WO1999038538A1

WO1999038538A1 - Mri contrast agents comprising ethylene diamine disuccinic acid as chelants

Info

Publication number: WO1999038538A1
Application number: PCT/IB1999/000117
Authority: WO
Inventors: Anthony Joseph Simpson; Stephen Wayne Heinzman; Barry Thomas Ingram
Original assignee: Procter and Gamble Co
Current assignee: Procter and Gamble Co
Priority date: 1998-01-31
Filing date: 1999-01-25
Publication date: 1999-08-05
Anticipated expiration: 2000-07-31
Also published as: GB9802050D0; GB2333704A

Abstract

The invention relates to contrasting compositions comprising a complex of one or more selected metal ions and a specific complexing agent. The invention also relates to the use of specific complexes for preparation of a contrasting agent for use in MRI methods. The invention also relates to methods of preparation of contrasting compositions.

Description

MRI CONTRAST AGENTS COMPRISING ETHYLENE DIAMINE DISUCCINIC ACID AS CHELANTS

Technical Field

The invention relates to contrasting compositions comprising a complex of one or more paramagnetic metal ions and a specific complexing agent.

Background to the Invention

Magnetic resonance imaging (MRI) has been developed in recent years for obtaining a map or image of the human body. In MRI, the contrast of the images generated may be enhanced by introducing into the zone being imaged an agent, generally referred to as a contrast agent, which affects the nuclear spin equilibration characteristics of the nuclei (generally water protons in body tissues or fluids) which are responsible for the magnetic resonance signals from which the MR images are generated. Therefore, paramagnetic contrast agents have been given to patients prior to imaging.

A number of patents disclose paramagnetic MRI contrast agents including, for example, US patents 4,647,447; 4,859,451; 4,957,939; 4,963,344; 5,021,216; 5,064,636 and 5,120,527; and PCT application WO92/21017. Paramagnetic agents of the type disclosed in these patents have been administered to the patient in the form of aqueous solutions. In addition, paramagnetic oil emulsions have been provided for MRI imaging in the gastro-intestinal tract as disclosed in US patents 5,064,636 and 5,120,527.

In the design of MRI agents, strict attention must be given to a variety of properties that will ultimately affect the physiological outcome apart from the ability to provide contrast enhancement. Two fundamental properties that must be considered are biocompatability and proton relaxation enhancement. Biocompatability is influenced by several factors including toxicity, stability (thermodynamic and kinetic), pharmacokinetics and biodistribution. Proton relaxation enhancement (or relaxivity) is chiefly governed by the choice of metal, the rotational correlation times and the accessibility of the metal to surrounding water molecules (rapid exchange of water with the bulk).

The lanthanide atom Gd(III), has generally been chosen as the metal atom for contrast agents because it has a high magnetic moment (μ =63BM ), a symmetric electronic ground state, (S ), the largest paramagnetic dipole and the greatest paramagnetic relaxivity of any element.

In the past decades the main aim has been to develop chelating agents which have an improved binding capacity for heavy metal ions. A well-known chelating agent thereto is, for example, EDTA and DTPA.

Gd(III) has been chelated with several substances to render the complex non-toxic. To date, a number of chelators have been used, including diethylenetriaminepentaacetic (DTPA), l,4,7,10-tetraazacyclododecane'-N,N'N",N'"-tetracetic acid (DOTA), and derivatives thereof. See US patent nos. 4,647,447, 5,155,215, 5,087,440, 5,219,553, 5,188,816, 4,885,363, 5,358,704, 5,626,532 and Meyer et al. nvest.Radiol. 25:S53 (1990).

The water soluble Gd(DTPA)-chelate is stable, nontoxic, and one of the most widely used contrast enhancement agents in experimental and clinical imaging research. It has been in use for clinical use in adult patients since the late 1980's. It is an extracellular agent that accumulates in tissue by perfusion dominated processes. Image enhancement improvements using Gd(DTPA) are well documented in a number of applications (Runge et al., Magn, Reson. Imag. 3:85 (1991); Russell et al., AJR 152:813 (1989). Another chelator used in Gd contrast agents is the macrocyclic ligand 1,4,7,10- tetraazacyclododecane-N,N',N",N'"-tetracetic acid (DOTA). Recently, the GdDOTA complex was approved as an MRI contrast agent in France. The present inventors now have found that even those chelating agents which have a very high binding capacity for those metal ions, preferably used in MRI methods, such as Gd(III) and Mn(II) and iron, do not always perform very effectively.

