Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
  • A61K33/244—Lanthanides; Compounds thereof
• • 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
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K33/00—Medicinal preparations containing inorganic active ingredients
  • A61K33/24—Heavy metals; Compounds thereof
• • 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
  • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
  • A61K9/0009—Galenical forms characterised by the drug release technique; Application systems commanded by energy involving or responsive to electricity, magnetism or acoustic waves; Galenical aspects of sonophoresis, iontophoresis, electroporation or electroosmosis
• • 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

Definitions

• the invention relates to contrast agent formulations, in particular to paramagnetic metal ion chelates, in particular for Magnetic Resonance Imaging, and methods for obtaining these formulations industrially.
• contrast agents based on lanthanide chelates in particular gadolinium, described for example in document US Pat. No. 4,647,447 are known. These products are often grouped under the term GBCA (Gadolinium-based Contrast Agent, gadolinium contrast media).
• GBCA Gadolinium-based Contrast Agent, gadolinium contrast media.
• Several products are marketed, in particular based on macrocyclic chelates, such as gadoterate DOTA (1,4,7,10-tetraazacyclododecane-N, N ', N ", N"' - tetraacetic acid), gadoteridol HPD03A and gadobutrol.
• D03A-butrol D03A-butrol
• linear chelates such as DTPA (diethylenetriaminepentaacetic acid), DTPA-BMA (gadodiamide) or BOPTA (gadobemate).
• DTPA diethylenetriaminepentaacetic acid
• DTPA-BMA gadodiamide
• BOPTA gadobemate
• macrocyclic chelate complexes such as bicyclopolyazamacrocyclocarboxylic acid (EP 0 438 206) or macrocyclic chelates derived from PCTA (that is to say comprising at least the chemical structure of the acid 3,6,9 15-tetraazabicyclo [9.3.1] pentadeca-1 (15), 11.13-triene-3,6,9-triacetic), as described in WO 93/1 1800, US 5,403,572, US 6,440,956 or EP 1 931 673.
• PCTA macrocyclic chelates derived from PCTA
• the lanthanide chelates are in a state of chemical equilibrium. There is therefore a risk of unwanted release of paramagnetic metal.
• the skilled person is thus led to seek technical solutions limiting this risk to resolve in a manner completely secure the complex technical problem of tolerance in the patient, especially when the paramagnetic metal is gadolinium. This problem is all the more delicate as the administration of contrast agents is often repeated during diagnostic tests and / or for guiding and monitoring the effectiveness of a therapeutic treatment.
• NSF Neurogenic Systemic Fibrosis, systemic nephrogenic fibrosis or fibrogenic dermopathy
• a first strategy to limit this risk is to select complexes that have the highest thermodynamic and kinetic stability possible. Indeed, the higher the stabilities of the complex, the more the amount of lanthanide released over time will be limited.
• No. 5,876,695 discloses formulations comprising an excess of free chelate, intended to compensate for an undesired release of the lanthanide, the excess chelate complexing the liberated lanthanide (eg gadolinium).
• US 5,876,695 in particular describes an excess of linear chelate, in particular free DTPA.
• This formulation strategy is used for products such as Magnevist ® , Vasovist ® or Primovist ® .
• WO 2009/103744 describes a similar formulation strategy, based on the addition of a precise amount of free chelate, so as to have a very small excess of said chelate and a zero concentration of free lanthanide.
• EP 0 454 078, US 5 876 695 and US 2004/0170566 describe the use of "weak" complexes of a macrocyclic or linear ligand with a metal or an alkaline earth metal, especially calcium, sodium, zinc, magnesium. .
• These "weak” complexes undergo a transmetallation in the presence of free lanthanide, since the complexes such macrocyclic ligands or lanthanides, especially gadolinium, are "stronger", i.e. they are more thermodynamically stable.
• An exchange takes place between calcium, sodium, zinc or magnesium and lanthanide: the latter is trapped by the ligand in the form of a complex, while the solution is released calcium, sodium, zinc or magnesium.
