994-11-24 Fresenius Ag Parenteral verabreichbare, unter Hitzesterilisationsbedingungen stabile O/W-Emulsion eines Röntgenkontrastmittels
JP4670229B2 (ja) * 2003-06-10 2011-04-13 味の素株式会社 Ｃｔコロノグラフィにおける消化管造影用組成物
WO2012080279A1 (fr) * 2010-12-17 2012-06-21 Universite De Strasbourg Produits radiopaques iodés destinés à être utilisés dans l'imagerie médicale et leurs procédés de préparation
JP6578504B2 (ja) 2013-04-30 2019-09-25 パナソニックＩｐマネジメント株式会社 スクロール圧縮機
CN114288427A (zh) * 2022-03-01 2022-04-08 福建宸润生物科技有限公司 一种肠胃道口服ct造影剂

Family Cites Families (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE1617275B1 (de) * 1966-04-13 1971-05-13 Ab Leo R¦ntgenkontrastmittel
DE2602907C2 (de) * 1976-01-27 1978-03-30 Stephan Dr.Med. 4400 Muenster Roth Röntgenkontrastmittel auf der Basis einer Emulsion von jodierten ölen
US4278654A (en) * 1978-07-04 1981-07-14 Nyegaard & Co. A/S Process for the preparation of a sterile injectable physiologically acceptable solution of an X-ray contrast agent and solutions of the X-ray contrast agent and a buffer
US4404182A (en) * 1980-01-08 1983-09-13 The United States Of America As Represented By The Department Of Health And Human Services Ethiodized oil emulsion for intravenous hepatography
ES2054706T3 (es) * 1987-06-11 1994-08-16 Kabi Pharmacia Ab Emulsion que contiene yodo.
DE3722540A1 (de) * 1987-07-08 1989-01-19 Fresenius Ag Fettemulsion, verfahren zu ihrer herstellung und ihre verwendung

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9218168A1 *

Also Published As

Publication number Publication date
FI934478A0 (fi) 1993-10-11
BR9205944A (pt) 1994-07-05
WO1992018168A1 (fr) 1992-10-29
JPH06506453A (ja) 1994-07-21
PT100378A (pt) 1993-06-30
IL101231A0 (en) 1992-11-15
NO933672D0 (no) 1993-10-12
HU9302863D0 (en) 1993-12-28
CN1065595A (zh) 1992-10-28
SK109793A3 (en) 1994-05-11
ZA922580B (en) 1992-11-25
NO933672L (no) 1993-10-12
CA2101430A1 (fr) 1992-10-13
NZ242237A (en) 1993-04-28
DE4111939C2 (fr) 1993-02-25
AU1536292A (en) 1992-11-17
CZ193993A3 (en) 1994-03-16
IE921027A1 (en) 1992-10-21
FI934478A (fi) 1993-10-11
HUT65238A (en) 1994-05-02
MX9201589A (es) 1992-10-01
DE4111939A1 (de) 1992-10-22

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