WO2012123229A1 - Produit de constraste radiographique négatif et fixe destiné à représenter le tube gastro-intestinal - Google Patents

Produit de constraste radiographique négatif et fixe destiné à représenter le tube gastro-intestinal Download PDF

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Publication number
WO2012123229A1
WO2012123229A1 PCT/EP2012/053074 EP2012053074W WO2012123229A1 WO 2012123229 A1 WO2012123229 A1 WO 2012123229A1 EP 2012053074 W EP2012053074 W EP 2012053074W WO 2012123229 A1 WO2012123229 A1 WO 2012123229A1
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WO
WIPO (PCT)
Prior art keywords
microspheres
solid
contrast agent
ray contrast
agent
Prior art date
Application number
PCT/EP2012/053074
Other languages
German (de)
English (en)
Inventor
Ulrich Speck
Matthias Bräutigam
Melanie Biedermann
Original Assignee
Innora Gmbh
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 Innora Gmbh filed Critical Innora Gmbh
Publication of WO2012123229A1 publication Critical patent/WO2012123229A1/fr

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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
    • A61K49/0409—Physical forms of mixtures of two different X-ray contrast-enhancing agents, containing at least one X-ray contrast-enhancing agent which is not a halogenated organic compound
    • A61K49/0414—Particles, beads, capsules or spheres
    • A61K49/0419—Microparticles, microbeads, microcapsules, microspheres, i.e. having a size or diameter higher or equal to 1 micrometer

