HK1089105B - Pharmaceutical composition of vinflunine for parenteral administration, preparation method thereof and use of same - Google Patents

Description

The present invention relates to a pharmaceutical composition for parenteral administration of vinflunine.

The study of the anti-neoplastic properties of Vinca Roséa alkaloids (family Apocynaceae) has already shown the interesting activities of indolic compounds such as vincristine, vinblastine or their derivatives such as vinflunine: 20',20'-difluoro-3',4'-dihydrovinorelbine of formula (a): - What? described in patent EP 0 710 240.

However, the development of injectable formulations of these active substances has always been subject to problems with their stability in aqueous solution.

For many years only the freeze-dried form was marketed, and the freeze-dried form had major drawbacks due to the dangers of handling, as it required extemporaneous reconstitution with the contents of a solvent ampoule before administration: Risk of clumsy reconstitution, whereby fine droplets of product are generated and may contaminate healthcare personnel or the premises;Use of an incorrect amount of solvent or inappropriate amount of active substance if the medicinal product is presented in different vials with different unit dosages.

This last point is particularly important, as it illustrates the potential for a non-therapeutic dose to be administered to the patient or for accidental overdose to be caused.

US Patent 4,619,935 suggested the possibility of formulating ready-to-use injectable solutions for Vinca alkaloids.

However, the formulas used are complex and include, in addition to the active principle: a sugar or a polyol derived from a sugar, such as mannitol,an acetate buffer, to maintain the pH of the solution in the range 3.0 to 5.0, and more particularly in the range 4.4 to 4.8.

It should be noted that despite the stabilizing effect attributed to the acetate buffer, which prevents any degradation due to a change in pH caused by the decomposition of alkaloids, the invention's formulation has only a stability of 1 year at 5°C.

The complexity of the patented formulae has increased: patent FR 2 653 998 describes a parenteral pharmaceutical composition containing a bis-indole alkaloid such as vincristine, vinblastine or 5'-nor-anhydrovinblastine.

The stability indicated for these compositions is at least 24 months when stored in the refrigerator.

European patent EP 0 298 192 highlights the favourable effect of ethylene diaminetetracetic acid salts, in particular sodium salt, on the stability of aqueous solutions of Vinca dimeric alkaloids.

Under these conditions, in accordance with the specifications (alkaloid content between 90% and 110% of the theoretical content), the solution remains stable for 30 months at a temperature of 2 to 8°C.

Canadian patent 2,001,643 for a solution for injection of vincristine also emphasizes the need to implement an acetic acid/sodium acetate buffer to maintain the pH of the solution between 3.5 and 5.5, more particularly between 4.0 and 4.5.

Vinflunine ditartrate or 20',20'-difluoro-3',4'-dihydrovinorelbine L- (+) tartrate is a white powder which must be stored at a negative temperature below - 15°C in an inert gas atmosphere such as nitrogen or argon.

Quite unexpectedly, vinflunine ditartrate was found to be much more stable when dissolved in water than when in powder form.

The aqueous solution for injection is stored at a positive temperature between + 2°C and + 8°C. This is quite surprising because it is well known that chemical degradation reactions occur more easily in liquid than in solid form.

The present invention therefore concerns a pharmaceutical composition of vinflunine, characterised by the presence of a stable and sterile aqueous solution of a water-soluble salt of vinflunine at a pH between 3 and 4.

The purpose of the invention is based on the extraordinary simplicity of the formulation which contrasts with the compositions described in the patents originally recalled.

The advantage is that the vinflunine salt is the vinflunine ditartrate.

The pharmaceutical composition according to the present invention is advantageously presented as a stable, sterile, apyrogenic, ready-to-use, injectable aqueous solution.

The advantage is that the composition according to the present invention contains no preservatives.

In a first embodiment of the present invention, the pharmaceutical composition according to the present invention is a simple aqueous solution of vinflunine ditartrate, without the addition of buffer solution. The composition is thus composed of vinflunine ditartrate and water for injection.

In a second embodiment of the present invention, the pharmaceutical composition according to the present invention includes a pH buffer system to maintain the pH between 3 and 4.

The buffer system is preferably an acetic acid/sodium acetate buffer or a citric acid/sodium citrate buffer.

The pH is obtained advantageously with buffer solutions of acetic acid/sodium acetate or citric acid/sodium citrate of molarities between 0.05 M and 0.2 M.

Even more advantageously, the pH buffer is acetic acid/sodium acetate buffer and the pH of the composition is then 3.5 or the pH buffer is citric acid/sodium citrate buffer and the pH of the composition is then 4.

The composition according to the present invention contains vinflunine ditartrate in a concentration of 1 to 50 mg/ml of basic vinflunine, preferably 25 to 30 mg/ml, especially 25 mg/ml or 30 mg/ml. This concentration is therefore expressed in base vinflunine.

