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
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
  • A61K49/10—Organic compounds
  • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
  • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
  • A61K49/108—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA the metal complex being Gd-DOTA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/28—Compounds containing heavy metals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
  • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K49/00—Preparations for testing in vivo
  • A61K49/06—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
  • A61K49/08—Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations characterised by the carrier
  • A61K49/10—Organic compounds
  • A61K49/101—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals
  • A61K49/106—Organic compounds the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals the complex-forming compound being cyclic, e.g. DOTA
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • G—PHYSICS
  • G01—MEASURING; TESTING
  • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
  • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
  • G01N33/15—Medicinal preparations ; Physical properties thereof, e.g. dissolubility

Definitions

• the invention relates to pharmaceutical formulations of contrast agents, in particular of complexes of chelates with paramagnetic metal ions, especially for magnetic resonance imaging, and to industrially efficient processes for obtaining these formulations.
• contrast agents based on complexes of chelates with lanthanides (paramagnetic metal), in particular with gadolinium are known, and are described, for example, in document U.S. Pat. No. 4,647,447.
• chelates with lanthanides paramagnetic metal
• gadolinium many contrast agents based on complexes of chelates with lanthanides (paramagnetic metal), in particular with gadolinium, are known, and are described, for example, in document U.S. Pat. No. 4,647,447.
• macrocyclic chelates such as DOTA gadoterate (1,4,7,10-tetraazacyclo-dodecane-N,N′,N′′,N′′′-tetraacetic acid) and gadoteridol HPDO3A
• linear chelates such as DTPA (diethylenetriaminepentaacetic acid) and DTPA-BMA (gadodiamide).
• the complexes of chelates with lanthanide are in a situation of chemical equilibrium, which may lead to a risk of undesired release of the lanthanide, and more especially of gadolinium.
• a person skilled in the art is thus led to seek technical solutions that limit this risk in order to solve the complex problem of tolerance in the patient as safely as possible. This problem is all the more difficult since the administration of contrast agents is often repeated during diagnostic examinations and/or for the guiding and monitoring of the efficacy of a therapeutic treatment.
• NSF nephrologic systemic fibrosis, or fibrogenic dermopathy
• the Applicant has worked on the specific case of macrocyclic chelates, and has demonstrated, for these chelates, the advantage of using an amount of free chelate, which is particularly advantageous in terms of tolerance.
• the Applicant had to develop a preparation process that makes it possible to ensure the reliability and reproducibility of the composition of commercialized batches.
• the Applicant found that the mixing of stoichiometric amounts on the basis of the theoretical calculation does not sufficiently satisfactorily give at the industrial scale the respective amounts of complex of chelate with the lanthanide and of free chelate in low concentration in the pharmaceutical formulation. The reason for this is that it is then necessary to perform several analysis steps, which takes several hours, and significantly increases the industrial cost price of the product.
• the Applicant's process makes it possible especially to prepare beforehand and to optimize the analytical device, which is important as regards its impact on the quality of the final product.
• the amount of DOTA to be added in excess after complexation of the DOTA with the lanthanide, to obtain an excess of free DOTA of 0.1 mol/mol % would be about 40 g of DOTA in 200 litres of the DOTA solution (40 g in addition to the 40 kg of DOTA initially placed in solution), which does not allow sufficiently reliable reproducibility at the industrial level.
• a 0.5 M solution of gadolinium chelate for example DOTA-Gd
• concentrations less than 10 ⁇ 10 M cannot be measured sufficiently reliably by the current analytical methods.
• the present invention relates to a process for preparing a liquid pharmaceutical formulation of complex of macrocyclic chelate with lanthanide, the said process comprising at least one step of measuring in the liquid pharmaceutical formulation concentrations of free macrocyclic chelate (C cl ) and/or of free lanthanide (C ll ) and at least one step of adjusting the C cl and/or the C 1l , so as to obtain (sufficiently stably in the final pharmaceutical solution, i.e. the pharmaceutical formulation intended to be administered to the patient) a mol/mol amount of free macrocyclic chelate of between 0.002% and 0.4%, advantageously between 0.02% and 0.3% and very advantageously between 0.025% and 0.25%.