• An object of the present invention therefore relates to a liquid pharmaceutical composition
• a liquid pharmaceutical composition comprising a complex derived from PCTA and further comprising a calcium complex of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7,10-tetraacetic acid, preferably a complex of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7,10-tetraacetic acid mono-calcium (DOTA-Ca) or a complex of 1, 4,7, 10-tetraazacyclododecane-1, 4 , 7,10-tetraacetic dicalcium (DOTA-Ca 2 ), and having a free paramagnetic metal concentration of less than 1 ppm (m / v), preferably less than 0.5 ppm (m / v).
• PCTA - paramagnetic metal an alternative way of designating a complex between a chelating ligand of formula (I) and a paramagnetic metal.
• PCTA-Gd the complex between this ligand chelator of formula (I) and a gadolinium ion
• DOTA-Gd DOTA and gadolinium
• Another subject of the invention relates to a contrast medium for medical imaging comprising said composition.
• Another object of the present invention relates to a process for preparing said composition.
• the present invention also relates to said composition or said contrast medium for use in a diagnostic method.
• the invention relates to a liquid pharmaceutical composition
• a liquid pharmaceutical composition comprising a complex of formula (I):
• D represents CH or N
• E represents CH or N
• M represents an ion of a paramagnetic metal
• composition further comprising a calcium complex of 1, 4,7, 10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid, preferentially a complex of 1, 4,7,10-tetraazacyclododecane-1, 4 , 7,10-tetraacetic mono-calcium (DOTA-Ca) or a complex of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7,10-tetraacetic acid dicalcium (DOTA-Ca 2) , and having a free paramagnetic metal concentration of less than 1 ppm (w / v), preferably less than 0.5 ppm (w / v).
• a calcium complex of 1, 4,7, 10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid preferentially a complex of 1, 4,7,10-tetraazacyclododecane-1, 4 , 7,10-tetraacetic mono-calcium (DOTA-C
• the calcium complex of 1, 4,7, 10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid according to the invention will be a complex of 1, 4,7,10-tetraazacyclododecane-1 acid. , 4,7,10-tetraacetic mono-calcium.
• alkyl group or “alkylene group” means any straight or branched chain, unsubstituted, of carbon atoms (preferably 1 to 5) and "hydroxyalkyl group", any chain alkyl as defined above having one or more hydroxyl groups.
• C1 -C n means any group comprising from 1 to n carbon atoms.
• C 1 -C 6 alkyl group in particular means a group selected from methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl.
• C1-C6 alkylene group means in particular a group selected from methylene, ethylene, n-propylene, i-propylene, n-butylene, i-butylene, t-butylene. pentylene, hexylene.
• DOTA-calcium or DOTA-Ca the calcium complex of 1, 4,7,10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid whether it is the monocalcic complex or the dicalcium complex.
• the composition according to the invention has the advantage of presenting a non-existent risk, before the expiry date, of undesired release of paramagnetic metal and this thanks to the choice of specific formulation of the complex of formula (I) as defined above in mixture with the DOTA-Calcium complex.
• the composition according to the invention thus has stability over time, that is to say that its composition remains in accordance with the specifications in terms of free paramagnetic metal concentration (in particular its concentration of free paramagnetic metal remains less than 1 ppm (m / v)) over a period of at least 3 years, preferably at least 4 years or more preferably at least 5 years, especially in terms of free paramagnetic metal content. According to the ICH guidelines, an observation of this stability for 6 months at 40 ° C is considered a good indication of stability of 3 years at 25 ° C.
• the complex of formula (I) is such that E represents a N atom and D and Fi represent CH.
• the complex of formula (I) is such that X 1 to X 3 independently represent - (CH 2 ) n -CO-N 78 or - (CH 2 ) n -NR 7 -CO-R 8, in which n is between 1 and 3, R 7 represents H or a methyl group, R 8 represents a C 1 -C 6 hydroxyalkyl group, advantageously C 2 -C 3 , preferably
• the complex of formula (I) is chosen from the complexes between a ligand of formula ( ⁇ ') and (I ")
• the paramagnetic metal ion M is chosen from the ions of a paramagnetic metal of atomic number 21 -29, 42-44 or 58-70, that is to say among the scandium ions (Se ), titanium (Ti), vanadium (V), chromium (Cr), manganese (Mn), iron (Fe), cobalt (Co), nickel (Ni), copper (Cu) or molybdenum ions (Mo), technetium (Te), ruthenium (Ru) or cerium (Ce) praseodymium (Pr), neodymium (Nd), promethium (Pm), samarium (Sm), europium (Eu), gadolinium (Gd), terbium (Tb) ions ), dysprosium (Dy), holmium (Ho), erbium (Er), thulium (Tm), ytterbium (Yb).
