DE102004006048B4 - An intravenous injection or infusion solution containing a combination drug for use as a contrast enhancer in MR angiography - Google Patents

Abstract

Intravenous injection or infusion solution containing as a first component a low molecular weight gadolinium complex and as a second component a biopolymer together with a pharmaceutically acceptable carrier or excipient in which the Gd complex is molecularly dispersed and the biopolymer is colloidally dissolved.

Description

The The present invention describes a combination medicament for Use as contrast-enhancing Means in MR angiography, which consists of a Gd complex and a colloid dissolved Biopolymer for intravenous Application exists.

Water soluble gadolinium Complexes have been diminishing in MR imaging for some time intravenous Gift for contrast enhancement used. As Gd complexes are essentially in the international market Gd-Dota, Gd-HP-DO3A, Gd-DTPA and Gd-DTPA_BMA known as non-specific, extracellular Contrast agent mainly for the Presentation of cerebrospinal lesions be used. The molecular weight of these Gd complexes is less than 1 kD.

drug make with these contrasting agents aqueous, molecular disperse, sterile solutions these Gd complexes are in a generally 0.5 molar concentration and in for the application of suitable containers.

In Lately, numerous applications have been described which the representation of diseases of the entire body for example the representation of the vascular system (Angiography, perfusion studies) have the goal. The improvement of the imaging techniques (fast imaging, very fast 3D techniques, subtraction techniques) are the prerequisite for this as well like application techniques of the contrast agent itself, which is based on a Synchronization of the i. v. Target Bolus with the so-called 'imaging time'.

The decisive disadvantages of these applications are that comparatively very high concentrations (up to three times the concentration of clinically usual Dosage according to z. Eg 0.3 mmol / kg body weight) of the contrast agent are required and these studies only with little disseminated so-called 'high end 'scanner possible are. Desirable would be a MR angiography method, which is applicable to standard MRI scanners would.

Of the essential reason for the unfavorable Characteristics of non-specific, extracellular MR contrast agents for angiography It can be found in a short time from the plasma chamber diffuse into interstitial space and thus those for imaging lose necessary concentration quickly.

Reported z. B. on attempts to extend by significantly increasing the molecular weight of Gd complexes at the same time high relaxivity of these compounds, the residence time in the vascular space. The disadvantage of this method, however, is that such compounds (for example: see polymer dendritic Gd complexes WO95 / 28966 , 1995) can be produced only with great expense synthetically and at high costs and have to be clinically extensively tested for diagnostic efficacy and tolerability before wide use can be made in diagnostic imaging.

In the patent DE 3640708 C2 is reported by a chemical conjugation of dextran to the complexing agent DTPA with subsequent complex formation with Gd, this method also has the above-mentioned disadvantages compared to the present invention.

In Clinical practice has long been artificial (exogenous) biopolymers than Volume substitutes used which are physically polydisperse colloidal solutions with particle sizes are to be described in the nanometer range. Are widely used for this Application artificial Colloids based on polypeptides (gelatin) and polysaccharides (Dextran, hydroxyethyl starch (HES)), acetyl starch, Hydroxypropyl starch.

These in addition to the cost advantage compared to endogenous colloids (human albumin, Plasma proteins) the property that they are in sufficient and in high quality to disposal stand and have a very long clinical experience safe use busy.

in the Compared to the earlier used crystalloid volume replacement agents (Ringer's lactate, physiological Saline) The Kollidalen products have the advantage of a long volume effect. While Crystalloids have an effectiveness over only 30-40 Minutes show that colloidal substitutes usually work for 3-4 hours (t1 / 2) p. appl.

From the DE 195 29 921 C2 is a mixture for the ventilation of the lung known wel ches next to a surfactant, a contrast agent, which can be based on a Gd complex contains. To achieve a higher density of relaxable protons in the lung tissue, the formulation may optionally be highly hydratable polymers and / or hydrogel formers such. As cellulose. Intravenous administration of this composition is not possible due to the surface active substances in any case, as there is an excessive risk of histamine release.

Especially HES based colloids have become common in the pharmaceutical industry Concentrations of 6-10% as a practically ideal well controllable and safe volume replacement proven, which does not cause tissue storage and plasma accumulation.

