Patent Application
20140322139
The present invention relates to a composition comprising a non-ionic X-ray contrast agent in a pharmaceutically acceptable carrier, and particularly to a supersaturated X-ray composition comprising X-ray contrast agents with a high dissolution temperature in water. Particularly, the invention provides such composition which is stable, and wherein crystallisation during storage is avoided. In a preferred aspect the X-ray contrast agent is Ioforminol. The invention further relates to a process for the preparation of such stable diagnostic X-ray composition.
All diagnostic imaging is based on the achievement of different signal levels from different structures within the body. Thus, in X-ray imaging for example, for a given body structure to be visible in the image, the X-ray attenuation by that structure must differ from that of the surrounding tissues. The difference in signal between the body structure and its surroundings is frequently termed contrast and much effort has been devoted to means of enhancing contrast in diagnostic imaging since the greater the contrast between a body structure and its surroundings the higher the quality of the images and the greater their value to the physician performing the diagnosis. Moreover, the greater the contrast the smaller the body structures that may be visualized in the imaging procedures, i.e. increased contrast can lead to increased spatial resolution. The diagnostic quality of images is strongly dependent on the inherent noise level in the imaging procedure, and the ratio of the contrast level to the noise level can thus be seen to represent an effective diagnostic quality factor for diagnostic images. Achieving improvement in such a diagnostic quality factor has long been and still remains an important goal.
In techniques such as X-ray, one approach to improve the diagnostic quality factor has been to introduce contrast enhancing materials formulated as contrast media into the body region being imaged. Thus for X-ray, early examples of contrast agents were insoluble inorganic barium salts which enhanced X-ray attenuation in the body zones into which they distributed. For the last 50 years the field of X-ray contrast agents has been dominated by soluble iodine containing compounds. Commercial available contrast media containing iodinated contrast agents are usually classified as ionic monomers such as diatrizoate (marketed e.g. under the trade mark Gastrografen™), ionic dimers such as ioxaglate (marketed e.g. under the trade mark Hexabrix™), nonionic monomers such as iohexol (marketed e.g. under the trade mark Omnipaque™), iopamidol (marketed e.g. under the trade mark Isovue™), iomeprol (marketed e.g. under the trade mark Iomeron™) and the non-ionic dimer iodixanol (marketed under the trade mark Visipaque™). The clinical safety of iodinated X-ray contrast media has continuously been improved over the recent decades through development of new agents; from ionic monomers (Isopaque™) to non-ionic monomers (e.g. Omnipaque™) and non-ionic dimers (e.g. Visipaque™).
The utility of the contrast media is governed largely by its toxicity, by its diagnostic efficacy, by adverse effects it may have on the subject to which the contrast medium is administered, but also by the ease of production, storage and administration. The toxicity and adverse biological effects of a contrast medium are contributed to by the components of the formulation medium, i.e. of the diagnostic composition, e.g. the solvent or carrier as well as the contrast agent itself and its components such as ions for the ionic contrast agents and also by its metabolites.
The manufacture of non-ionic X-ray contrast media involves the production of the active pharmaceutical ingredient (API), i.e. the contrast agent prepared in the primary production, followed by the formulation into the drug product, herein denoted the X-ray composition, prepared in the secondary production. In the preparation of an X-ray composition, the contrast agent is admixed with additives, such as salts, optionally after dispersion in a physiologically tolerable carrier. The contrast agent has to be completely solved in the carrier when additives are included and the composition is prepared. A well-known process for preparing X-ray compositions includes heating the contrast agent in the carrier, such as water for injection, to ensure complete dissolution. For instance, for the contrast media Visipaque™ the secondary production process includes dissolution of the contrast agent iodixanol in water for injection and heating to about 98° C. Heating at this temperature for an adequate period of time ensures that the contrast agent is completely dissolved.
However, different X-ray contrast agents have different solubility. For instance WO 2009/008734 of GE Healthcare AS discloses a new class of compounds and their use as X-ray contrast agents. The compounds are dimers containing two linked iodinated phenyl groups. Compound I, now called Ioforminol, falling within the formula I of WO2009/008734, has been found by the applicant to have particularly favourable properties. Ioforminol is supersaturated at the relevant storage conditions.
Compound I, Ioforminol: 5-[formyl-[3-[formyl-[3,5-bis(2,3-dihydroxypropylcarbamoyl)-2,4,6-triiodophenyl]amino]-2-hydroxypropyl]amino]-N,N′-bis(2,3-dihydroxypropyl)-2,4,6-triiodobenzene-1,3-dicarboxamide.