• the present invention thus relates to a process for preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide and a mol/mol amount of free macrocyclic chelate of between 0.002% and 0.4%, advantageously between 0.02% and 0.3% and very advantageously between 0.025% and 0.25%, the macrocyclic chelate advantageously being chosen from DOTA, NOTA, DOTAGA, DO3A, BT-DO3A (gadobutrol), HP-DO3A and PCTA, and is advantageously DOTA, the said process comprising the following successive steps:
• the term “amount of free macrocyclic chelate” means the proportion of free macrocyclic chelate relative to the amount of complexed macrocyclic chelate (gadoteric acid in the case of DOTA-Gd) present in the formulation in mol/mol. In the rest of the description, it will be referred to without preference as the “amount of free macrocyclic chelate” or the “excess free macrocyclic chelate”.
• free macrocyclic chelate means any macrocyclic chelate not complexed with lanthanide.
• free lanthanide means any lanthanide not complexed with a macrocyclic chelate.
• any suitable equipment is used.
• a potentiometer or capillary electrophoresis is used for the macrocyclic chelate. More specifically, in the presence of copper sulfate, the free DOTA contained in the solution obtained from the complexation step (in bulk) complexes the copper. The excess copper sulfate is assayed in pH 5 buffered medium, by potentiometry, with a solution of EDTA in the presence of a copper-indicating electrode and a reference electrode.
• the analysis/assay of the free lanthanide is performed by using, for example, a solution of EDTA in the presence of xylenol orange Arsenezo as turning-point indicator.
• step d In order to perform step d), several solutions are possible as a function of the C ll and C cl measured in step c).
• the elimination of free lanthanide is performed by passing through an ion-exchange resin. It is thus possible, for example, to use a resin of styrene/divinylbenzene copolymers which contains iminodiacetate ions acting as chelating group for the binding with the metal ions (Gd 3+ in particular).
• the elimination of free macrocyclic chelate is performed, for example, by filtration, advantageously using resins (for example anionic resins).
• step b) consists in mixing a solution of free macrocyclic chelate (initial) and of free lanthanide (initial) so as to obtain complexation of the lanthanide by the macrocyclic chelate.
• the lanthanide is advantageously added in the form of oxide (gadolinium oxide in particular), but the invention also covers other possible forms of lanthanide, especially the lanthanide salts known to those skilled in the art.
• step b) The precise experimental conditions of step b) are detailed in the examples.
• the temperature for step b) is between 60 and 100° C., and is advantageously about 80° C.
• the pharmaceutical formulation is then cooled before the adjustment step d).
• the duration of step b) is, for example, from 1 hour to 3 hours.
• step b) may be performed in several sub-steps which would be equivalent to an overall complexation step.
• the complexation may be performed, for example, by preparing about half the final volume of the tank, and then adding gadolinium oxide at acidic pH.
• the expression “the amounts of free macrocyclic chelate and of free lanthanide added are equal to the stoichiometric proportions” means that the amounts added are such that, in the light of the stoichiometry of the complexation reaction, all the lanthanide and all the chelate should be in complex form and there should be no free macrocyclic chelate.
• the expression “difference between the stoichiometric proportions and the amounts of free lanthanide and of free macrocyclic chelate added in step b)” means that the amounts of free lanthanide and of free chelate added in step b) are such that, in the light of the stoichiometry of the complexation reaction, not all the lanthanide is complexed by the chelate (excess lanthanide and/or deficit of chelate relative to the stoichiometry) or not all the chelate is complexed with the lanthanide (excess chelate and/or deficit of lanthanide).
• this difference is such that the macrocyclic chelate/lanthanide or lanthanide/macrocyclic chelate mol/mol ratio is less than or equal to 1.4, advantageously between 1.001 and 1.3, particularly advantageously between 1.005 and 1.2, and in particular between 1.005 and 1.02. It is also pointed out that this ratio may be adapted depending on whether an excess of chelate or an excess of lanthanide is used. When an excess of lanthanide is used for the complexation, advantageously the lanthanide/macrocyclic chelate mol/mol ratio is typically less than or equal to 1.2. When an excess of chelate is used for the complexation, the macrocyclic chelate/lanthanide mol/mol ratio is advantageously less than or equal to 1.4.