• Se scandium ions
• Ti titanium
• the paramagnetic metal ion M is preferably chosen from manganese, iron and lanthanide ions, more preferentially chosen from Mn 2+ ions, Fe 3+ ions and gadolinium ions such as Gd 3+ and even more preferably chosen from lanthanide ions and especially gadolinium ions such as Gd 3+ .
• the complexes of formula (I) as defined above have a relaxivity (efficiency in imaging) and a mass efficiency (industrial cost) very significantly improved, including relaxivity values r1 of the order of 9 to 15 mM. s "1 .Gd " 1 , that is to say relaxivity values multiplied by a factor of 2 to 3 relative to those of the derivatives in particular D03A, DOTA or DTPA earlier. These compounds are well suited to high magnetic field imaging (for example for 3 Tesla fields).
• the complexes of formula (I) have several particularly effective functional characteristics when combined:
• Non-ionicity this makes it possible to strongly limit the osmolality of the product to be injected and therefore the dose of product injected, which is an important characteristic for the contrast products in order to improve the comfort of the patients and to reduce the cost of injection;
• the composition according to the invention has a concentration of between 0.001 and 1.5 mol.L -1 , preferably between 0.2 and 0.7 mol.L -1 , more preferably between 0.3 and 0. , 6 mol.L -1 in complex of formula (I) described above.
• the complex of formula (I) is determined by methods known to those skilled in the art. In particular, it can be assayed after mineralization and assay of the total paramagnetic metal present in the composition. In the case of the total gadolinium assay present in the solution, the assay is performed by optical emission spectrometry (also known as ICP-AES or ICP Atomic Emission Spectrometry).
• optical emission spectrometry also known as ICP-AES or ICP Atomic Emission Spectrometry.
• the complex content of formula (I) allows this composition to have optimum contrasting power while having a satisfactory viscosity. Indeed, below 0.01 mol.L -1 of complex of formula (I) described above, the performance as a contrast product is less satisfactory, and at a concentration greater than 1 .5 mol.L 1 , the viscosity of this composition becomes too important for easy handling.
• the proportion of the DOTA-calcium complex is from 0.002 to 5 mol / mol, for example from 0.002 to 1 mol / mol, preferably from 0.01 to 5 mol, more preferably from 0, 25 to 5% or from 0.01 to 0.5% mole / mole, still more preferably from 0.25 to 0.5 mole% / mole, this proportion being reduced to the proportion of complex of formula (I) in said composition.
• the DOTA-calcium complex is also determined by methods known to those skilled in the art, for example by HPLC (for example by ion pair HPLC: using a liquid chromatograph equipped with a iodine detector (detection made by UV at 205 nm) and a C18 column, the solvent used is methanol (Prolabo)).
• HPLC for example by ion pair HPLC: using a liquid chromatograph equipped with a iodine detector (detection made by UV at 205 nm) and a C18 column, the solvent used is methanol (Prolabo)).
• the proportions specified in the present invention and in particular above are proportions before sterilization of the composition.
• the pH of the composition is between 4.5 and 8.5, preferably between 5 and 6.5.
• these ranges of pH make it possible in particular to limit the appearance of certain impurities and to promote the complexation of the paramagnetic metal ion M.
• the composition according to the invention can be buffered, that is to say that it may further comprise a buffer chosen from the buffers of established use for the range of pH 5 to 6.5 and preferably from the buffers lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, Tris (Tris (hydroxymethyl) aminomethane), HEPES (2- [4- (2-hydroxyethyl) -1-piperazine] ethanesulfonic acid), MES (2-morpholino ethanesulphonic acid) and mixtures thereof, and preferably a buffer selected from lactate buffers, tartrate, carbonate, MES and mixtures thereof.
• the composition which is the subject of the invention may furthermore comprise a complex between DOTA and a metal, preferably in a proportion of 0.002 to 0.5 mol% / mol, preferentially from 0.01 to 0.5 mol / mol, this proportion being reduced to the proportion of complex of formula (I) in said composition.