Definitions

  • the present invention relates to a solid X-ray contrast agent for displaying the gastrointestinal tract comprising microspheres having a void volume of at least 25% of the total volume, wherein in the cavity at least one gas is contained and which is characterized in that the microspheres are embedded in a dry binder.
  • X-ray contrast agents also referred to as "contrast agent” in the following
  • contrast agent increases the contrast of organs and organ systems with the aim of differentiating between tissues of similar radiopacity
  • the increase in contrast may be due to substances of low or absent absorption, so-called negative contrast agents, or by substances of high absorption, Examples of negative contrast agents are air and gases, which do not absorb x-rays and therefore appear black compared to the soft tissues in the x-ray Positive positives are less permeable to x-rays than soft tissue and therefore appear white in the image.
  • CT computed tomography
  • HE Hounsfield units
  • Imaging of the upper gastrointestinal tract is often accomplished with the aid of oral contrast agents which have increased electron density, for example
  • Barium sulfate or iodine-containing contrast agents positive contrast agents
  • help conventional or digital X-ray techniques such as computed tomography.
  • the imaging of the colon is usually done by barium enema.
  • Positive contrast agents can not always differentiate wall changes, for example in tumors. Likewise, they do not allow for improved visualization of the intestinal wall by additional intravenous administration of a positive contrast agent.
  • Aqueous suspensions are heterogeneous mixtures of water and finely divided solids, which are often suspended in the liquid. Suspensions are thermodynamically unstable and often require additional components to keep the suspension stable. Such systems involve several limitations that hinder the development and approval of the competent authorities. The stability of the aqueous suspensions is limited and simple sterilization is not possible. Furthermore, the patient must be administered a large volume of the suspension, which is cumbersome for this. In addition, aqueous suspensions require a complicated pharmaceutical formulation which complicates development, among other things because time-consuming and costly stability tests must be performed.
  • the volume of negative contrast agent required for imaging after oral administration is dependent on the gas content of the selected formulation. tion. Unger describes a maximum gas content of his liquid formulations, but this would lead to a very high volume to be recorded for the patient.
  • the object of the present invention was to provide an X-ray contrast agent which overcomes the above-mentioned disadvantages, i. in particular has an improved stability to the aqueous suspensions, is a simple pharmaceutical preparation formulation and is therefore suitable for approval by the competent authorities and the clinical application.
  • a fixed X-ray contrast agent for displaying the gastrointestinal tract which in a preferred form comprises microspheres with a void volume of at least 25% of the total volume, wherein at least air or another gas is contained in the cavity and which is characterized in that the microspheres embedded in a dry binder.
  • the word "comprise” here means “consist of”, i. the solid X-ray contrast agent preferably consists of microspheres with a void volume of at least 25% of the total volume, wherein the cavity contains at least air or another gas embedded in a dry binder.
  • the solid X-ray contrast agent is preferably used for enteral administration.
  • enteral refers to the delivery or loss of drugs or food, electrolytes or trace elements via the intestine. Enteral access routes are therefore the mouth (oral) and the rectum (actually rectum, therefore rectal access routes). Enteral administration may be by gavage, PEG tube or PEJ. Particularly preferred is the use of the solid X-ray contrast agent for oral or rectal administration.
  • the dry binder is preferably a dried agglutinating agent or a pudding or jelly powder having at least one gelling agent.
  • the microspheres are embedded therein in a solid matrix formed by the agglutinating agent.
  • the pudding or jelly powder as a binder the microspheres are present in non-demixable form. "Non-demixable" means that no separation takes place even after prolonged mechanical action (shaking).
  • the binder may contain additional substances such as mannitol and / or flavorings. The primary goal is to pack as dense a package as possible
  • microspheres which are then taken by the patient (possibly with a little liquid). Since these microspheres contain gas (s), it is a negative contrast agent.
  • gas s
  • the agglutinating agent enables the improved cohesion of the individual microspheres in the solid preparation. It must have agglutinating properties and preferably a pleasant or at least neutral taste for oral administration and be toxicologically safe. It may be a natural product such as a vegetable or fruit pulp, sugars (for example, sucrose) or sugar derivatives (for example, sugar alcohols such as mannitol) or syrup or chocolate, or a synthetic product. "Sugars" here include both mono- and Di-saccharides Preference is given to vegetable or fruit pulp or their combination, particularly preferably fruit pulp based on fruit, cereal or maize flour, in particular applesauce, but also better defined substances such as proteins, polysaccharides or fats are also preferred.
  • Another preferred embodiment is a non-separable pulverulent coating, on the one hand microspheres and on the other hand a pudding or