• the amounts of free macrocyclic chelate and of free lanthanide added are such that not all the macrocyclic chelate is complexed with the lanthanide or such that not all the lanthanide is complexed with the macrocyclic chelate. Consequently, after this step b), the pharmaceutical formulation will typically comprise macrocyclic chelate-lanthanide complex and:
• the preparation process according to the present invention is characterized in that, in step b), there is a difference between the amounts of free macrocyclic chelate and of free lanthanide added and the stoichiometric proportions, this difference advantageously being such that the macrocyclic chelate/lanthanide or lanthanide/macrocyclic chelate mol/mol ratio is less than or equal to 1.4, advantageously between 1.001 and 1.3, particularly advantageously between 1.005 and 1.2 and in particular between 1.005 and 1.02.
• the ratio will be, for example, 1.01, 1.02, 1.03 or 1.04. This gives, for example, the concentrations presented in Table 1 below, which shows the case of an excess of initial free lanthanide, given that an excess of initial chelate may also be used.
• the difference is thus, for example, advantageously between 0.1 mol % and 2 mol % of the concentration at stoichiometry of the pharmaceutical formulation.
• the adjustment step d) is performed without touching the total amount of lanthanide present in the formulation, i.e. without adding or removing any lanthanide. In this case, only the total amount of macrocyclic chelate and/or the pH is modified.
• total amount of lanthanide means all the lanthanide present in free form and in complexed form.
• total amount of macrocyclic chelate means all the macrocyclic chelate present in free form and in complexed form.
• step b) an excess of lanthanide relative to the macrocyclic chelate is added in step b) and step d) consists in adding free macrocyclic chelate.
• the preparation process according to the present invention is characterized in that:
• step b In a second case (case B of the preferred mode), an excess of macrocyclic chelate relative to the lanthanide is added in step b).
• step d) consists in adding or removing macrocyclic chelate.
• the preparation process according to the present invention is characterized in that:
• the adjustment step d) comprises at the end a step of adjustment of the pH and of the volume, advantageously with meglumine for DOTA.
• case C the pH of the formulation (and optionally other functionally equivalent chemical parameters) is controlled so as to shift the reaction equilibrium in order to obtain at the end the target pharmaceutical solutions (excess amount of target ligand).
• the preparation process is such that:
• the complexation is performed at a pH below 6 (for example between 3 and 6 and advantageously between 5 and 6) and the pH is then raised, for example, to about 12 (for example with NaOH), and the pH is then adjusted to about 7.
• a pH below 6 for example between 3 and 6 and advantageously between 5 and 6
• the pH is then raised, for example, to about 12 (for example with NaOH), and the pH is then adjusted to about 7.
• step 2 the complexation is typically performed at a pH below 6 (for example between 3 and 6), the pH being brought directly to about 7.
• step b1 of the process with pH adjustment is such that it makes it possible to achieve the target range of excess free chelate in the pharmaceutical solution at least up to the expiry of the shelf life of the pharmaceutical solution.
• Increasing the pH makes it possible to shift the equilibrium in the direction from an excess of macrocyclic chelate to a level substantially equal to the target excess amount.
• step b) consists in preparing a solid complex [chelate-lanthanide] and in dissolving it (in water).
• step d) is performed on a liquid formulation obtained by dissolving a solid [chelate-lanthanide] complex.
• step b) of the process according to the invention comprises two sub-steps:
• step d) may be performed as described previously in detail (addition of chelate or of lanthanide, removal of chelate or of lanthanide, adjustment by pH modification).
• the preparation of the solid complex which is advantageously crystalline [chelate-lanthanide], involves, where appropriate, at least one treatment step (filtration, concentration, crystallization, drying, spraying, etc.) for obtaining the appropriate physicochemical characteristics, especially in terms of solubility and purity.
• a further technical problem was solved by the Applicant for the industrial manufacture of a pharmaceutical formulation of contrast agent based on a macrocyclic chelate-lanthanide complex, while at the same time making it possible to maximize the tolerance profile of the contrast product.
• the Applicant contrary to the prior-art teaching, for example U.S. Pat. No. 5,876,695, which suggests the presence of large quantities of calcium (introduced in the form of calcium chelate) in the pharmaceutical formulation, the Applicant has demonstrated that, in the case of the process according to the present invention, a very low amount of calcium would make it possible to ensure the industrial control of this process and to obtain a very well-tolerated product.