A solution in which the concentration of the solute (API) exceeds the equilibrium solute concentration at a given temperature is said to be supersaturated. This is possible because the solute does not precipitate immediately when the solution is cooled below the saturation temperature. Such solutions are denoted supersaturated.
As the solubility of loforminol decreases with decreasing temperature, the supersaturation increases. At room temperature the solubility of loforminol is limited. To achieve solutions with a concentration higher than the thermodynamic equilibrium concentration, at room temperature, Ioforminol is dissolved at a temperature above room temperature. When a clear solution has been achieved the solution is cooled and enters a state defined as supersaturated.
Supersaturated solutions are thermodynamically unstable and prone to nucleate and therefore to precipitate on storage. Among several factors, the onset of the precipitation depends on the degree of supersaturation, presence of the crystals of the solute and foreign particles such as dust or other impurities, i.e. purity, and storage temperature of the solution.
The injection solution of loforminol, i.e. the administrable X-ray composition, is highly supersaturated. The nucleation (precipitation) in the injection solution at storage conditions is strongly undesirable. The physical stability of the solution, i.e. prevention of the nucleation for a certain time at storage conditions, may be improved substantially by heat treatment of the solution well above its saturation temperature for a sufficiently long period of time. WO2011/117236 of the applicant is directed to a process involving hea treatment at low pH to avoid degradation and precipitation of an X-ray contrast agent composition. However, a high heat load is needed to obtain a seed-free solution. This heat load causes a greater degradation of the product and a lower pH in the final product resulting in liberation of iodine. This sets a restriction to the total heat load that may be given to the formulated solution. To overcome this challenge, alternative methods of stabilising the composition comprising Ioforminol have been investigated.
Therefore, a supersaturated stable X-ray composition comprising an X-ray contrast agent with a high dissolution temperature, and wherein crystallisation during storage is avoided, has been sought. It has surprisingly been found that if such composition comprising an X-ray contrast agent further includes a second compound which is structurally related to the contrast agent, the composition is kept stable and crystallisation is avoided during storing.
Thus, in a first aspect the invention provides a composition comprising the contrast agent Ioforminol and a second compound with structural similarity with the contrast agent, functioning as an inhibitor of primary nucleation or crystal growth. Hence, the inhibitor stabilizes the Ioforminol composition.
The use of inhibitors of primary nucleation or crystal growth has been found to be a feasible and effective solution to the crystallisation problem. The Ioforminol composition e.g. at the concentration 320 mg I/ml, (˜50 mass %) is highly supersaturated at room (or storage) temperature. In the case of secondary production of ioforminol, using water for injection as the solvent, the dissolution temperature within the concentration range of e.g. 270-380 mg I/ml will differ only a few degrees from 110° C. This means, that the system is unstable in thermodynamic terms and thus presupposed to crystallize. Stability of such a system is then only dependent on kinetics of the crystallization. To prevent crystallization, it is required to remove or deactivate all crystalline or heterogeneous nuclei from the solution, prevent or at least minimize primary nucleation and prevent growth of the eventually formed crystalline nuclei. It has been found that this can be achieved by including an inhibitor of primary nucleation or crystal growth in the Ioforminol composition.
There are several mechanisms of the nucleation- and growth inhibition, and the main groups are:
The contrast agent compound to be stabilized, preferably Ioforminol, is the main compound of the composition, by weight. In one embodiment this is present in the composition in an amount of 85-99.99 weight %. More preferably the weight % of Ioforminol is 85-99 weight % and most preferably 85-95 weight %. The composition should comprise the inhibitor in an amount sufficient for the inhibitor to inhibit any nucleation or crystal growth, providing a stable solution, but not as much that it significantly changes other properties of the composition, such as e.g. the viscosity or the osmolality. The amount needed will depend on which inhibitor is chosen. The inhibitor could e.g. be present in the composition in an amount from 0.1 to 15 weight %, such as 1 to 15 weight %, more preferably in an amount of 5-15 weight % and most preferably 10-15 weight %.