HES Nanoparticles are over intravasal degradation enzymes (alpha-amylases) enzymatically cleaved and lose within a few hours depending on mol. weight and degree of substitution the used biopolymer their physical form and are called Low molecular substances over the kidney excreted.

HES does not influence any diagnostic tests, it is easy to combine with Medicines and exhibits in the clinically used dosages no antigenic or allergenic properties.

HES binds in considerable Scope water at the surface the spherical one HES nanoparticles. The water binding capacity is usually 20 times the net weight of the HES nanoparticles. HES also has one short-term increase of colloidal pressure (KOD) and potentially occludes endothelial Gaps by its high molecular weight, and thereby acts the physiological or increased pathologically Vascular permeability contrary.

task The invention is to provide a contrast agent which overcome the mentioned disadvantages.

The Task is solved by an intravenous to be administered injection or Infusion, the first component of a low molecular weight gadolinium complex contains and as a second component a biopolymer together with a pharmaceutical acceptable vehicle or excipients, in which the Gd-complex is molecularly disperse and the biopolymer colloidally solved is.

in the Course of investigations that have led to this invention, A simple method was found to be very detrimental to imaging Effect of rapid diffusion (= extravasation) of nonspecific Slowing down Gd complexes in the interstitial space significantly.

combined you very well water-soluble low molecular weight Gd complexes in a suitable ratio with colloidally dissolved Biopolymers, not only as described above, a considerable Volume of water bound to the biopolymer, but surprisingly and so far also not described therein in molecularly dispersed Gd complexes.

The water shell the HES nanoparticle serves as a temporary storage for the used Gd-complexes, with the effect of a delayed Extravasation of Gd complexes in the interstitial space. The increase of colloid-osmotic pressure and postulated in the literature Closure of endothelial gaps supports and reinforced the effect of the intended extravasation delay.

The inventive combination of HES nanoparticles and Gd complexes allows the easy production and use of MR contrast agents in the whole body representation in particular angiography with conventional MR tomographs and avoids the disadvantages of the risks associated with other approaches and the high costs.

These The invention preferably relates to Gd-DTPA and gadobutrol in Combination with hydroxyethyl starch having a molecular weight (Mw) between 450 kD and 100 kD and C2 / C6 substitution levels in the Range from 0.7 to 0.3.

The claimed product preferably contains the Gd-DTPA in a 0.25-0.5 molar, the gadobutrol in a 0.5-1 molar concentration and HES in the medically used concentration range of 4-10% (w / w) and about that. The volume of the solution can be chosen to allow both iv bolus application and iv infusion. The primary containers include conventional pharmaceutical containers made of glass or plastic as well as pre-filled syringes, cartridges or other ge Suitable application systems that can contain the contrast agent and the biopolymer in separate compartments (eg: dual-chamber syringe) of the application system.

Independent of the preferred combination claimed is to be expected that too other Gd complexes with the same or with Gd-DTPA or gadobutrol comparable properties in combination with HES or others in clinical practice suitable biopolymers the desired Show properties and thus included in this invention are.

Special Attention is paid to the selection of a suitable collidual bioplymer to use.

While Dextrane and gelatin by molecular weight averages (mass average, Mw or Number average molar mass, Mn) are characterized and these Key figures for the biological and pharmacokinetic properties of these colloids are relevant, play at HES more metrics, the place and the Extent of C2 / C6-hydroxyethylation describe, for his biological properties an essential role (Lit. al. 1999). It is between high (HES 450 / 0.7), medium (HES 200 / 0.5) and low-substituted HES types (HES 130 / 0.4) at the same time Differentiation of the molecular weight distinguished.

The optimal benefit risk ratio for the inventive application is achieved when in vivo a molecular weight or adjusts a molecular weight distribution, which is just above the renal threshold (about 60,000 to 70,000 daltons) is as possible few primary kidney common and as possible few high molecular weight (> 450 kD, Mw) contains components. The C2 / C6 degree of substitution the inventive HES materials should be in the range 0.7-0.4.

About the mentioned parameters can also be the distribution behavior of the HES nanoparticles probably also in combination with Gd-complexes regarding their Enrichment in the RES or in the skin to be controlled and thus their side effect profile can be influenced.

