Method for preparing a pharmaceutical formulation of lanthanide chelate in powder form

Abstract

The present invention relates to a method for preparing a pharmaceutical formulation of lanthanide chelate in powder form, wherein the powder constitutes a mol/mol excess of free chelate of between 0.002 and 0.4%.

Claims

1. A method for preparing a pharmaceutical formulation of a macrocyclic chelate of a lanthanide, said macrocyclic chelate being DOTA, said lanthanide being Gadolinium, said macrocyclic chelate of a lanthanide being DOTA-Gd complex, and said method comprising the following successive steps of: (1) mixing in a solution a macrocyclic chelate and a lanthanide so as to obtain a complexation solution of the lanthanide by the macrocyclic chelate, the complexation solution comprising, in addition to the macrocyclic chelate-lanthanide complex, an excess amount X1 of free macrocyclic chelate, wherein a step (1) is carried out in a single step or in several successive steps by measuring and adjusting, so as to have an amount X1 of free macrocyclic chelate, and the step (1) comprises the following successive substeps of: (1.1) complexing in solution the lanthanide with the macrocyclic chelate, (1.2) measuring the macrocyclic chelate and/or the lanthanide that is free, and (1.3) adding free macrocyclic chelate, so as to complex the free lanthanide if any remains at the end of step (1.1), and to obtain an amount X1 of free macrocyclic chelate; (2) optionally measuring X1 and/or adjusting X1 so as to have X1 between 0.002 and 0.4% mol/mol; (3) precipitating or crystallizing the complexation solution obtained in step (1) from an organic solvent, so as to obtain a powder of the macrocyclic chelate-lanthanide complex, said powder containing an excess amount X2 of free macrocyclic chelate, wherein X2 represents the amount of free macrocyclic chelate obtained after precipitation or crystallization and X2 is less than X1; (4) adjusting X2 by adding or removing free macrocyclic chelate or by adding or removing lanthanide so as to obtain: (4.a) X2 between 0.002 and 0.4% mol/mol, and (4.b) X2 corresponding to between 0.2 and 5 times X1, wherein said powder obtained after step (4) comprises a mol/mol excess of free macrocyclic chelate of between 0.002 and 0.4%; and (5) returning said powder to solution so as to form a pharmaceutical composition in liquid form, said pharmaceutical composition in liquid form being ready for administration to a patient.

2. The method of claim 1, wherein, in step 3), the precipitating or crystallizing of the complexation solution obtained in step (1) is carried out at a pH in the range 1 to 9.

3. The method of claim 1, wherein the solvent of step (3) is chosen from ethanol, methanol and propanol.

4. The method of claim 1, wherein the solvent of step 3) is used according to a ratio of from 10 to 20 volumes of solvent per volume of complexation solution.

5. The method of claim 1, wherein the solvent of step 3) is used at a temperature included in the range of 0° C. to 80° C.

6. The method of claim 1, wherein the complexation solution of step (1) is a solution of [DOTA-Gd], further comprising a meglumine salt.

7. The method of claim 1, wherein in step (4), X2 is adjusted so as to be comprised between 0.02 and 0.3% mol/mol.

8. The method of claim 1, wherein in step (4), X2 is adjusted so as to be comprised between 0.025 and 0.25% mol/mol.

9. The method of claim 1, wherein in step (4), X2 is adjusted so as to belong to the range: [0.5-0.95]×X1.

10. The method of claim 5, wherein the temperature is included in the range of 30 to 70° C.

11. The method of claim 1, wherein any free gadolinium is removed by virtue of a chelex resin in the complexation solution S with a level X1 of free macrocyclic chelate obtained after step 1.3.

12. The method of claim 11, wherein a quantification of the free gadolinium is carried out by means of a colorimetric assay with 2,2′-(1,8-dihydroxy-3,6-disulfonaphthylene-2,7-bisazo)bisbenzenearsonic acid before and optionally also afterwards the removal of this free gadolinium.

13. The method of claim 11, wherein the said resin is removed by filtration.

Description

(1) According to embodiments, the solvent of step 3) is chosen from: ethanol, methanol, propanol, isopropanol, methyl ethyl acetone, ethyl acetate, and mixtures thereof (including water/solvent in any proportions) known to those skilled in the art, advantageously ethanol, methanol and propanol.

(2) According to embodiments, the solvent of step 3) is used according to a ratio of from 5 to 20 volumes of solvent per volume of complexation solution, advantageously 10 to 20 volumes of solvent per volume of complexation solution.

(3) According to embodiments, the solvent of step 3) is used at a temperature included in the range [0-80° C.], in particular between 30 and 70° C.

(4) According to embodiments, a partial concentration of the complexation solution is performed (for example by evaporation), before carrying out step 3) of precipitating from the solvent.

(5) According to embodiments, the pH of the complexation solution used in step 3) is between 1 and 9.

(6) Advantageously, the following conditions will be used during step 3):

(7) pH: [2-8]

(8) [ethanol solvent]: 10 to 20 volumes per volume of complexation solution Temperature: [0; 50]° C.