In addition to stabilising the composition the inhibitor added to the composition must meet certain requirements of tolerability and stability. To sufficiently act as an inhibitor of nucleation and crystal growth, acting according to any of the above mentioned mechanisms, it has been found that the inhibitor should have a chemical structure wherein at least an element of the chemical structure, such as a building block, a part or a component, is similar or identical with the chemical structure of the contrast agent, i.e. with Ioforminol. Accordingly, other elements of the structure of the inhibitor differ from the structure of the contrast agent. Chemical compounds containing one, two or three triiodinated aryl groups, i.e. monomers, dimers and trimers are relevant inhibitors. In particular, compounds comprising aryl groups with iodine atoms in the 1, 3 and 5 positions are preferred, i.e. such as elements derived from 2-amino-isophtalic acid. These compounds form the class of compounds denoted non-ionic iodinated X-ray contrast compounds or agents. Preferable, such an inhibitor comprises a compound which can act as an X-ray contrast agent, such as a structurally similar non-ionic iodinated dimeric compound, a non-ionic iodinated monomeric compound or a non-ionic iodinated trimeric compound. Preferably, the inhibitor comprises a non-ionic iodinated dimeric compound. In one embodiment, the inhibitor comprises a mixture of different compounds.
The dissimilarity between the contrast agent and the inhibitor compound may be manifested by any suitable variation in structure. Preferred variations are differing multiplicity of elements, variation or absence of the linking moiety between elements or variation of carboxylic acid anilides. It should be understood that the effectiveness of a particular inhibitor can only be assessed by empirical means. The given criteria are only given as a mean to define the preferred type of molecules and not necessarily a description of effective inhibitors.
In one embodiment, the inhibitor comprises a dimeric compound comprising two linked triiodinated phenyl groups, of formula (I)
R—N(R6)-X—N(R6)-R Formula (I)
wherein
X denotes a C3 to C8 straight or branched alkylene moiety optionally with one or two CH2 moieties replaced by oxygen atoms, sulphur atoms or NR4 groups and wherein the alkylene moiety optionally is substituted by up to six —OR4 groups;
R4 denotes a hydrogen atom or a C1 to C4 straight or branched alkyl group;
R6 denotes a hydrogen atom or an acyl function; and
each R independently is the same or different and denotes a triiodinated phenyl group, preferably a 2,4,6-triiodinated phenyl group, further substituted by two groups R5 wherein each R5 is the same or different and denotes a hydrogen atom or a non-ionic hydrophilic moiety, provided that at least one R5 group in the compound of formula (I) is a hydrophilic moiety.
X preferably denotes a straight C3 to C8 alkylene chain optionally substituted by one to six —OR4 groups. More preferably X denotes a straight C3 to C5 alkylene chain having at least one —OR4 group, preferably with at least one hydroxyl group in a position that is not vicinal to the bridge nitrogen atom. More preferably the alkylene chain is substituted by one to three hydroxyl groups and still more preferably the alkylene chain is a straight propylene, butylene or pentylene chain substituted by one, two or three hydroxyl groups. Particularly preferred groups X are selected from 2-hydroxy propylene, 2,3-dihydroxy butylene, 2,4-dihydroxy pentylene and 2,3,4-trihydroxy pentylene, and most particularly X is the 2-hydroxy propylene entity.
R4 preferably denotes a hydrogen atom or a methyl group, most preferably a hydrogen atom.
The R6 substituents may be the same or different and preferably R6 denotes a hydrogen atom or a residue of an aliphatic organic acid, and in particular a C1 to C5 organic acid such as formyl, acetyl, propionyl, butyryl, isobutyryl and valeriyl moieties. Hydroxylated and metoxylated acyl moieties are also feasible. In a particularly preferred embodiment one R6 group in the compound of formula (I) denotes a formyl moiety and one denotes the acetyl moiety, or both R6 groups denote acetyl.
Each of the iodinated R groups can be the same or different and preferably denote a 2,4,6-triiodinated phenyl group, further substituted by two groups R5 in the remaining 3 and 5 positions in the phenyl moiety. The non-ionic hydrophilic moieties, R5, may be any of the non-ionizing groups conventionally used to enhance water solubility. Hence, the R5 substituents may be the same or different and shall preferably all denote a non-ionic hydrophilic moiety comprising esters, amides and amine moieties, optionally further substituted by a straight chain or branched chain C1-10 alkyl groups, preferably C1-5 alkyl groups, where the alkyl groups also may have one or more CH2 or CH moieties replaced by oxygen or nitrogen atoms. The R5 substituents may also further contain one or more groups selected from oxo, hydroxyl, amino or carboxyl derivative, and oxo substituted sulphur and phosphorus atoms. Each of the straight or branched alkyl groups preferably contains 1 to 6 hydroxy groups and more preferably 1 to 3 hydroxy groups. Therefore, in a further preferred aspect, the R5 substituents are the same or different and are polyhydroxy C1-5 alkyl, hydroxyalkoxyalkyl with 1 to 5 carbon atoms and hydroxypolyalkoxyalkyl with 1 to 5 carbon atoms, and are attached to the iodinated phenyl group via an amide or a carbamoyl linkage, preferably amide linkages.