The inventive composition of the combined preparation refers to the Use of Gd-DTPA. However, it is foreseeable that other Gd complexes with sufficient water solubility such as GD-DOTA, Gd-DTPA-BMA, Gd-HP-DO3A or gadobutrol with the same or similar Composition of the combined preparation are included.

The inventive composition can in the pharmaceutical Technology known to be varied using additives the antimicrobial, antioxidant, solubilizing or viscosifying properties and improve the application or quality of the claimed Products improved.

to Ensuring sterility and pyrogen free of the claimed composition can be used in the pharmaceutical science usual procedures such as sterilization with strained water vapor in the final container, pasteurization, sterile filtration over a suitable membrane filter under aseptic conditions as well as ultrafiltration applied; these methods can if necessary, also be applied to intermediates.

The Preparation of the inventive Composition can be done directly, by allowing the biopolymer introduced as a solid in the previously prepared solution of the Gd complex and brought to dissolution or by doing that separately prefabricated solutions of both Components combined in the intended mixing ratio and the Be further processed end product.

Of the pH of the inventive Composition should be adjusted in the range 4.5 to 7.5, to the hydrolysis of the biopolymers on the one hand at pH values outside of the claimed area and also to reduce the stability of the Gd complex (Inhibition of dissociation) in the solution falls below the to ensure the claimed area.

The Application of the inventive combination preparation can both over an i. v. Bolus application as well as an i. v. Infusion done. The bolus injection is usually done using a 0.5 molar concentration of the Gd complex, in the infusion application is a lower concentration of z. Ex. 0.25 mol based on applied the Gd complex with a correspondingly higher application volume.

As dispensing container, the usual containers in pharmaceutical practice are included, which consist either of glass with the usual pharmaceutical quality grades with regard to their surface finish (glass type I-II) or of medical grade polymer materials (PE, PET, PVC, COC). The dispensing containers can be designed either as conventional primary containers (ampoule, Injektionsvial, infusion bottle, bag) or prefilled systems (syringes, cartridges), which contain the appropriate amount for the diagnostic purpose of the inventive combination in a directly ready for use Ausbeitungsform.

Examples

example 1

Preparation of a sterile solution of Gd-DTPA and HES from the starting materials

A dispensing container with 10 ml of sterile injection solution of the following composition Gadopentetic acid, dimeglumine salt 4,690 g diethylenetriaminepentaacetic 0.004 g meglumine 0.010 g hydroxyethyl starch 0.700 g Water for injections 6.985 g 12.189 g is by complete dissolution if necessary. With gentle heating of the stoichiometric amount of z. B. 90.7 mg gadolinium oxide in a solution of 197.1 mg Diethylentriaminpentaessigsäure and 196.2 mg meglumine in a subset of the water for injection and by subsequent addition of 700.0 mg HES produced. The batch is filled with water for injections to the final volume or final weight. The mixture is then filtered through a membrane filter (0.2 .mu.m) into a glass vial and sealed. Thereafter, the solution is autoclaved at 121 ° C. The result is a sterile, clear, slightly yellowish solution with a pH of 6.5-7.5.

Example 2

Preparation of a sterile solution of Gd-DTPA and acetyl starch:

A dispensing container with 10 ml of sterile injection solution of the following composition Gadopentetic acid, dimeglumine salt 4,690 g diethylenetriaminepentaacetic 0.004 g meglumine 0.010 g acetyl 0.700 g Water for injections 6.985 g 12.178 g is by complete dissolution if necessary. With gentle heating of the stoichiometric amount of z. For example, 90.7 mg of gadolinium oxide were prepared in a solution of 197.1 mg of diethylenetriaminepentaacetic acid and 196.2 mg of meglumine in a subset of the water for injection and then by adding 700.0 mg of acetyl starch. The batch is filled with water for injections to the final volume or final weight. Subsequently, filtered through a membrane filter (0.2 .mu.m) under aseptic conditions into a glass vial and sealed. The result is a sterile, clear, slightly yellowish solution with a pH of 6.5-7.5. The resulting solution is then stored under controlled temperature conditions.