(9) Advantageously, the powder obtained in step 3) or in step 4) is returned to solution so as to form a pharmaceutical composition in liquid form.

(10) Step 1 preferably uses an excess chelate, advantageously of DOTA, relative to the stoichiometric proportions, so as to obtain an amount X1 of free chelate, advantageously of free DOTA.

(11) Step 1 can be carried out in a single step or optionally in several successive steps by measuring and adjusting so as to have an amount X1 of free chelate, advantageously of free DOTA (preferably between 0.002 and 0.4% mol/mol). For example, step 1) comprises the following successive substeps: 1.1. complexation in solution 1.2. measuring the chelate, advantageously the DOTA, and/or the lanthanide that is free (advantageously Gd) 1.3. adding chelate, advantageously DOTA, so as to complex the possible free lanthanide (if there is any at the end of step 1) and to obtain an amount X1 of free chelate, advantageously of free DOTA (preferably between 0.002 and 0.4% mol/mol).

(12) For the purpose of the present invention, the term “free lanthanide” is intended to mean any lanthanide that is not complexed and in particular not complexed by the chelate.

(13) This variant with step 1.1 to 1.3 is advantageous since the isolation of a powder makes it possible to be able to purify the product.

(14) Advantageously, the lanthanide complex is the DOTA-Gd complex.

(15) Thus, the controlling of the precipitation step coupled with the prior measuring of the amount X1 of free chelate, advantageously free DOTA, provides an adjustment of the level of chelate, advantageously of DOTA, making it possible to solve the problems addressed by the invention.

(16) Typically, the detailed measurements will be carried out for each industrial production batch. It will also be possible, provided that the characterization of the products used is completely controlled, to construct a calibration reference matrix obtained by virtue of the measuring and adjusting step(s) described in the application.

(17) It is clear for those skilled in the art that optimization substeps can be inserted between these main steps.

(18) The precipitation in step 3) can be carried out by adding the solvent to the complexation solution, or conversely by adding the complexation solution to the solvent.

(19) Advantageously, the powder obtained after precipitation (step 3) is subsequently returned to solution, firstly, with or without optional further adjustment by adding free chelate (DOTA, for example) to this solution, and secondly, with an optional addition of formulation excipient, this excipient being advantageously meglumine for DOTA-Gd. A final liquid solution ready to be administered to the patient is obtained. If meglumine has been introduced into the complexation solution at the start, the powder will comprise DOTA-Gd, excess free DOTA, and meglumine.

(20) According to one embodiment, the solution of step 1 does not comprise the positive counterion (typically meglumine or the Na.sup.+ ion). Step 3 will thus consist in precipitating not DOTA-Gd in salt, typically sodium salt, or meglumine form (more specifically, [DOTA]Gd].sup.−,Na.sup.+ or [DOTA-Gd].sup.−, CH.sub.2OH—(CHOH).sub.4—CH.sub.2—N.sup.+—CH.sub.3), but its protonated form [DOTA-Gd].sup.−,H.sup.+, this step being carried out in an acidic medium.

(21) According to another embodiment, which is moreover advantageous and not described in the prior art, the solution of step 1 comprises the positive counterion (meglumine in particular); step 3 thus consists in precipitating, according to suitable conditions (in particular of pH and of amount of solvent), the DOTA-Gd meglumine salt [[DOTA-Gd].sup.−, CH.sub.2OH—(CHOH).sub.4—CH.sub.2—N.sup.+—CH.sub.3]. For this, 10 to 20 volumes, for example 10 to 15 volumes, of ethanol or methanol solvent, per complexation volume, are for example used, advantageously at a pH between 5 and 8 and a temperature of 25-60° C. This makes it possible to use a DOTA-Gd complex in salt form, which is more stable than the protonated form (owing to the complexation constants).

(22) To this effect, the invention also relates to a method as described above in the application, the complexation solution of step 1 being a solution of DOTA-Gd meglumine salt or sodium salt, the [DOTA-Gd] complex not being in its protonated form in this solution. Very preferably, the complexation solution of step 1 is a solution of [DOTA-Gd] meglumine salt, which has the advantage, compared with a solution of DOTA-Gd sodium salt, when a meglumine formulation that is advantageous for the patient from the tolerance point of view is prepared, of not having to subsequently replace the sodium with meglumine, this being an operation that is industrially complex.

(23) The invention also relates to the use of a powder obtained by means of the method of the applicant, for preparing a liquid pharmaceutical formulation comprising a mol/mol excess of free chelate of between 0.002 and 0.4%.

(24) The invention also relates to a method for preparing a liquid pharmaceutical formulation comprising a mol/mol excess of free chelate of between 0.002 and 0.4%, said method comprising the following successive steps: a) obtaining a powder according to the precipitation method of the present invention, b) putting the powder obtained in step a) into solution, with, where appropriate, the addition of at least one formulation excipient and, where appropriate, the addition of additional free chelate.

(25) Moreover, it is specified that the method by precipitation of the present application includes the method described, and optional variants (particular variants of crystallization methods, for example) which are reflected by a modification of the proportions of the complexed-chelate and free-chelate entities between, on the one hand, the pharmaceutical composition in liquid solution form and, on the other hand, the pharmaceutical composition in powder form.