The R5 groups of the formulas listed below are particularly preferred:
Even more preferably the R5 groups will be equal or different and denote one or more moieties of the formulas —CONH—CH2—CH2—OH, —CONH—CH2—CHOH—CH2—OH, —CON(CH3)CH2—CHOH—CH2OH, —CONH—CH—(CH2—OH)2 and —CON—(CH2—CH2—OH)2. Still more preferably both R groups are the same and the R2 groups in each R are the same or different and denote —CONH—CH2—CH2—OH, —CONH—CH2—CHOH—CH2—OH, CON(CH3)CH2-CHOH—CH2OH, —CON—(CH2—CH2-OH)2 and —CONH—CH—(CH2—OH)2. In a particularly preferred embodiment, both R groups are the same and all R5 groups denote the entity of formula —CONH—CH2—CHOH—CH2—OH.
In a preferred embodiment, the inhibitor is the dimeric compound Iodixanol or the Compound II shown below, or mixures thereof. Compound II can been seen as a related impurity to Ioforminol, as it is a dimer structurally very similar to Ioforminol, but rather than having two formyl groups attached to the 2-hydroxypropane-1,3-diyl bridge, it has one formyl group and one acetyl group. It can be seen as half Iodixanol and half Ioforminol.
In another embodiment, the inhibitor comprises a non-ionic iodinated monomeric compound, and this should have structural similarities to Ioforminol. When the inhibitor comprises a monomeric compound this comprises compounds of the general formula (II),
wherein each of R1, R2 and R3 are the same or different and denote a hydrogen atom or a non-ionic hydrophilic moiety, provided that at least one of the R1, R2 and R3 groups in the compound of formula (II) is a hydrophilic moiety.
In formula (II), the non-ionic hydrophilic moieties R1, R2 and R3 may be any of the non-ionizing groups conventionally used to enhance water solubility. Hence, the R1, R2 and R3 substituents may be the same or different and shall preferably all denote a group as defined for R5 for formula (I) above, with the same preferred groups. Most preferably, at least two of the groups R1, R2 and R3 shall denote the entity of formula —CONH—CH—(CH2—OH)2 or —CONH—CH2—CHOH—CH2—OH.
If the inhibitor comprises a monomeric compound this is preferably selected from the group of iopamidol, iomeprol, ioversol, iopromide, iobitridol, iopentol, iohexol and Compound III. Compound III has structural similarities with Iohexol and Ioforminol and is shown below.
Preferred monomeric inhibitors are the compounds iohexol and Compound III.
Most preferably the inhibitor is a dimeric compound as disclosed above.
The diagnostic composition of the invention preferably includes excipients and additives, such as salts.
Adverse effects of non-ionic contrast media can be reduced by the inclusion of metal ions such as sodium and calcium ions in the diagnostic composition. The sodium compound and the calcium compound of the composition may be provided in the form of salts, i.e. the compounds include physiologically tolerable counter ions, e.g. selected from the group of chloride, sulphate, phosphate and hydrogen carbonate. Preferably, the sodium compound is sodium chloride and the calcium compound is calcium chloride. The contrast agent is hence formulated with conventional carriers and excipients to produce a diagnostic composition. In addition to plasma ions, such as sodium and calcium ions, dissolved oxygen may be included. Further, chelating agents such as EDTA (ethylenediaminetetraacetic acid) or DTPA (diethylene triamine pentaacetic acid) may be included in the prepared composition to sequester metal ions from the solution. EDTA is preferred.
Increasing the stability of a saturated X-ray composition comprising X-ray contrast agents with a high dissolution temperature in water, as presented, by including an inhibitor of primary nucleation and crystal growth in the composition, may also be useful for other X-ray agents than Ioforminol. Hence, compositions comprising contrast agents that have a low solubility may include an inhibitor having a chemical structure wherein at least an element of the chemical structure is similar or identical with the contrast agent structure. Hence, in one aspect the invention provides a composition comprising a monomeric contrast agent, such as Iopamidol, and an inhibitor of primary nucleation or crystal growth. As for the first aspect, the inhibitor should have a chemical structure wherein at least one element of the chemical structure is similar or identical with the chemical structure of the contrast agent.