• step c) of measuring the amounts of chelate and/or of lanthanide with common industrial analytical tools is markedly improved when the amount of calcium in the components used (in particular in the macrocyclic chelate, the lanthanide and the water used in step b)) is less than a very low target value of around 15 to 200 ppm.
• the amount of calcium (quantity of calcium) in the macrocyclic chelate used in step b) is advantageously less than 200 ppm and advantageously in the region of or less than 15 ppm.
• the amount of calcium in the DOTA (active principle in the form of powder supplemented with water in step b)—see the detailed Example 2—dissolution step 1) is too high (and especially greater than 200 ppm), calcium may complex the chelate and the adjustment of the amount of free chelate will not be performed sufficiently satisfactorily.
• the low amount of calcium in the pharmaceutical solution makes it possible to avoid possible disadvantageous interferences regarding the assays of free macrocyclic chelate (for example by complexing the calcium with the chelate) and thus to obtain an assay of the free chelate and its adjustment in a manner that is particularly effective for manufacture at the industrial scale at the required high level of quality.
• a very low calcium concentration controlled in the final product administered to the patient is advantageous as regards the calcaemia of the patients in so far as it makes it possible to avoid any homeostasis imbalance: the impact of the injected product (typically at a dose of less than 20 ml) on the calcaemia is at most in the region of 0.5%.
• the amount of calcium in the administered contrast product is advantageously less than 50 ppm and especially less than 20 ppm, for example between 1 and 5 ppm.
• a limit of 15 ⁇ g of Ca/g of DOTA powder (15 ppm) used in step b) corresponds to 3 ⁇ g Ca/ml of liquid contrast product administered to the patient (there is about 0.202 g of DOTA per ml of administered liquid contrast product), i.e. 3 ppm in this contrast product.
• the different variants of the process according to the invention as described previously thus advantageously comprise, before the measuring and adjustment steps c) and d), an intermediate step b2) of controlling the amount of calcium in the formulations obtained in step b).
• this intermediate step comprises, following this control, the removal of the excess calcium.
• the process according to the present invention is characterized in that the amount of calcium in the liquid pharmaceutical formulation administered to the patient is less than 50 ppm, especially less than 20 ppm, and preferably less than 5 ppm, the process advantageously comprising, before step c), an intermediate step b2) of measuring the amount of calcium and, where appropriate, of removing the excess calcium.
• the different variants of the process according to the invention as described previously advantageously comprise, before step b), control of the amount of calcium in the components used in step b), and especially in the macrocyclic chelate intended to be dissolved, in the lanthanide (typically used in oxide form), and in the water.
• the amount of calcium in these components is less than 150 ppm and preferably less than 15 ppm.
• the Applicant has succeeded in removing the excess calcium in the chelate (powder) used in step b), by means, in particular for DOTA, of a purification by crystallization using a water-ethanol mixture, which makes it possible to obtain an amount of calcium advantageously less than 50 ppm.
• the water used for step b) is also advantageously purified, where appropriate by means of a suitable treatment, for example descaling with acids to prevent any undesired amount of calcium.
• a gadolinium oxide with a purity very close to 100%, substantially of 99.999%, will preferably be used in particular.
• the meglumine used at the end of the adjustment step d) also comprises a small amount of calcium.
• the process is also advantageously such that it uses components that have extremely low amounts of metals (for example nickel and aluminium) liable to interact with the chelate, disrupting the assays.
• the process advantageously includes a step of checking the amount of these metals before the measuring and adjustment steps b) and/or c) and/or d).
• the process according to the present invention also advantageously comprises an additional step e) of checking C cl and C ll , irrespective of the variant described above.
• the process according to the present invention is, according to one preferred embodiment, characterized in that the pharmaceutical formulation is a pharmaceutical formulation of meglumine salt of the DOTA-gadolinium complex.
• the Applicant's process makes it possible to obtain the target formulations safely.
• This process makes it possible to solve the problem represented by the in situ complexation, in a pharmaceutical manufacturing reactor (into which is added the pharmaceutical formulation agent).
