EP1341555A2

EP1341555A2 - Pharmaceutical oxaliplatinum preparation for parenteral administration and method for obtaining same

Info

Publication number: EP1341555A2
Application number: EP01270345A
Authority: EP
Inventors: Houssam Ibrahim; Henri Pourrat; Christine Deuschel
Original assignee: Debiopharm SA
Current assignee: Debiopharm SA
Priority date: 2000-12-12
Filing date: 2001-12-12
Publication date: 2003-09-10
Also published as: US20040127557A1; US7012072B2; WO2002047725A3; AU2002223013A1; WO2002047725A2

Abstract

The invention concerns a stable pharmaceutical oxaliplatinum preparation for parenteral administration wherein the oxaliplatinum is in solution in a solvent with a concentration of at least 7 mg/ml having been subjected to a moist heat treatment with saturated and pressurised water vapour at a high temperature not exceeding 110 °C. The invention also concerns a method for obtaining same.

Description

Pharmaceutical preparation of oxaliplatin for parenteral administration and process for obtaining said preparation

The present invention relates to a pharmaceutical preparation of oxaliplatin, for parenteral administration, intended to be infused or injected. It also relates to a process for obtaining said preparation.

Oxaliplatin (DCI, also called / -OHP), a complex platinum derivative

(CAS RN: 61825-94-3) described by Kidani et al. in J. Med. Chem., 1978, 21, 1315, is an antineoplastic agent used intravenously especially in the treatment of metastatic colorectal cancers.

Oxaliplatin, in its form of pure active substance, is known to be slightly soluble in water, very slightly soluble in methanol and practically insoluble in ethanol and acetone. More specifically, the maximum solubility of oxaliplatin at saturation in water at 37 ° C is 7.9 mg / ml and it is 6 mg / ml at 20 ° C.

Currently, it is used in hospitals in a lyophilized form and its liquid preparation is reconstituted using a glucose solution just before its administration generally in short-term infusion.

In order to offer hospital staff the great advantage, on the one hand, of no longer having to handle a cytotoxic powder or cake during the reconstitution of the pharmaceutical preparation and, on the other hand, of avoiding any risk of '' mistakenly use a reconstitution solution containing chloride ions, such as a sodium chloride solution usually used in this kind of operation and which has the serious consequence of breaking down the metal complex, several liquid preparations of oxaliplatin, ready to be administered parenterally as an infusion have already been proposed. Thus, Ibrahim et al. described in WO 96/04904 a pharmaceutically stable oxaliplatin preparation, ready to be administered parenterally by infusion. This preparation, which has undergone successive operations of clarification filtration then aseptic filtration, consists of an aqueous solution of oxaliplatin at a concentration of approximately 2 mg / ml and not containing other adjuvants.

Mauvernay described in WO 00/21527 that this type of pharmaceutical preparation in which the oxaliplatin is at a concentration of approximately 2 mg / ml can advantageously be stored and transported in a flexible infusion bag in order to simplify even more. handling when administered to a patient. It is indicated in this document that the material chosen constituting this flexible pouch is capable of withstanding the high temperatures applied during sterilization operations in an autoclave.

Anderson et al. described in WO 99/43355 two types of liquid formulation containing oxaliplatin. In the first, oxaliplatin is found in solution at a concentration of 2 mg / ml in pure water as recommended in WO 96/04904. In the second, oxaliplatin is in solution at a concentration of 5 mg / ml in water buffered with oxalic acid. The two types of preparations, contained in sealed ampoules, were placed in an autoclave in order to undergo a termination treatment with moist heat, this by subjecting them to several heating cycles at a temperature of 121 ° C.

These known pharmaceutical preparations meet most of the quality criteria set by the health authorities, in particular that of sterility.

On the other hand, their uses are greatly limited due to their very low concentrations of oxaliplatin, requiring the conservation and handling of a large number of vials or flexible bags and prohibiting the use of particularly suitable containers such as so-called syringes pre-filled or so-called multi-dose vials. The present inventors have successfully resolved this problem caused by the low concentrations of oxaliplatin, this by providing a stable pharmaceutical preparation of oxaliplatin for parenteral administration in which the oxaliplatin is in solution in a solvent at a concentration of at least 7 mg / ml. To do this, they have found that the use of the solvent comprising a sufficient amount of at least one hydroxylated derivative chosen from 1, 2-propane-diol, glycerol, maltitol, sucrose and inositol makes it possible to obtain preparations in which the oxaliplatin concentration went well beyond 7 mg / ml.

However, they encountered some problems when it came to ensuring for these preparations a high degree of sterility as required by the health authorities.

In fact, in order to guarantee better safety of pharmaceutical sterilization on an industrial scale, they preferred to implement a method of terminal heat sterilization such as, for example, that described in WO 99/43355, rather than a aseptic filtration method such as, for example, that mentioned in WO 96/04904.