• the complex between DOTA and a paramagnetic metal is a complex between DOTA and a gadolinium ion (in particular Gd 3+ ).
• the nature of the metal chelated by DOTA is predominantly the same as that of the paramagnetic metal chelated by the ligand of the complex of formula (I).
• composition according to the invention may further comprise a small proportion of complex between DOTA and another metal than that chelated by the ligand of the complex of formula (I).
• the composition may further comprise a complex between DOTA and an ion of any metal extractable from the containers in which the composition is prepared and / or stored, particularly an iron, copper and / or magnesium ion.
• the complex between a chelating ligand and a lanthanide is preferably chosen from the complexes of formula (I) for which M represents a lanthanide ion, and more preferentially from the complexes of formula:
• composition which is the subject of the invention is preferably sterile.
• the present invention also relates to a method for preparing a composition according to the invention.
• the paramagnetic metals released during the formulation of these complexes and / or during the storage of contrast products comprising these complexes come mainly from aging in conservation of chelates, a technical solution could be provided to allow extremely rapid trapping of lanthanides released.
• the process for preparing the liquid pharmaceutical composition described above comprises the following successive stages:
• step a) the dissolution of the complex of formula (I) as defined above, in a pharmaceutically acceptable medium, b) adding to the solution obtained at the end of step a) an amount of free DOTA of between 0.002 and 5 mol / mol relative to the amount of complex of formula (I) present in the composition and
• step b) adding to the solution obtained at the end of step b) from 0.002 to 5 mol% / mol of a calcium salt or calcium oxide.
• a medium compatible with intravenous injection is sterile water, or a sterile saline solution, preferably sterile water.
• This medium is preferably buffered, that is to say that it may further comprise a buffer chosen from buffers of established use for the range of pH 5 to 6.5 and preferably from lactate, tartrate and malate buffers. , maleate, succinate, ascorbate, carbonate, Tris, HEPES, MES and mixtures thereof, and preferentially a buffer selected from lactate, tartrate, carbonate buffers, MES and mixtures thereof.
• the term "free DOTA” is intended to mean that the DOTA ligand is present in uncomplexed form, in particular not complexed to a paramagnetic metal, and is not added in the form of an excipient X [X ' Where X and X are a metal or alkaline earth ion, particularly independently selected from calcium, sodium, zinc, and magnesium.
• the free DOTA is not in salt form, in particular the free DOTA is not in the form of a calcium salt, such as DOTA-Ca (monocalcium salt), DOTA-Ca 2 (dicalcium salt) or DOTA-Ca-Na 2 (disodium calcium salt).
• An example of free DOTA is its tetraacid form (1, 4,7,10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid).
• the calcium salt is calcium chloride (CaCl 2 ).
• Step a) of dissolution of the complex of formula (I) defined above is preferably carried out by heating the pharmaceutically acceptable medium to a temperature of at least 45 ° C, or even at least 60 ° C.
• steps b) of adding free DOTA and / or c) of adding a calcium salt are advantageously carried out, after a reduction of the temperature of the solution obtained in step a), to a temperature of 20 ° C. at 40 ° C.
• This temperature range is optimal for limiting the gadolinium exchanges between the complex of formula (I) defined previously and the DOTA.
• the amount (in molar percentage) of calcium salt or calcium oxide added to the solution in step c) is identical to the amount of free DOTA added in step b) .
• the method according to the invention further comprises a step c ') of adjusting the pH of the solution obtained in step c), at a pH of 4.5 to 8.5, preferably from 5 to 6.5.
• This step c ') of pH adjustment is preferably carried out by adding one of the buffers mentioned below and / or by adding a solution of NaOH sodium hydroxide solution or a solution hydrochloric acid HCI 0, 1 N.
• the method according to the invention further comprises, after step c) or step c ') a step d) of adjusting the concentration of said complex of formula (I), after measuring the density of the the composition, by adding a pharmaceutically acceptable medium.
• the final target complex concentration of formula (I) in the composition is preferably between 0.001 to 1.5 mol. L “1 , more preferably between 0.2 and 0.7 mol.L “ 1 and even more preferably between 0.3 and 0.6 mol.L “1 .