The present inventors have now found that this can be due to the fact that these chelating agents do not just have a high binding capacity for heavy metal ions but also for other metal ions which may be present. It has been found that, for example, the presence of calcium ions can reduce the efficiency or effectiveness of certain chelating agents, such as DTPA and DOTA. The nature of the systems and the methods where the contrasting agents, containing the chelating agents, are used is such that the presence of calcium ions is unavoidable, in particular when the contrasting agent is used in bone tissue or blood . Thus, this can result in loss of the essential properties of the contrasting agent. Thus, there is a need for improved MRI contrast agents, which comprise stable complexes of the selected metal ions and a complexing agent.

However, the inventors have now found that EDDS is an excellent, specific complexing agents for forming complexes with the selected paramagnetic metal ions, used for MRI, such as GD(III) and Mn(II) and iron, in particular in the presence of calcium. Thus, these specific agents are very effective complexing agents for use in contrasting compositions for use in MRI.

Summary of the Invention

In accordance with the present invention, there is provided a contrasting composition, comprising a complex formed by of one or more selected paramagnetic metal ions, preferably Gd(III) and/or Mn(II), and ethylene diamine disuccinic acid (EDDS) complexing agent. The invention also relates to the use of a complex comprising a complexing agent and a paramagnetic metal ion for preparation of contrasting compositions. Such contrasting compositions are used in diagnostic methods, such as MRI.

Detailed Description of the Invention

Complexing Agents.

The complexing agents for use in the contrasting composition of the invention is N, N ethylene diamine disuccinic acid or its salts (EDDS).

It is known that the (S,S) EDDS isomer is more readily biodegradable than the (R,R) isomer. Thus, depending of the application of the aqueous compositions of the invention, it may be desirable to use only one of the isomers of EDDS. Furthermore, it can be preferred that a racemic mixture of the (R,R) EDDS and the (S,S) EDDS isomers are used in the aqueous compositions, for example because the racemic mixture is less expensive.

Paramagnetic Metal Ion

The paramagnetic metal ion for use in the composition of the invention is preferably a lanthanide element of atomic numbers 58-70 or a transition metal of atomic numbers 21- 29, 42 or 44, most preferably selected from a group consisting of Gd(III), Mn(II), Fe(III) or (II) iron and dysprosium.

Contrasting Composition

The contrasting composition of the invention comprises a complex of a paramagnetic metal ion and ethylene diamine disuccinic acid or salts thereof , as described herein. The contrasting agent and the paramagentic metal ion are preferably present in the composition in a stoichiometric amount; it may be preferred that the contrasting agent is present in a stoichiometric excess.

The compositions according to this invention can preferably contain from 0.001 to 5.0 moles per litre and preferably from 0.1 to 1.2 moles per litre of the complex of the complexing agent and the paramagnetic metal ion.

The compositions of the invention are administered to patients for imaging in incorporation in the contrasting compositions of the invention amounts which are sufficient to yield the desired contrast, whereby typically the amounts are calculated such that a dosages of from 0.001 to 5.0 mmoles of the complex of the complexing agent and the paramagnetic metal ion, per kilogram of patient body weight are given

Additional Components

The compositions can comprise a variety of additional conventional pharmaceutical or veterinary formulation aids, for example stabilisers, antioxidants, buffers, pH adjusting agents, etc.

The compositions of the present invention may be in conventional pharmaceutical administration forms such as solutions, suspensions, dispersions, syrups, suppositories, etc. and solutions, suspensions and dispersions in physiologically acceptable carrier media, for example oils and/ or water for injections, will generally be preferred.

The contrast media according to the invention may therefore be formulated for administration using physiologically acceptable carrier as known in the art.