In an advantageous embodiment, the composition according to the present invention is one of the following formulae: 68,35 mg vinflunine ditartrate qsp 2ml water or 136,70 mg vinflunine ditartrate qsp 4 ml water or 341,75 mg vinflunine ditartrate qsp 10 ml water, the corresponding amount of vinflunine ditartrate in each of the formulae at 50 mg base vinflunine, 100 mg base vinflunine and 250 mg base vinflunine respectively. These data are summarised in Table 1 below. - What?

Vinflunine ditartrate	68,35 mg	136,70 mg	341,75 mg
correspondant à Vinflunine base	50,00 mg	100,00 mg	250,00 mg
Eau pour préparations injectables	qsp 2 ml	qsp 4 ml	qsp 10 ml

Table 1 above shows the possibility of preparing 3 unit doses of vinflunine in vials resulting from the distribution of the same aqueous solution of vinflunine ditartrate at a concentration of 25 mg/ml expressed as basic vinflunine into different volumes.

In another embodiment of the invention, the composition according to the present invention remains stable for at least 36 months at 5 °C ± 3 °C.

In one particular embodiment of the invention, the pharmaceutical composition according to the present invention is administered by infusion, intravenously, after dissolving in solutions for infusion such as 0.9% sodium chloride or 5% glucose solutions.

The present invention therefore also concerns the pharmaceutical composition according to the present invention for use as a drug, in particular to treat cancer, advantageously for parenteral administration, advantageously by intravenous infusion, even more advantageously, during chemotherapy as an antineoplastic and antitumor.

The present invention also concerns the use of a composition according to the present invention for the manufacture of a drug for parenteral administration, preferably intravenously by infusion, preferably for the treatment of cancer.

Parenteral administration, including intravenous administration, of a pharmaceutical composition of vinflunine according to the present invention is useful in treating cancers susceptible to vinflunine.

The present invention also relates to a process for preparing a composition according to the present invention comprising the following successive steps: (a) Dissolution of the vinflunine salt in water for injections (b) possible addition of a pH buffer (c) sterilization by filtration of the bulk solution.

In a particular embodiment of the invention, the process according to the present invention includes the additional step (d) of aseptic distribution, under nitrogen atmosphere, of the sterile composition obtained in step (c) in a packaging; preferably, this packaging is chosen from glass ampoules, preferably amber or colourless type I, glass vials preferably amber or colourless type I with an elastomer cap and a closed aluminium cap or any compatible ready-to-use system such as a pre-filled syringe.

The present invention therefore also concerns a packaging container containing the composition according to the present invention.

This container may be chosen from ampoules of glass preferably amber or colourless type I, vials of glass preferably amber or colourless type I with an elastomer stopper and a sealed aluminium cap or any compatible ready-to-use system such as a pre-filled syringe.

The following examples are given for guidance purposes only.

Example 1: Comparison of stability between vinflunine ditartrate in powder form and vinflunine ditartrate in aqueous solution (composition according to the present invention).

Table 2 below shows the stability results obtained for a batch of lyophilised powdered vinflunine ditartrate (lot 503) and a batch of 25 mg/ ml aqueous solution of base vinflunine (lot SB0222) manufactured with the same batch of vinflunine ditartrate after 3 months and 6 months storage at 25°C. Stability is monitored through the evolution of total impurities present, related to vinflunine.

1,17	1,23
2,75	1,45
3,48	2,00

After 6 months of storage at 25°C, the total impurities related to vinflunine are increased by: 62% in the aqueous solution of vinflunine ditartrate, 197% for the powdered vinflunine ditartrate

Example 2: pH stability study of compositions according to the present invention

Stability studies were conducted on aqueous solutions of vinflunine ditartrate in a pH range of 2.5 to 5.0, and more particularly 3.0 to 4.0, pH was obtained with acetic acid/sodium acetate or citric acid/sodium citrate buffer solutions of 0.2 molar.

The percentages used are given in Table 3 below and correspond to a baseline vinflunine concentration of 30 mg/ ml.

4,101 g	4,101 g	4,101 g
3 g	3 g	3 g
1,185 g
0,100 g
	2,885 g	2,460 g
	1,903 g	2,497 g
qsp 100 ml	qsp 100 ml	qsp 100 ml

The results were compared with those obtained with a simple aqueous solution of vinflunine ditartrate, without the addition of buffer solution, kept under the same conditions, with a pH of 3.5.

The composition and references of the tested solutions are summarised in Table 4 below. - What?