• the step of adjusting the concentration of the complex of formula (I) as defined above is preferably a volume adjustment step by the addition of a pharmaceutically acceptable medium so as to adjust the density of the liquid composition to a minimum. density preferably between 0.1 and 1.3 g. cm "3, more preferably 1, 0 to 1, 3 g. cm" 3.
• the method according to the invention may further comprise a step of measuring the amount of DOTA and / or excess paramagnetic metal at the end of step a) and / or step b) and / or of step c) and / or step c '), and / or step d). These assays are performed according to methods known to those skilled in the art.
• the gadolinium assay is, for example, carried out by colorimetry with Xylenol Orange.
• a sterilization step, advantageously after step c), c ') or d) of the process according to the invention, can also advantageously be added to this process.
• This sterilization is performed according to methods known to those skilled in the art.
• the composition is sterilized according to over-destructive parameters, that is to say in Anglo-Saxon terms according to an "overkill" approach. This approach requires little information regarding the bio-contaminants of the composition.
• Any sterilization process which shows that lethality indices Fbio and Fphy (lethality calculated on the basis of physical parameters of the sterilization cycle - This is the integration of the lethal rate (L) over time) are greater than 12 minutes is suitable for the implementation of this "overkill" approach
• An example of sterilization using an "overkill” approach is a wet heat sterilization at 121 ° C for 15 minutes (Decision three for the selection of Sterilization Methods, Annex to Note for Guidance on Pharmaceutical Development (CPMP / QWP / 054/98 Corr), EMBA, April 2000)
• An Alphaklave® 23 autoclave (HMCE - France) can be used to perform this sterilization.
• the method comprises the successive steps a), b), c), c '), d), and a sterilization step, said steps being as defined above .
• the concentration of the complex composition of formula (I) is typically between 1 mM and 0.6 M.
• the dose administered in the patient is typically in the range of 0.01 to 5 mmol / kg.
• the invention also relates to the use of a composition according to the invention for the preparation of a diagnostic composition for medical imaging, or a diagnostic follow-up of the effectiveness of a therapeutic treatment, and a diagnostic method comprising the administering a pharmaceutically acceptable amount of a pharmaceutical composition as described above.
• the invention therefore relates to a contrast medium for medical imaging comprising such a liquid pharmaceutical composition.
• the invention also relates to the compositions or the contrast medium described above for their use for the diagnosis of diseases, in particular cancerous, inflammatory, neurodegenerative or vascular diseases, in particular cardiovascular diseases.
• the invention also relates to said compositions or contrast material described above for use in an imaging method, particularly a method as described below.
• the invention relates to a method for imaging the whole body or part of the body of an individual comprising a step of obtaining one or more images of the whole body or part of the body of a body. an individual by a medical imaging technique, wherein said whole body or said part of the body of the individual comprises the composition defined above or the contrast product defined above (preferably in an effective amount) and wherein the image (s) is (are) associated with the magnetic particles based on an iron compound contained in the composition defined above or in the contrast product defined above.
• the imaging method according to the invention does not include a step of injection or invasive administration of the composition or the contrast product to the individual.
• the imaging method according to the invention comprises a prior step of injection or administration of the composition or the contrast product to the individual, preferably an intravascular injection.
• the images are preferably obtained by Magnetic Resonance Imaging (or MRI).
• an effective amount is meant a quantity of composition according to the invention or a contrast medium comprising this composition, which makes it possible to obtain the images by the medical imaging technique used.
• intravenous administration by injection usually in saline solution, is typically at a dose of 1 to 500 ⁇ Gd / kg.
• the pharmaceutically acceptable unit doses will depend on the route of administration, as well as on the patient and in particular on the nature of the disorder to be studied.
• the concentration of the solution is typically between 0.001 and 1 mole / liter, and the dose administered to the patient according to its weight will be from 0.001 to 0.3 millimole / kilo.
• indications already used in clinical practice and indications for which the results are improved by the formulations.
• the following indications and their improvements can be cited: angiography, brain imaging (of the central nervous system in particular), vascular imaging, imaging of cardiovascular pathologies, cancerous, neurodegenerative, inflammatory, any indication with perfusion imaging, any indication combining the use of several contrast agents including MRI, X-ray scanner, SPECT, PET, PET CT, any indication with successive administrations of contrast media or multimodal imaging.
