Contrast medium formulation and related preparation method

Abstract

The present invention relates to a liquid pharmaceutical composition including a complex of formula (I), in which M is an ion of a paramagnetic metal and R1 to R3, X1 to X3 and K1 to K12 are such as defined in claim 1, said composition also including a calcium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid. The invention also relates to the preparation method thereof and to an imaging method involving said composition.

Claims

1. A liquid pharmaceutical composition comprising a complex of formula (I): ##STR00006## in which R.sub.1, R.sub.2 and R.sub.3 represent COOH, X.sub.1, X.sub.2 and X.sub.3 represent, independently of one another, L-Y in which L represents (CH.sub.2).sub.n with n=1 to 3, and Y represents CONH.sub.2, CONR.sub.7R.sub.8 or NR.sub.7COR.sub.8, in which R.sub.7 represents H or a C.sub.1-C.sub.6 alkyl group or a C.sub.1-C.sub.6 hydroxyalkyl group, and R.sub.8 represents a C.sub.1-C.sub.6 alkyl or C.sub.1-C.sub.6 hydroxyalkyl group, provided that at least R.sub.7 or R.sub.8 represents a C.sub.1-C.sub.6 hydroxyalkyl group; D represents CH; E represents N; Fi represents CH; K.sub.1 to K.sub.12 each independently represent H; and M represents Gd.sup.3+; or an enantiomer or a diastereoisomer; wherein said composition also comprises a calcium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA); wherein M complexed with DOTA is more thermodynamically stable than M complexed in formula (I); wherein said composition has a concentration of free paramagnetic metal of less than 1 ppm (m/v); wherein a concentration of said complex of formula (I) comprised between 0.001 and 1.5 mol.Math.l.sup.1; and wherein a proportion of DOTA-Ca is from 0.01% to 5% mol/mol, with respect to the proportion of complex of formula (I) in said composition.

2. The composition as claimed in claim 1, characterized in that its pH is between 4.5 and 8.5.

3. The composition as claimed in claim 1, characterized in that it also comprises a buffer chosen from lactate, tartrate, malate, maleate, succinate, ascorbate, carbonate, Tris, HEPES and MES buffers and mixtures thereof.

4. The composition as claimed in claim 1, characterized in that the complex of formula (I) is chosen from the complexes of formulae: ##STR00007##

5. The composition as claimed claim 1, characterized in that it is sterile.

6. A contrast product for medical imaging, comprising the liquid pharmaceutical composition as claimed in claim 1.

7. A method for imaging the whole body or a part of the body of an individual, comprising a step of administering the composition as claimed in claim 1 to the individual and a step of obtaining one or more images of the whole body or of a part of the body of an individual by means of a medical imaging technique, in which said whole body or said part of the body of the individual comprises the composition as claimed in claim 1 and in which the image(s) is (are) associated with the complex between a chelating ligand of formula (I) as defined in claim 1 and a paramagnetic metal contained in the composition as claimed in claim 1.

8. A process for preparing a liquid pharmaceutical composition as defined in claim 1, said process comprising the following successive steps: a) dissolution of the complex of formula (I) as defined in claim 1, in a pharmaceutically acceptable medium, b) addition, to the solution obtained at the end of step a), of an amount of free DOTA comprised between 0.002% and 5% mol/mol relative to the amount of complex of formula (I) present in the composition, and c) addition, to the solution obtained at the end of step b), of 0.002% to 5% mol/mol of a calcium salt or of calcium oxide.

9. The process as claimed in claim 8, characterized in that it also comprises a step c) of adjustment of the pH of the solution obtained in step b) to a pH of 4.5 to 8.5.

10. The process as claimed in claim 8, characterized in that it also comprises a sterilization step.

11. A liquid pharmaceutical composition obtained according to a process comprising the following successive steps: a) dissolution of the complex as defined in claim 1, in a pharmaceutically acceptable medium, b) addition, to the solution obtained at the end of step a), of an amount of free DOTA comprised between 0.002% and 5% mol/mol relative to the amount of complex of formula (I) present in the composition, and c) addition, to the solution obtained at the end of step b), of 0.002% to 5% mol/mol of a calcium salt or of calcium oxide.

12. A method for imaging the whole body or a part of the body of an individual, comprising a step of administering the contrast product as claimed in claim 10 to the individual and a step of obtaining one or more images of the whole body or of a part of the body of an individual by means of a medical imaging technique, in which said whole body or said part of the body of the individual comprises the contrast product as claimed in claim 6 and in which the image(s) is (are) associated with the complex between a chelating ligand of formula (I) and a paramagnetic metal contained in the contrast product as claimed in claim 6.

13. The composition of claim 1, wherein the complex of formula (I) is a diastereoisomer selected from the group consisting of RRS, RSR, RSS and mixtures thereof.