• the lanthanide is Gd 3+
• meglumine will be used as formulation agent.
• the process according to the invention that allows this problem to be solved consists in engaging the complexation, measuring the difference relative to the target, and adjusting.
• the Applicant's process thus makes it possible to incorporate the chelation process into the pharmaceutical production, with an advantage especially in terms of cost price and quality.
• an agent for blocking the free lanthanide, other than the free macrocyclic chelate is added in step b).
• this blocking agent is a polycarboxylic acid, especially a dicarboxylic, tricarboxylic or tetracarboxylic acid, in particular a citrate or a derivative thereof.
• the Applicant's target range is very narrow, and corresponds to a selection within the very broad range presented in the said document.
• the invention relates to a pharmaceutical formulation that may be obtained via the process according to the present invention, characterized in that it contains between 0.002 and 0.4 mol/mol %, more especially between 0.02 and 0.3 mol/mol % and very advantageously between 0.025 and 0.25 mol/mol %, of free macrocyclic chelate, advantageously of free DOTA.
• the concentration of complexed chelate in the formulation is typically between 1 ⁇ M and 1 M, with an administered dose of about from 0.01 to 5 mmol/kg.
• the concentration of the injected formulation is typically about 0.5 M.
• the process particularly advantageously relates to the preparation of the pharmaceutical formulation of the meglumine salt of the DOTA-gadolinium complex: the macrocyclic chelate and the free macrocyclic chelate are DOTA, the lanthanide is gadolinium, and the prepared salt is the meglumine salt.
• the pharmaceutical formulation according to the present invention is characterized in that the macrocyclic chelate is DOTA and in that the formulation contains between 0.02 and 0.08 mol/mol % of free DOTA.
• the pharmaceutical formulation according to the present invention is characterized in that the macrocyclic chelate is DOTA and in that the formulation contains between 0.15 and 0.25 mol/mol % of an excess amount of free DOTA.
• This higher range is also an advantage for further improving the stability of the formulation to be injected over time (dechelation under unsuitable storage conditions: heat, depressurization in aircraft, excessive exposure to light, etc.).
• the amount of free macrocyclic chelate is between 0.09% and 0.15%. This median range is liable to combine advantages of the lower and higher ranges.
• the choice of the amount of free macrocyclic chelate may be optimized in particular as a function of the risk of the patients for various pathologies or pathological risks associated with the mechanisms presented hereinabove. For example, in the case of patients presenting a risk of NSF, an excess of macrocyclic chelate in the median or high range may be preferred, to minimize any release of gadolinium.
• the calcium content of the pharmaceutical formulation (administered to the patient) according to the invention is less than 50 ppm, advantageously less than 30 ppm and advantageously less than 15 ppm.
• the invention relates to use of a contrast product formulation, the said formulation comprising a complex of macrocyclic chelate with a paramagnetic metal ion and an amount of free macrocyclic chelate of between 0.025% and 0.25%, advantageously of a formulation according to the present invention, for improvement of the tolerance.
• the invention relates to a method for improving the in vivo tolerance of an MRI contrast product based on macrocyclic chelate, and more especially on DOTA, which consists in using an excess of free chelate in an amount of between 0.025 and 0.25 mol/mol %, especially 0.025-0.08%, 0.09-0.15%, 0.16-0.25%.
• the concentration of chelate (complexed chelate) in the formulation is between 0.5 and 0.9 M.
• the macrocyclic chelate that is useful in the context of the present invention is advantageously chosen from the following chelates: DOTA, NOTA, DO3A, BT-DO3A, HPDO3A, PCTA, DOTAGA and derivatives thereof, and is most particularly DOTA.
• the chemical formulae of these chelates are widely known to those skilled in the art, and are recalled, for example, in WO 2007/042 504, on pages 20 to 23, and WO 2003/011 115, on pages 8 to 11.
• the invention also relates to the use of a pharmaceutical formulation according to the invention for the preparation of a diagnostic composition for medical imaging, or for diagnostic monitoring of the efficacy of a therapeutic treatment, and to a diagnostic method comprising the administration of a pharmaceutically acceptable amount of a formulation according to the invention.
• the intravenous administration by injection usually as a saline solution is typically performed at a dose of from 1 to 500 ⁇ mol Gd/kg.