• the diagnostic compositions of the invention may further comprise additives such as antioxidants, buffers, osmolality regulators, stabilizers.
• additives such as antioxidants, buffers, osmolality regulators, stabilizers.
• formulation can be found in the general literature and in particular in Remington's for Pharmaceutical Science 18th Edition (1990), Mack. Pub.
• galenic adjuvants lactose, methylcellulose, mannitol
• surfactants lecithins, Tween® or similar products
• excipients such as mannitol.
• a pharmaceutically acceptable dose refers to a dose suitable for therapeutic or diagnostic use.
• the method of manufacturing a composition is carried out by following the following steps: a) 485.1 g (or 0.5 M) of complex between a chelating ligand of formula ( ⁇ ) and a gadolinium ion (Gd 3+ ) , which is in the form of an odorless white powder, is dissolved in water (qs 1 liter) by heating the vessel to a temperature of 50 ° C and carrying out a strong agitation of the solution until complete dissolution of this complex in water. The solution is then cooled to about 30 ° C.
• step c) if necessary, the pH of the solution obtained in step c) is adjusted to a pH of 5 to 6 by decreasing, if necessary, the pH by the addition of a hydrochloric acid solution 0, 1 N or by increasing, if necessary, the pH by adding 0.1 N sodium hydroxide solution.
• a calcium complex of 1, 4,7,10-tetraazacyclododecane-1, 4,7,10-tetraacetic acid is formed in the composition ( DOTA) and in particular predominantly a complex of 1, 4, 7, 10-tetraazacyclododecane-1, 4, 7,10-tetraacetic acid mono-calcium (DOTA-Ca).
• step c ' The density of the composition thus obtained in step c ') is adjusted to a value of 1, 2010 to 1, 2219 g. cm "3 by the addition of water.
• the liquid composition is then filtered through a polyethersulfone membrane and placed in the final container which is finally subjected to sterilization at 121 ° C for 15 minutes.
• accelerated conditions is used to mean a study carried out at 40 ° C over 6 months and by a "long-term” stability study, a study carried out at 25 ° C over 36 months (ICH conditions).
• DOTA-Calcium complex decreases significantly due to sterilization but remains stable after six months under accelerated conditions and over the long term. About half of the DOTA-Ca complex that formed in the composition after addition of DOTA and calcium salt remains available in the composition for its function of free gadolinium scavenging.
• the concentration of free Gd 3+ is less than 0.5 ppm (m / v).
• the decrease in the DOTA-Ca content over time reflects a consumption of the formulation excipient. Nevertheless, for an initial proportion of DOTA-Ca greater than or equal to 0.25 mol / mol relative to the complex A, the amount of DOTA-Ca available after 3 months of storage at 40 ° C. remains, at least, greater than more than half of the amount initially introduced. This excess of formulation excipient provides an additional guarantee in terms of capturing the gadolinium released by the complex A during storage of the product.
• Gadolinium assay results in PCTA-Gd compositions after addition of a solution of DOTA-Calcium or after addition of DOTA then of CaCl 2 (in accordance with the invention)
• a complex parent solution between the chelating ligand of formula ( ⁇ ) and a gadolinium ion enriched with free gadolinium is used.
• this solution is added either DOTA in powder form and then CaCl 2 (process in accordance with the invention), or a solution of DOTA-calcium adjusted to pH 6.0 (by extrapolating from the methods described in the art prior).
• DOTA-calcium assay results in PCTA-Gd compositions after addition of a solution of DOTA-Calcium or after addition of DOTA then of CaCl 2 (in accordance with the invention)
• DOTA-Ca Consumption of DOTA-Ca is greater when DOTA is added as a powder than when it is added directly as a DOTA-Ca complex.
• DOTA is added as a powder, it is able to directly complex Gd 3+ in solution.
• CaCl 2 becomes complex with the remaining free DOTA which explains the lower amount of DOTA-Ca.
• gadolinium and Ca must be exchanged (Complex-Gd + DOTA-Ca - * Complex-Ca + DOTA-Gd). The reaction is slower and is not complete since traces of Gd 3+ are present more than 2h after the addition of DOTA-Calcium.
• the consumption of DOTA-Ca is of little importance during sterilization for both manufacturing processes.

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