14. The composition of claim 1, wherein the concentration of the free paramagnetic metal is less than 0.5 ppm (m/v).

15. The composition of claim 1, wherein R.sub.7 represents H or a C.sub.1-C.sub.6 alkyl group or a C.sub.2-C.sub.4 hydroxyalkyl group selected from the group consisting of CH.sub.2CH.sub.2OH, CHOHCH.sub.2OH, CH(CH.sub.2OH).sub.2, (CH.sub.2).sub.m(CHOH).sub.pCH.sub.2OH with m=1 to 3, p=1 to 4 and m+p=2 to 5 and C(CH.sub.2OH).sub.3.

16. The composition as claimed in claim 1, wherein R.sub.8 represents a C.sub.1-C.sub.6 alkyl or C.sub.2-C.sub.4 hydroxyalkyl group selected from the group consisting of CH.sub.2CH.sub.2OH, CHOHCH.sub.2OH, CH(CH.sub.2OH).sub.2, (CH.sub.2).sub.m(CHOH).sub.pCH.sub.2OH with m=1 to 3, p=1 to 4 and m+p=2 to 5 and C(CH.sub.2OH).sub.3.

17. The composition as claimed in claim 1, wherein its pH is between 5 and 6.5.

Description

DETAILED EXAMPLES

Example 1

Example of a Production Process in Accordance with the Invention

(1) The process for producing a composition is carried out according to the following steps:

(2) a) 485.1 g (i.e. 0.5 M) of complex between a chelating ligand of formula (I) and a gadolinium ion (Gd.sup.3+), which is in the form of an odorless white powder, are dissolved in water (qs 1 liter) by heating the vessel to a temperature of 50 C. and stirring the solution vigorously until complete dissolution of this complex in the water. The solution is then cooled to approximately 30 C.

(3) ##STR00005##
b) 1.011 g (i.e. 0.5% mol/mol relative to the proportion of complex added in step a)) of DOTA (Simafex, France) are added to the solution obtained in step a). c) 0.368 g (i.e. 0.5% mol/mol relative to the proportion of complex added in step a)) of calcium chloride (CaCl.sub.2, 2H.sub.2O) (Merck) is added to the solution obtained in step b).
c) if required, the pH of the solution obtained in step c) is adjusted to a pH of 5 to 6 by decreasing, where appropriate, the pH by adding a 0.1N solution of hydrochloric acid or by increasing, where appropriate, the pH by adding a 0.1 N solution of sodium hydroxide.

(4) In the DOTA and calcium chloride proportions as indicated above, a calcium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) and in particular predominantly a monocalcium complex of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA-Ca), forms in the composition.

(5) The density of the composition thus obtained in step c) is adjusted to a value of from 1.2010 to 1.2219 g.Math.cm.sup.3 by adding water. The liquid composition is then filtered through a polyethersulfone membrane and placed in its final container, which is finally subjected to sterilization at 121 C. for 15 minutes.

Example 2

Example of a Composition in Accordance with the Invention and Results from Studies on Said Composition

(6) By virtue of the process of example 1, the following formulation is obtained:

(7) TABLE-US-00001 Ingredients Proportions in the composition Complex of formula (I) in which 485.1 g (0.5M) M represents a gadolinium ion (named complex A) DOTA 1.011 g (2.5 mM, i.e. 0.5% mol/mol vs complex A) CaCl.sub.2, 2H.sub.2O 0.368 g (2.5 mM, i.e. 0.5% mol/mol vs complex A) NaOH or HCl Qs pH 5.5 0.5 Free gadolinium* <1 ppm m/v WFI (water for injection) Qs 1 L *Measurement carried out by colorimetric method with xylenol orange
Studies of Stability Under Accelerated Conditions and of Long-Term Stability

(8) The expression study of stability under accelerated conditions is intended to mean a study carried out at 40 C. over the course of six months and the expression study of long-term stability is intended to mean a study carried out at 25 C. over the course of 36 months (ICH conditions).

(9) Measurements, over the course of time, of the two main entities present in the composition were carried out.

(10) TABLE-US-00002 T0 T 1 T 3 T 6 Bef. month months months s* Aft. s** 40 C. 25 C. 40 C. 25 C. 40 C. Amount of free gadolinium <2 NA*** <2 NA*** <1 NA*** NA*** (ppm m/V) Amount of DOTA-Calcium 0.40 0.18 0.16 0.23 0.23 0.20 0.18 complex (% mol/mol) *Bef. s = Before sterilization **Aft. s = After sterilization ***NA = Not analyzed

(11) Free gadolinium is neither detected nor quantified in the composition. The amount of DOTA-Calcium complex decreases significantly due to the sterilization, but remains stable after six months under accelerated conditions and in the long term. Approximately half of the DOTA-Ca complex which formed in the composition after addition of the DOTA and of the calcium salt remains available in the composition to perform its free-gadolinium-trapping function.

(12) Studies of Stability According to the Proportion of the DOTA-Ca

(13) Several other formulations were prepared with an increasing proportion of DOTA-Ca (in particular of monocalcium complex) relative to the complex A. The concentration of free lanthanide and the concentration of DOTA-Ca were measured after the sterilization step and after three months of storage at 25 C. and 40 C.