In a further aspect, the invention provides a method of increasing the stability of a composition comprising a contrast agent that has a low solubility, by including in the composition an inhibitor of primary nucleation or crystal growth. As for the first aspect, the contrast agent is preferably Ioforminol. The inhibitor should have a chemical structure wherein at least a part of the chemical structure is similar or identical with the contrast agent structure. The type and amount of inhibitor to be used in the method is selected according to the first aspect of the invention and preferably the inhibitor comprises a non-ionic iodinated dimeric compound.
In yet another aspect, the invention provides a process for preparation of a stable composition comprising the contrast agent Ioforminol in a carrier, wherein the process includes a step of including, such as adding, an inhibitor of primary nucleation or crystal growth in the Ioforminol composition. Ioforminol and an inhibitor can be combined in a composition by means of several methods. Either appropriate amounts of the two solid compounds are combined and subsequently dissolved in the carrier by necessary means, or two previously prepared solutions of the compounds are combined in suitable proportions. The following treatment of the composition follows established procedures for obtaining sterile solutions with appropriate salt balance and physiologically acceptable pH.
Accordingly, the process of the invention comprises the steps of either
The carrier is preferably a pharmaceutically acceptable carrier, and preferably an aqueous solution, preferably pure water.
The amount of inhibitor needed, and which inhibitor to include, should be selected as outlined in the first aspect.
To solve the Ioforminol powder completely the composition should be heated to e.g. 60-135° C. for as long as it takes to achieve complete dissolution, such as e.g. for 20-240 minutes.
In addition to the steps described, the process of the invention may further include the steps of:
Ioforminol can be prepared as outlined in WO 2009/008734. A general procedure is outlined on pages 16-20, and a specific method for preparation is provided in Example 1 of WO 2009/008734. The WO 2009/008734 application, with its description of a process for preparation is hereby incorporated by reference.
The diagnostic composition prepared by the process of the invention is in a ready to use concentration. Generally compositions in a ready to use form will have iodine concentrations of at least 100 mg I/ml, such as at least 150 mg I/ml, or with concentrations of at least 300 mg I/ml, e.g. 320 mg I/ml, or even 350, 360 or 400 mg I/ml, but also lower concentrations can be relevant.
The diagnostic composition of the invention is preferably for use in X-ray diagnosis. The composition may be administered as a bolus injection or by infusion. Further, the composition may be administered by intravascular, intravenous or intra-arterial administration. Alternatively, the composition may also be administered orally.
Formulated Ioforminol (320 mg I/ml) and Visipaque (Iodixanol 320 mg I/ml) were filled on 100 ml glass vials in mixtures with ratios according to Table 1. The filling was performed by using a Flexicon PF5 peristaltic pump. The vials were sealed by closures comprising stoppers and overlying caps. The vials were split into two populations, one that was subjected to heat steam sterilisation at 121° C. (autoclaving) for 20 minutes and one that was used without further treatment.
The autoclaved and non-autoclaved samples of different mixtures were placed on storage at 25, 40 and 60° C. respectively. The samples were subjected to visual inspection weekly for the first 5 weeks before inspection was carried out monthly.
For autoclaved samples stored at 60° C. and 40° C. crystallisation of the reference samples started after 1 and 8 weeks, respectively. No crystallisation was observed for the reference samples or mixtures containing Visipaque stored at 25° C. For autoclaved samples the first crystallisation at 60° C. was observed for the mixture containing 5% Visipaque after 4 weeks while the corresponding crystallisation for 40° C. was detected after 6 months. No crystallisation was observed for the mixture containing 15% Visipaque regardless of the storage temperature.
For non-autoclaved samples only a minor effect was observed.
In summary, mixtures of loforminol with 5-15% Visipaque or more is showing a significant delay in crystallisation for autoclaved samples. This indicates that the Iodixanol (API in Visipaque) is a potent inhibitor of primary nucleation and hence is able to prevent crystallisation of loforminol
| Number | Date | Country | Kind |
|---|---|---|---|
| 20111762 | Dec 2011 | NO | national |
| Filing Document | Filing Date | Country | Kind | 371c Date |
|---|---|---|---|---|
| PCT/EP2012/076261 | 12/20/2012 | WO | 00 | 6/17/2014 |