  • This pudding or jelly powder contains at least one gelling agent, e.g. Carrageenan or gelatin.
  • Other food-containing additives e.g., egg whites, preservatives
  • egg whites, preservatives may be included (such as in instant cream puddings or jellies).
  • stabilizers, emulsifiers etc. commonly used in foods.
  • This non-demixable pulverulent spread is mixed with a liquid only before application.
  • the initial mass or cream (pudding, porridge jelly, e.g., jelly) is then ingested by the patient.
  • gelling agent is synonymous with “thickening agent”. This refers to food additives which swell or bind with water, that is to say by thickening a wished to give consistency. In the present context, only the gelling agents acceptable from a food-technical point of view are included here. These are primarily made of polygons or vegetable or animal proteins.
  • agar-agar E 406
  • alginic acid E 400
  • ammonium alginate E 403
  • calcium alginate E 404
  • potassium alginate E 402
  • sodium alginate E 401
  • pectin E 440
  • amidated pectin E 440N
  • carrageenan E 407
  • furcellaran E 407 assigned
  • gelatin gellan (E 418)
  • guar gum E 412
  • gum arabic E 414)
  • locust bean gum E 410
  • karaya E 416)
  • Propylene glycol alginate E 405)
  • tara gum E 417
  • tragacanth E 413)
  • xanthan E 415) and modified starches.
  • microspheres are hollow bodies with a void volume of at least 75% of the total volume of the individual microsphere which contain at least one gas in this void
  • the term "at least one gas” comprises pure gases and gas mixtures of two or more gases.
  • the at least one gas is preferably selected from air, carbon dioxide, oxygen, nitrogen, helium, neon, argon or xenon, any at room temperature (20 ° C) gaseous organic compounds such as hydrocarbons, or halogenated, preferably fluorinated hydrocarbons.
  • Gaseous hydrocarbons at room temperature are preferably CrC 5 -hydrocarbons which are branched or unbranched (methane to pentane).
  • microspheres which have the gas / gases distributed over several cavities, ie for example microspheres made of styrofoam. Also included are microspheres, which have inside a single filled with gas / gases central cavity. The latter, ie microspheres with an internal central cavity, are preferred.
  • microspheres are generally described, for example, by Unger in US Pat. No. 6,528,039 B2.
  • materials of the microspheres biocompatible, metabolically stable and slowly biodegradable natural and synthetic polymers or copolymers, eg cyanoacrylates, polylactides
  • the density of the microspheres is preferably less than 0.1 g / cm 3 . More preferably, the density of the microspheres is between 0.020 and 0.10 g / cm 3 , most preferably less than 0.050 g / cm 3 .
  • the outer diameter, ie the size of such microspheres is preferably 1 to 500 ⁇ .
  • the microspheres have no uniform outer Diameter, but there is a size distribution between 1 and 500 ⁇ , preferably between 10 to 250 ⁇ , more preferably between 10 and 100 ⁇ , in the sense of a normal distribution. Accordingly, the average outer diameter between 1 and 500 ⁇ , preferably between 10 and 250 ⁇ , more preferably between 10 and 100 ⁇ .
  • a non-uniform size distribution allows a denser packing in the solid form.
  • a greater variance in size distribution may be desirable.
  • Suitable microspheres are commercially available, for example, under the trade name Expancel® from AkzoNobel. Examples include Akzo Nobel Expancel® 551 DE 40 d42 with a density of 0.042 ⁇ 0.004 g / cm 3 and an average outer diameter of 40 ⁇ m (30-50 ⁇ m) or Akzo Nobel Expancel® 461 DET 40 d25 with one density of 0.025 ⁇ 0.003 g / cm 3 and an average outer diameter of 40 ⁇ (35-55 ⁇ ) or Akzo Nobel Expancel® 461 DET 80 d25 with a density of 0.025 ⁇ 0.003 g / cm 3 and a mean outer diameter of 80 ⁇ (60-90 ⁇ ⁇ ), or expander 092 DET 100 d25 with a density of 0.025 ⁇ 0.003 g / cm 3 and a mean diameter of 80-120 ⁇ .
  • microspheres preferably consist of a biocompatible and toxicologically harmless synthetic polymer or copolymer as described by Unger in US Pat. No. 6,528,039 B2. They may have a surface modification that enhances the solid state agglutination properties, but must ensure rapid separation of the microspheres when ingested by the patient with a liquid or in the gastrointestinal fluids.
  • the shell of the microspheres is preferably flexible and smooth, so that compression with deformation during the drying process of the X-ray contrast agent with dried agglutinating agent is possible. This allows a further reduction of the space requirement and thus a reduction in the density of the X-ray contrast agent and improves patient acceptance.
  • European Pharmacopoeia excipients such as disintegrants may also be included in the solid X-ray contrast agent to achieve rapid release and distribution of microspheres in the gastrointestinal tract after ingestion.
  • non-absorbable or poorly absorbable osmo-active substances such as mannitol or sorbitol may be included. These give an initale
  • Hyperosmolarity in the gastrointestinal tract which improves CT imaging via extension of the gastrointestinal tract.
  • the preparation of the solid X-ray contrast medium which comprises microspheres in a matrix of dried agglutinating agent, takes place in such a way that the
  • Microspheres are mixed with an agglutinating agent, the mixture is molded and / or pressed into a predetermined shape and then dried. Preferably, temperatures of up to 40 ° C, more preferably between 20 and 30 ° C are used for the drying. Alternatively, a freeze or spray drying can take place. There are no restrictions on the shape and size of the compacts.
  • the pellets can be crushed and encapsulated as beads or granules or coated like dragees to protect against premature decay.