(14) TABLE-US-00003 % mol/mol of Amount of free Amount of DOTA- DOTA-Ca vs gadolinium Ca complex complex A (ppm m/v) (% mol/mol) 0.01 T0 Aft. s* <0.50 ND** T 3 25 C. <0.50 ND** months 40 C. <0.50 ND** 0.25 T0 Aft. s* <0.50 0.14 T 3 25 C. <0.50 0.16 months 40 C. <0.50 0.16 0.5 T0 Aft. s* <0.50 0.34 T 3 25 C. <0.50 0.33 months 40 C. <0.50 0.30 0.75 T0 Aft. s* <0.50 0.53 T 3 25 C. <0.50 0.57 months 40 C. <0.50 0.51 5 T0 Aft. s* <0.50 4.60 T 3 25 C. <0.50 4.80 months 40 C. <0.50 4.80 Aft. s*: After sterilization ND**: Not detected

(15) For a proportion of DOTA-Ca of between 0.01% and 5% mol/mol relative to the complex A, the concentration of free Gd.sup.3+ is less than 0.5 ppm (m/v).

(16) The decrease in the DOTA-Ca content with time reflects a consumption of the formulation excipient. Nevertheless, for an initial proportion of DOTA-Ca of greater than or equal to 0.25% mol/mol relative to the complex A, the amount of DOTA-Ca available after three months of storage at 40 C. remains, at least, greater than more than half the amount initially introduced. This excess of formulation excipient provides an additional guarantee in terms of uptake of the gadolinium released by the complex A during the storage of the product.

Example 3

Comparison of the Production Process According to the Invention and of Prior Art Processes

(17) Results of Assaying Gadolinium in the Compositions of PCTA-Gd after Addition of a Solution of DOTA-Calcium or after Addition of DOTA then CaCl.sub.2 (in Accordance with the Invention)

(18) A stock solution of complex between the chelating ligand of formula (I) and a gadolinium ion, enriched with free gadolinium, is used.

(19) Added to this solution is either DOTA in powder form and then CaCl.sub.2 (process in accordance with the invention), or a solution of DOTA-calcium adjusted to pH 6.0 (by extrapolating from the processes described in the prior art).

(20) TABLE-US-00004 Amount of Gd.sup.3+ Addition of Addition of a DOTA in solution of powder form DOTA-calcium and then adjusted to CaCl.sub.2 pH 6.0 Stock solution of complex between the 73 ppm m/v 73 ppm m/v chelating ligand of formula (I) and a gadolinium ion, enriched with free gadolinium 1 h after addition of DOTA in powder <1 ppm m/v form and adjustment of pH 5 minutes after the addition of DOTA- 3 ppm m/v calcium 1 h after the addition of DOTA-calcium 3 ppm m/v 1 h 30 after the addition of DOTA-calcium 3 ppm m/v 2 h 15 after the addition of DOTA-calcium 3 ppm m/v Before sterilization <1 ppm m/v 4 ppm m/v After sterilization <1 ppm m/v <3 ppm m/v

(21) The successive addition of DOTA in powder form and then of calcium chloride CaCl.sub.2 makes it possible to efficiently complex all the Gd.sup.3+ present in the solution of complex of chelating ligand of formula (I) and gadolinium, enriched with free gadolinium. Indeed, the considerable amount of Gd.sup.3+ in the stock solution is no longer detected one hour after addition of the DOTA.

(22) Conversely, when a DOTA-Calcium complex previously formed is added in the form of a solution, gadolinium ions Gd.sup.3+ persist even after having maintained the stirring for 2 h15.

(23) The mode of addition of the DOTA-calcium therefore has an influence on the amount of Gd.sup.3+ in solution.

(24) Results of Assaying of the DOTA-Calcium in the PCTA-Gd Compositions after Addition of a Solution of DOTA-Calcium or after Addition of DOTA then of CaCl.sub.2 (in Accordance with the Invention)

(25) TABLE-US-00005 Amount of DOTA-Ca (as % mol/mol) Addition of Addition of a DOTA in solution of powder form DOTA-calcium then of adjusted to CaCl.sub.2 pH 6.0 After addition of DOTA in 0.27 powder form and adjustment of pH 1 h after the addition of 0.47 DOTA-calcium 1 h 30 after the addition 0.40 of DOTA-calcium Before sterilization 0.25 0.37 After sterilization 0.25 0.40

(26) The consumption of DOTA-Ca is greater when the DOTA is added in powder form than when it is added directly in the form of DOTA-Ca complex. When the DOTA is added in powder form, it is capable of directly complexing the Gd.sup.3+ in solution. The CaCl.sub.2 then complexes with the remaining free DOTA, thereby explaining the smaller amount of DOTA-Ca. When the addition is carried out directly in the form of DOTA-Ca complex, there has to be an exchange of gadolinium and Ca (Complex-Gd+DOTA-Ca Complex-Ca+DOTA-Gd). The reaction is slower and it is not complete since traces of Gd.sup.3+ are present more than 2 h after the addition of DOTA-Calcium. The consumption of DOTA-Ca is not very significant during the sterilization for the two production processes.