Example 3

Preparation of a sterile solution of Gd-DTPA and HES by mixing solutions of the components

A dispensing container with 10 ml of sterile injection solution of the following composition Gadopentetic acid, dimeglumine salt 2.345 g diethylenetriaminepentaacetic 0.004 g meglumine 0.005 g hydroxyethyl starch 1,000 g Water for injections 7.188 g 10.542 g is prepared by mixing a 0.5 molar solution of Gd-DTPA with a 20% solution of HES in the ratio 1: 1. The mixture is then filtered through a membrane filter (0.2 .mu.m) into a glass vial and sealed. Thereafter, the solution is autoclaved at 121 ° C. The result is a sterile, clear, slightly yellowish solution with a pH of 6.5-7.5.

Example 4

Preparation of a sterile solution of Gadobutrol and HES by mixing solutions of the components

A dispensing container with 10 ml of sterile injection solution of the following composition gadobutrol 3,003 g Calcobutrol sodium 0.004 g Trometamol / HCl 0.015 g hydroxyethyl starch 1,000 g Water for injections 6.656 g 10.678 g is prepared by mixing a 1 molar solution of gadobutrol with a 20% solution of HES in the ratio 1: 1. The mixture is then filtered through a membrane filter (0.2 .mu.m) into a glass vial and sealed. Thereafter, the solution is autoclaved at 121 ° C. The result is a sterile, clear, slightly yellowish solution with a pH of 6.5-7.5.

Claims (11)

intravenous to be administered solution for injection or infusion, as the first component contains a low molecular weight gadolinium complex and as a second component a biopolymer together with a pharmaceutically acceptable carrier or Excipient in which the Gd-complex is molecularly disperse and the biopolymer colloidally solved is. intravenous An injection or infusion solution to be administered according to claim 1, which is known as first component contains a low molecular weight gadolinium complex and as second component is a compound from the group of hydroxyethyl starch and acetyl as a biopolymer together with a pharmaceutically acceptable carrier or excipient contains in which the Gd-complex is molecularly disperse and the biopolymer colloidally solved is. intravenous to be administered injection or infusion solution according to one of claims 1 or 2, which is the first component of a compound from the group of Gd-DTPA and gadobutrol as a low molecular weight gadolinium complex and as a second component a compound from the group of hydroxyethyl starch and acetyl as a biopolymer together with a pharmaceutically acceptable carrier or Excipient in which the Gd-complex is molecularly disperse and the biopolymer colloidally solved is. intravenous To be administered injection or infusion solution according to one of claims 1 to 3, the first component of a compound from the group of Gd-DTPA and gadobutrol as a low molecular weight gadolinium complex in a concentration of 0.1-1.0 mol / ltr. contains and as a second component, a compound from the group of hydroxyethyl starch and acetyl as a biopolymer together with a pharmaceutically acceptable carrier or Excipient in which the Gd-complex is molecularly disperse and the biopolymer colloidally solved is. An intravenous injection or infusion solution according to any one of claims 1 to 4, comprising as a first component a compound from the group of Gd-DTPA and gadobutrol as a low molecular weight gadolinium complex in a concentration of 0.1-1.0 mol / ltr. contains and as a second component a compound of the group of hydroxyethyl starch and acetyl starch as a biopolymer in a concentration of 1-25% (w / w) together with a pharmaceutically acceptable carrier or excipient in which the Gd complex is molecularly dispersed and the biopolymer is colloidally dissolved. intravenous To be administered injection or infusion solution according to one of claims 1 to 5, in which the hydroxyethyl starch has a molecular weight of 100 kD to 500 kD. intravenous To be administered injection or infusion solution according to one of claims 1 to 6, in which the hydroxyethyl starch a C2 / C6 degree of substitution from 0.7 to 0.3. intravenous To be administered injection or infusion solution according to one of claims 1 to 7, in the drug carrier a pharmaceutical usual Contains buffer. Use of intravenously administered injection or infusion solution according to one of the claims 1 to 8 for the MR whole body representation. Use of intravenously administered injection or infusion solution according to one of the claims 1 to 9 for the MR angiography or for MR Perfusionstudien. Use of intravenously administered injection or infusion solution according to one of the claims 1 to 10 for the appearance of cerebrospinal lesions.