Solution à pH = 2,5 (tampon citrate)	BS 1325
Solution à pH = 3 (tampon citrate)	BS 1326
Solution à pH = 3,5 (tampon citrate)	BS 1330
Solution à pH = 4 (tampon citrate)	BS 1327
Solution à pH = 5 (tampon citrate)	BS 1328
Solution à pH = 3,5 (tampon acétate)	BS 1332
Solution aqueuse non tamponnée	BS 1331

Figure 1 shows the HPLC evolution of the total vinflunine-related impurity content over time under stressful conditions (45 days at 60°C) for each formula given in Table 4.

They are supplemented by the results shown in Table 5 below of the colour change of the solutions for 7 days at 60°C.

Monitoring of the absorbance of these solutions in the ultraviolet at 410 nm reveals the occurrence of non-chromatographed vinflunine oxidation derivatives in HPLC.

BS 1325
pH = 2,5	0,021	0,645
Tampon citrate : 0,2 M
BS 1326
pH = 3,0	0,020	0,520
Tampon citrate : 0,2 M
BS1330
pH = 3,5	0,020	0,354
Tampon citrate : 0,2 M
BS1327
pH = 4,0	0,023	0,346
Tampon citrate : 0,2 M
BS1328
pH = 5,0	0,020	0,896
Tampon citrate : 0,2 M
BS1332
pH = 3,5	0,021	0,226
Tampon acétate : 0,2 M
BS1331
pH = 3,5	0,019	0,171
Sans tampon

Only the unbuffered solution, pH = 3.5, has an absorbance of less than 0.200 after 7 days at 60°C.

The results indicate that vinflunine stability is better at a pH value between 3.0 and 4.0 but is dependent on the nature of the ions making up the buffer. At pH = 3.5, the acetic acid/sodium acetate buffer provides better stability than the citric acid/sodium citrate buffer. For the latter buffer the results are better at pH = 4.

Surprisingly, it turns out that the stability of the vinflunine ditartrate aqueous solution at its instantaneous pH of 3.5 is better than the stability of vinflunine ditartrate aqueous solutions buffered at pH = 3.5.

These good results are confirmed by the long-term results summarised in Table 6 below which indicate that the aqueous pharmaceutical composition of vinflunine injectable according to the present invention can be stored for at least 36 months at 5°C ± 3°C without significant degradation. - What?

30,8	30,4	30,4	30,4	30,3	30,2

Claims (13)

1. Vinflunine pharmaceutical composition, characterized in that it is in the form of a stable and sterile aqueous solution of a watersoluble vinflunine salt at a pH of between 3 and 4 and in that it does not contain any preservatives agent.
2. Composition according to Claim 1, characterized in that the vinflunine salt is vinflunine ditartrate.
3. Composition according to Claim 2, characterized in that the composition consists of vinflunine ditartrate and water for an injectable preparation.
4. Composition according to Claim 1 or 2, characterized in that it comprises a pH buffer system in order to maintain the pH between 3 and 4.
5. Composition according to Claim 4, characterized in that the molarity of the pH buffer system is between 0.002 M and 0.2 M.
6. Composition according to either of Claims 4 and 5, characterized in that the pH buffer system consists of an acetic acid/sodium acetate buffer or a citric acid/sodium citrate buffer.
7. Composition according to any one of Claims 2 to 6, characterized in that the composition contains vinflunine ditartrate with a base vinflunine concentration of between 1 and 50 mg/ml, advantageously between 25 and 30 mg/ml and in particular 25 mg/ml.
8. Composition according to any one of Claims 2 to 7, characterized in that it corresponds to one of the following formulations: 68.35 mg of vinflunine ditartrate qs 2 ml in water or 136.70 mg of vinflunine ditartrate qs 4 ml of water or 341.75 mg of vinflunine ditartrate qs 10 ml of water, the vinflunine ditartrate corresponding, respectively, to 50 mg of base vinflunine, 100 mg of base vinflunine and 250 mg of base vinflunine.
9. Composition according to any one of the preceding claims, characterized in that it remains stable for at least 36 months at 5°C±3°C.
10. Use of a composition according to any one of Claims 1 to 9, for the manufacture of a medicinal product for parenteral administration, advantageously via intravenous perfusion.
11. Use according to Claim 10, characterized in that the medicinal product is intended for treating cancer.
12. Process for preparing a composition according to any one of Claims 1 to 9, comprising the following successive steps:

    - (a) dissolution of the vinflunine salt in water for injectable preparations,

    - (b) optional addition of a pH buffer,

    - (c) sterilization by filtration of the bulk solution,

    - (d) aseptic distribution, under a nitrogen atmosphere, of the sterile composition obtained in step (c) in the container, advantageously chosen from glass phials, glass bottles and prefilled syringes.
13. Packaging container containing the composition according to any one of Claims 1 to 9.