(26) Detailed examples are now described, illustrating the method for preparing lanthanide chelate formulations with a precipitation step, and more particularly the preparation by precipitation of formulations comprising an excess chelate for DOTA.

(27) The following table indicates an example of the amounts used for producing a solution of 100 liters of DOTA (industrial amount).

(28) TABLE-US-00001 Component Amount DOTA (1) 20.100 kg (i.e. 0.497M) Gadolinium oxide (expressed as 9.135 kg (i.e. 0.252M) anhydrous product) Gd.sub.2O.sub.3 Meglumine (expressed as anhydrous 9.215 kg product) Solution for adjustment of DOTA at 15% 15-35 mg per 100 ml (w/v) qs level of free DOTA Solution of meglumine at 2N qs pH = 6.8-7.4 at 20° C. Injectable water . . . qs 100 liters (1) 1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetraacetic acid
Step 1.1: Complexation in Solution

(29) The DOTA and the gadolinium oxide are dispersed in injectable water at approximately 80° C. The gadolinium oxide in the presence of DOTA forms a complex-acid that is soluble in water.

(30) 40 liters of injectable water at 80° C. are placed in a 100 liter production tank, the injection of nitrogen is started, and then the 20.100 kg of DOTA and the 9.135 kg of gadolinium oxide are incorporated with stirring. The complexation is carried out at a pH below 6.

(31) Steps 1.2. and 1.3.: Adjustment of the Free Entities

(32) The adjustment of the solution is advantageously carried out with gadolinium oxide or DOTA.

(33) At the end of step 1.1, the following steps are carried out: 1.2. taking a sample and assaying the free gadolinium, 1.3. adding a solution for adjustment of DOTA, quantity sufficient for an amount of 15-35 mg per 100 ml.

(34) A complexation solution S with a level X1 of free chelate that can be measured (step 2) is obtained. It is also possible to remove any residual gadolinium by virtue of a chelex resin for example prerinsed with water (a quantification of the free gadolinium can be carried out by means of a colorimetric assay with Arsenazo (III) before this removal, and optionally also afterwards). For this, the reaction mixture can be brought back to pH 5 (the resin is more effective). The whole mixture is left to stir at ambient temperature for 2 hours. The pH rises again to between 6.5 and 7. The resin is removed by filtration.

(35) The value X1 (as a percentage mol/mol) is, according to batches, for example between 0.005 and 0.1%, in particular 0.01 and 0.05% mol/mol of free DOTA (DOTA not complexed by Gd, nor by cations such as Ca.sup.2+).

(36) Step 3: Precipitation of the Complexation Solution

(37) The solution obtained in step 2 can be directly added to the solvent, but, in order to reduce the amounts of solution to be treated, a prior concentration under vacuum is typically carried out without significant modification of the level of free DOTA.

(38) The aqueous solution of DOTA-Gd is concentrated under vacuum at a temperature below 80° C. (for example between 20 and 60° C., for example 50 to 70° C.) to a concentration of 0.5 kg (+/−0.2 kg) per kg of solution. The solution is cooled to ambient temperature. For an amount of 1 kg of concentrated solution, a solution of 5 to 20 liters (preferably 10 to 20 liters, and typically 20 liters) of ethanol is added to 1 kg of concentrated solution. The precipitated DOTA-Gd obtained is filtered off, and then taken up with 3-4 liters of ethanol.

(39) Related back to an industrial amount of 100 kg of DOTA-Gd solution, an amount of about 2000 liters of ethanol will thus, for example, be used to carry out the precipitation. The product obtained is dried under vacuum at a temperature below 80° C.

(40) The following denatured ethanol is, for example, used: 95% ethanol, 5% mixture of ethyl acetate and isopropanol.

(41) The compound obtained by precipitation (powder) contains an amount X2 of free chelate. According to the solvents used, an amount X2 (as a percentage mol/mol) which varies according to the tests, for example, between 0.02% and 0.15% mol/mol, is obtained.

(42) Moreover, the results are not always identical depending on whether the precipitation is carried out from a solution of DOTA-Gd (with excess X1 of free DOTA) with meglumine, or from a solution of DOTA-Gd (with excess X1 of free DOTA) without meglumine, wherein the meglumine is to be taken into account from the point of view of the solubilization.

(43) Step 2a Optional after Step 2 and Before Step 3: Cooling

(44) The final solution of step 2 is cooled to 30° C., for example by circulation of cold water in the jacket of the tank.

(45) Step 2b Optional after Step 2a and Before Step 3: Adjustment of the pH and of the Density

(46) 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 injectable water.

(47) The following are placed in the production tank:

(48) 9.125 kg of meglumine

(49) and a solution of meglumine at pH=7.3-7.4 at 2 N and qs injectable water.

(50) Step 5 after Step 3 or 4:

(51) The precipitated product in powder form obtained is returned to a pharmaceutical aqueous solution (typically comprising meglumine), subsequently filtered, and then placed in vials that are typically sterilized by autoclaving.