Highly preferred is the incorporation of a surfactant in the compositions of the invention. Surfactants are usually needed to form stable emulsions indicated above where the MRI agent has insufficient surfactant activity. Any suitable surfactant may be employed alone or in combination with other surfactants. For example, egg yolk phospholipids or Pluronics emulsifying agents may be used. Ploronics agents are block polymer polyols sold by Wyandotte, e.g., Pluronics F68, having a molecular weight of about 8,000, may be employed. Ethoxylates of cholesterol, diacyl glycerol and dialkyl ether glycerol are useful surfactants. Also, using backbones of cholesterol, diacyl glycerol or dialkyl ether glycerol, block copolymers are made by adding ethylene oxide, propylene oxide and ethylene oxide, in that order, in varying amounts to produce surfactant. In some applications for nonintravenous use, anionic or cationic surfactants may be used. The emulsions of this invention may contain alkylphosphoryl choline or alkylglycerophosphoryl choline surfactants described in Kaufman and Richard, US Serial No. 791, 420, filed November 13, 1991.

Anionic surfactants include alkyl or aryl sulfates, sulfonates, carboxylates or phosphates. Cationic surfactants include such as mono-, di-, tri- and tetraalkyl or aryl ammonium salts. Non-ionic surfactants include alkyl or aryl compounds, whose hydrophilic part consists of polyoxyethylene chains, sugar molecules, polyalcohol derivatives or other hydrophilic groups. Zwitter-ionic surfactants may have a combination of the above anionic or cationic groups, and whose hydrophobic part consists or any other polymer, such as polyisobutylene or polypropylene oxides.

The compositions can comprise as an additional component, a fluorochemical. These fluorochemicals are either highly fluorinated organic compounds or perfluorcarbon or fluorinated chemicals.

The compositions preferably comprise a oil. A large class of physiologically acceptable substances whether of mineral, vegetable, animal, essential or synthetic origin, can be used herein. Preferred can be, petroleum-derived oils such as refined paraffin oil, oils derived from seeds or nuts, linseed oil, tung oil, safflower oil, soy bean oil, castor oil, cottonseed oil, coconut oil, palm oil and coconut oils and oils derived from fat such as tallow, lard, stearic acid and oleic acid. Included are some vegetable oils, such as olive, cottonseed, corn and peanut, as well as some special fish oils such as cod-liver, haliver, shark liver, and so forth which are used largely as medicines for their high vitamin 7

content. A liquid fatty oil such as a mono-,di-, or triglyceride, or a mixture thereof, is the preferred oil. Medium chain triglycerides also serve as useful oils according to this invention.

Process for Preparation of a Gadolinium-EDDS Complex

A stoichiometric equivalent of gadolinium oxide and ethylene diamine disuccinic acid, in 75:22:3 (V/V/V) CHCl₃:CH₃OH:H₂O («0.1 mole of complex/L of solvent) iss heated at reflux with stirring for 18-25 hours. After cooling to ambient temperature, the solution is filtered through Celite to remove trace Gd₂O₃. The filtrate is concentrated to yield an off-white solid or glass. The resulting solid is recrystallised from appropriate solvent. The resulting solid is dried in a vacuum oven at 500-650°C and 29mm Hg vacuum overnight. Successful complexation is evident by the dissolution of Gd₂O₃ into the organic solvent mix The complex can be detected by use of thin layer chromatography (TLC), relative to the free ligand, and/ or infrared spectroscopy. Completion of the reaction could be monitored by TLC. Upon completion of the reaction, aq. NaOH was used to neutralise the reaction mixture and precipitated NaCl was removed by filtration through Celite.

Claims

1. A contrasting composition comprising a complex formed by of one or more paramagnetic metal ions and ethylene diamine disuccinic acid complexing agent.

2. A composition according to claim 1 wherein the paramagnetic metal ion is a Gd ion and/or a Mn ion.

3. A composition according to claim 1 or 2 wherein calcium ions are present.

4. A contrasting composition according to claim 3, obtainable by a process comprising the addition of a paramagnetic metal ion and an EDDS complexing agent to an aqueous solution, comprising calcium ions.

5. Use of a complex formed by EDDS complexing agent and a paramagnetic metal ion for preparation of a contrasting composition according to any of claim 1 to 4 for use in a method of magnetic resonance imaging.

6. Use of a complex formed by ethylene diamine disuccinic acid and a paramagnetic metal ion for preparation of a contrasting composition according to any of claims 1 to 5, for use in a method of magnetic resonance imaging.