  • At least one further evaporation solvent is additionally added to the mixture of microspheres and agglutinating agent, which is, for example, water.
  • agglutinating agent which is, for example, water.
  • water is preferred as an additional evaporating agent, since the pulp also contain water and water is harmless from a food-technical point of view.
  • Other preferred liquids for flooding and mixing the components prior to molding and drying are volatile, low dose, nontoxic solvents such as ethanol.
  • the mixture is sterilized before or after drying, whereby most common sterilization methods can be used, preferably by means of ethylene oxide.
  • the microspheres are uniformly mixed with the pudding or jelly powder. This mixture does not separate even after prolonged storage or after transport, even by mechanical shocks, it is virtually unmemable.
  • the solid X-ray contrast agent has a minimal content of agglutinant or pudding / jelly powder or other excipients. This allows a high content of gas (s) and thus increases the efficiency of this negative X-ray contrast agent.
  • at least 50% (VA /), more preferably at least 70% (VA), most preferably at least 90% (VA /) of the solid X-ray contrast agent is encapsulated gas (s), and the capsule material is not during the gastrointestinal passage dissolved, digested or degraded.
  • the solid X-ray contrast agent based on the dried agglutinating agent can also be converted into granular pharmaceutical formulations by careful comminution and suitable screening methods.
  • the solid X-ray contrast agent is then preferably in the form of tablets or granules, wherein granules preferably also include pellets (spherical or cylindrical shape, preferably spherical shape). These forms can be encased or coated by established pharmaceutical procedures.
  • the X-ray contrast agent in its solid form is stable in storage and transport.
  • the solid forms based on the dried agglutinating agent for example pellets, may be taken with some water.
  • the powder preparation is mixed with a liquid before application. After the stiffening or solidification of the powder or jelly, the solidified mass, the porridge or the firm cream is taken by the patient.
  • a positive extracellular X-ray contrast agent can additionally be administered intravenously. Its administration improves the contrast between the gastrointestinal lumen containing the negative X-ray contrast agent of the invention and the perfused blood-labeled gastrointestinal wall. Description of the pictures
  • Figure 1 shows whole body CT images of rats given a formulation of Akzo Nobel Expancel® 551 DE 40 d42 balls in dried applesauce.
  • the solid contrast agent was prepared for administration in an animal experiment by gavage with a little water to a slurry.
  • a control rat (Tier 3) received applesauce without microspheres.
  • the whole-body CT images show a very well-visible blackened rat stomach with a smooth stomach wall (animals 1, 2, 4.5), which does not show up in the CT image of the control animal (animal 3 only applesauce).
  • a solid formulation of Akzo Nobel Expancel® 551 EN 40 d42 microspheres and applesauce was prepared by mixing three volumes of microspheres with one volume of applesauce. From the mixture (the slurry) cubes were molded with volumes of about 4-5ml and dried at room temperature (20 ° C) for three days. The density of a dried cube was about 0.26 g / cm 3 .
  • a formulation with Akzo Nobel Expancel® 551 DE 40 d42 balls in applesauce was prepared as indicated above.
  • the solid contrast agent (volume about 4-5 ml per test animal) was prepared for administration in an animal experiment through a nasogastric tube with a small amount of water to form a gavage that was common in the stomach. Rats weighing about 250g were deprived of food for 12 hours. Subsequently, about 4-5 ml of the porridge was administered to the rats via a probe into the stomach (animals 1, 2, 4, 5). A control rat received 4-5ml applesauce (Tier 3). All rats were anesthetized. Approximately 30 minutes after the formulation or apple sauce was administered, whole body CT images were taken.
  • Fig. 1 shows after application of the negative contrast agent a very visible, blackened rat stomach with smooth stomach wall (animals 1, 2, 4, 5) in the CT image of the control animal (Tier 3, only applesauce ) does not represent.
  • Example 2 shows after application of the negative contrast agent a very visible, blackened rat stomach with smooth stomach wall (animals 1, 2, 4, 5) in the CT image of the control animal (Tier 3, only applesauce ) does not represent.
  • a solid formulation of Akzo Nobel Expancel® 551 DE 40 d42 microspheres and mannitol was obtained by mixing 1.18 g of mannitol, about 30 ml of mirospheres, and 5 ml of water. From the mixture (the slurry) cubes were formed with a volume of about 5ml and dried at room temperature for three days. The density of a dried cube was 0.12 g / ml.
  • a powder formulation for direct preparation before ingestion by the patient was prepared as follows. 10 g of a finished cream pudding powder, here paradise cream Oetker (contains as emulsifier mono- and diglycerides of fatty acids and as gelling agents carrageenan) were mixed with 25 ml Akzo Nobel Expancel® 551 DE 40 d42 microspheres. For the application, the finished mixture was made up to 50 ml with milk and stirred. After solidification, a semi-solid cream was present.
  • a finished cream pudding powder here paradise cream Oetker (contains as emulsifier mono- and diglycerides of fatty acids and as gelling agents carrageenan) were mixed with 25 ml Akzo Nobel Expancel® 551 DE 40 d42 microspheres.
  • the finished mixture was made up to 50 ml with milk and stirred. After solidification, a semi-solid cream was present.