• the pharmaceutically acceptable unit doses will depend on the nature of the chelate, the route of administration, and on the patient and especially on the nature of the disorder to be studied.
• the concentration of the solution will typically be between 0.001 and 0.5 mol/litre, and from 0.001 to 0.1 millimol/kg will be administered to the patient, depending on the case. Higher clinical doses may also be practised, for example a triple dose (0.3 millimol/kg).
• indications already used clinically and the indications for which the results are improved by virtue of the formulations according to the invention. Mention will thus be made of the following indications and improvements thereof: angiography, cerebral imaging, vascular imaging, imaging of cardiovascular, cancer, neurodegenerative and inflammatory pathologies, any indication with perfusion imaging, any indication combining the use of several contrast products, especially MRI, X-ray scanner, SPECT, PET, PET CT, and any indication with successive administrations of contrast products or in multimodal imaging.
• these novel formulations may be chosen to be administered in combination with or in place of prior-art formulations as a function of the diagnostic profile of the patient, and especially of the profile of tolerance of the patient to the contrast products.
• An installation comprising a device for evaluating the tolerance of the patient, and a device for administering the formulation of the contrast product as a function of the result given by the evaluation device may thus be used.
• a device for evaluating the tolerance of the patient and a device for administering the formulation of the contrast product as a function of the result given by the evaluation device may thus be used.
• Several risks may be evaluated, especially the risk of NSF (nephrogenic fibrosis).
• the MRI product is co-administered simultaneously with or subsequently to at least one anti-NSF therapeutic agent (anti-fibrosis agent known therapeutically, especially steroids, anti-inflammatories or vitamins, for example).
• an evaluation of the patient's risk with respect to NSF is performed to optimize the dose of injected contrast product (for example, the dose may be reduced relative to the common clinical dose, if it makes it possible, while avoiding any risk, to obtain sufficiently satisfactory information to obtain the signal in imaging).
• At least one anti-NSF therapeutic agent especially an anti-inflammatory, steroid or vitamin, may be co-administered.
• blocking agents that will especially be used are organic anions such as monocarboxylic or polycarboxylic acids (advantageously tricarboxylic or tetracarboxylic, such as citrate and derivatives thereof), hydroxy acids, or other agents capable of an advantageous coordination interaction with the lanthanide.
• organic anions such as monocarboxylic or polycarboxylic acids (advantageously tricarboxylic or tetracarboxylic, such as citrate and derivatives thereof), hydroxy acids, or other agents capable of an advantageous coordination interaction with the lanthanide.
• the blocking agent may thus be introduced into the formulation and/or co-administered to the patient.
• step 1 a sample is taken and the free gadolinium is assayed.
• Step 3 Adjustment of the Free Species
• the adjustment of the solution is advantageously performed with gadolinium oxide or DOTA.
• a DOTA-adjusting solution is thus added qs an amount of 15-35 mg per 100 ml.
• the final solution from step 3 is cooled to 30° C., for example by circulating cold water in the tank jacket.
• Step 5 Adjustment of the pH and of the Mass Per Unit Volume
• the acid function of the complex formed is salified with meglumine and the pH at 20° C. is adjusted to 6.8-7.4. The concentration is adjusted by adding injection-grade water.
• the final solution is then filtered and then placed in bottles typically sterilized by autoclaving.
• This example illustrates the manufacture of a small amount of product, the appropriate transposition being performed at the industrial scale.
• the residual free gadolinium is removed by means of a chelex resin prerinsed with water. To do this, the reaction mixture is brought to pH 5 (the resin is more efficient). The whole is left for 2 hours with stirring at room temperature. The pH rises to between 6.5 and 7. The resin is removed by filtration.
• the complex is precipitated in ethanol to remove the salts (5 volumes of EtOH per 1 volume of water).
• An assay of the salts is performed by titration with a 0.05N silver nitrate solution. Quantification of the free gadolinium is also performed by calorimetric assay with Arsenazo (III). 11.5 g of product are obtained (white powder).
• the dissolution in water is then performed via suitable methods, for example using a water at 45° C., with stirring for about 30 minutes, and with adjustment of the pH.

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• 2008
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• 2017
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