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

Abstract

L'invention concerne un produit de contraste radiographique fixe comprenant des microsphères pour la représentation du tube gastro-intestinal, lesdites microsphères étant dotées d'un volume des vides d'au moins 25 % du volume total, au moins un gaz étant contenu dans les vides. Ledit produit est caractérisé en ce que les microsphères sont enrobées dans un liant sec. L'invention concerne en outre la fabrication de ce produit de contraste radiographique et l'utilisation dudit produit.
PCT/EP2012/053074 2011-03-11 2012-02-23 Produit de constraste radiographique négatif et fixe destiné à représenter le tube gastro-intestinal WO2012123229A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102011005444A DE102011005444A1 (de) 2011-03-11 2011-03-11 Festes, negatives Röntgenkontrastmittel zur Darstellung des Gastrointestinaltraktes
DE102011005444.8 2011-03-11

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WO2012123229A1 true WO2012123229A1 (fr) 2012-09-20

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Citations (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980002365A1 (fr) * 1979-05-04 1980-11-13 Rasor Ass Inc Amelioration d'images ultrasoniques
WO1991015244A2 (fr) * 1990-04-02 1991-10-17 Sintetica S.A. Suspensions stables de microbulles injectables dans des organism es vivants
EP0458745A1 (fr) * 1990-05-18 1991-11-27 BRACCO International B.V. Microcapsules polymères remplies d'air ou de gaz, utilisables sous forme de suspensions dans les supports liquides pour l'échographie ultrasonore
WO1992017514A1 (fr) 1991-04-05 1992-10-15 Unger Evan C Microspheres de faible densite et leur utilisation comme agents de contraste en scanographie
WO1995006518A1 (fr) * 1993-09-03 1995-03-09 Nycomed Imaging A/S Microbulles encapsulees par tensioactifs polymeres et leur utilisation dans l'imagerie par ultrasons
WO1999030620A1 (fr) * 1997-12-18 1999-06-24 Imarx Pharmaceutical Corp. Agents de contraste optoacoustiques et procedes d'utilisation
WO1999053963A1 (fr) * 1998-04-22 1999-10-28 Marsden, John, Christopher Ameliorations apportees a des agents de contraste ou en rapport avec ces agents
WO2000051136A1 (fr) * 1999-02-25 2000-08-31 Nycomed Amersham Plc Instrument ou outil medical a visibilite amelioree aux ultrasons
WO2002030482A1 (fr) * 2000-10-11 2002-04-18 Ethicon Gmbh Implant zonal à éléments détectables par ultrasons
US20030064027A1 (en) * 1990-05-18 2003-04-03 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
WO2003061593A2 (fr) * 2002-01-23 2003-07-31 Imarx Therapeutics, Inc. Nouvelles compositions ciblees destinees a une utilisation diagnostique et therapeutique

Family Cites Families (1)

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DE19813174A1 (de) * 1998-03-25 1999-05-27 Schering Ag Mikropartikel aus Polymeren und mindestens einer gerüstbildenden Komponente und ihre Herstellung und Verwendung in der Ultraschalldiagnostik und zur ultraschallinduzierten Wirkstofffreisetzung

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1980002365A1 (fr) * 1979-05-04 1980-11-13 Rasor Ass Inc Amelioration d'images ultrasoniques
WO1991015244A2 (fr) * 1990-04-02 1991-10-17 Sintetica S.A. Suspensions stables de microbulles injectables dans des organism es vivants
EP0458745A1 (fr) * 1990-05-18 1991-11-27 BRACCO International B.V. Microcapsules polymères remplies d'air ou de gaz, utilisables sous forme de suspensions dans les supports liquides pour l'échographie ultrasonore
US20030064027A1 (en) * 1990-05-18 2003-04-03 Bracco International B.V. Ultrasound contrast agents and methods of making and using them
WO1992017514A1 (fr) 1991-04-05 1992-10-15 Unger Evan C Microspheres de faible densite et leur utilisation comme agents de contraste en scanographie
US6528039B2 (en) 1991-04-05 2003-03-04 Bristol-Myers Squibb Medical Imaging, Inc. Low density microspheres and their use as contrast agents for computed tomography and in other applications
WO1995006518A1 (fr) * 1993-09-03 1995-03-09 Nycomed Imaging A/S Microbulles encapsulees par tensioactifs polymeres et leur utilisation dans l'imagerie par ultrasons
WO1999030620A1 (fr) * 1997-12-18 1999-06-24 Imarx Pharmaceutical Corp. Agents de contraste optoacoustiques et procedes d'utilisation
WO1999053963A1 (fr) * 1998-04-22 1999-10-28 Marsden, John, Christopher Ameliorations apportees a des agents de contraste ou en rapport avec ces agents
WO2000051136A1 (fr) * 1999-02-25 2000-08-31 Nycomed Amersham Plc Instrument ou outil medical a visibilite amelioree aux ultrasons
WO2002030482A1 (fr) * 2000-10-11 2002-04-18 Ethicon Gmbh Implant zonal à éléments détectables par ultrasons
WO2003061593A2 (fr) * 2002-01-23 2003-07-31 Imarx Therapeutics, Inc. Nouvelles compositions ciblees destinees a une utilisation diagnostique et therapeutique

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Title
MALIK N; KHANDELWAL N; GARG K; SURI S, AUSTRALAS RADIOL., vol. 36, no. 1, February 1992 (1992-02-01), pages 31 - 3

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