In doing so, they found that the implementation of this method, necessitating bringing the preparations to be sterilized to a temperature of 121 ° C. in an autoclave, was not satisfactory.

Indeed, if the degree of sterilization was well acceptable, the appearance of disorders, or even blackish particles, was observed during the final opening of the autoclave and the release of the bottles containing the preparations. It was then clear that preparations of oxaliplatin presenting such a physical aspect would have been discarded for a provision of the patients.

The aim of the present invention is thus to provide a stable pharmaceutical preparation of oxaliplatin for administration by the parenteral in which the oxaliplatin is in solution in a solvent at a concentration such that it allows, on the one hand, a net reduction in the number of flasks or flexible bags to be stored or handled and, on the other hand, a use of appropriate containers such as so-called pre-filled syringes or so-called multi-dose vials, while meeting the criteria required by health authorities for the approval of pharmaceutical liquid preparation as a high degree of sterility and a clear appearance and free of solid particles.

To this end, the present invention relates to a stable pharmaceutical preparation of oxaliplatin for parenteral administration, intended for infusion or injection, in which the oxaliplatin is in solution in a solvent at a concentration of at least 7 mg / ml and having been subjected to a moist heat treatment operation with a saturated water vapor and under pressure at an elevated temperature not exceeding 110 ° C.

Preferably, said solution has been subjected to a moist heat treatment operation at an elevated temperature between 110 ° C and about 70 ° C. More preferably, this elevated temperature is about 80 ° C.

Preferably, said wet heat treatment operation is carried out during at least two cycles consisting of a heating phase at said high temperature and then a return and rest phase at room temperature. More preferably, the heating phase at the elevated temperature has a duration of approximately 30 minutes and the return and rest phase at ambient temperature has a duration of approximately 24 hours.

Preferably, the solvent of said solution in which the oxaliplatin is found comprises a sufficient amount of at least one hydroxylated derivative chosen from 1, 2-propanediol, glycerol, maltitol, sucrose and inositol. More preferably, said solvent further comprises water. The present invention also relates to a process for obtaining said preparation implementing a wet heat treatment operation with water vapor in a saturated state and under pressure in an autoclave at a high temperature n '' not exceeding 110 ° C.

More specifically, this process comprises, prior to said wet heat treatment operation, the implementation of the following steps: a) bringing an amount of oxaliplatin to a quantity below a temperature below 80 ° C. sufficient of said solvent to obtain an oxaliplatin concentration of at least 7 mg / ml; and b) establishing the mixture obtained in step a) at a temperature between 15 ° C and 30 ° C.

Preferably, said wet heat treatment operation comprises at least two cycles consisting of a heating phase at said high temperature, then a return and rest phase at room temperature. More preferably, the heating phase at the elevated temperature has a duration of approximately 30 minutes, and the return and rest phase at ambient temperature has a duration of approximately 24 hours.

The specialist, realizing all the advantages of this obtaining process, will be able to apply each of its operations to any aseptic filling chain of liquid pharmaceutical preparations that are usually found in the pharmaceutical industry, and this by adapting each of the parameters mentioned in their indicated value ranges.

Thus, he will prepare a filling solution in which the oxaliplatin is at a concentration of at least 7 mg / ml in the appropriate solvent. He will then fill, on a continuous or batch filling line, the appropriate sterilized containers, preferably under an atmosphere of an inert gas. These containers will, as the case may be, be closed by a stopper or sealed, then placed in an autoclave in order to undergo the processing operations at the humid heat by saturated steam under pressure in an autoclave at an elevated temperature not exceeding 110 ° C.

The invention, and its advantages, will be described below with the aid of the following examples:

Example 1: Preparation of solutions containing oxaliplatin at a concentration of 10 mg / ml

In the laboratory, an oxaliplatin powder (250 mg) is placed in a 50 ml container calibrated to 25 ml. Respectively one of the co-solvents chosen from 1, 2-propanediol, glycerol, maltitol is introduced into the container jointly or before addition of water in addition to 25 ml, according to the corresponding volume / volume or weight / volume as indicated in the various tables.

Two other co-solvents, namely sucrose and inositol, were also used and results identical to those described in the examples were obtained.

The mixtures obtained are, if necessary, brought to a temperature not exceeding 80 ° C. and to atmospheric pressure in order to perfect the complete dissolution of the oxaliplatin.

After returning to ambient temperature, namely around 20 ° C., a clarification filtration operation is possibly implemented in order to ensure clarity.

Example 2: Comparative treatment test at a temperature of approximately 121 ° C.

The mixtures as obtained by applying the method described in Example 1 and in the relative amounts indicated in Table 1 were subjected to a wet heat treatment operation at a temperature of 121 ° C. in an autoclave according to methods well known to the specialist.

The results observed at the end of the treatment after returning to room temperature are described in Table 1.

Table 1

At a temperature of 121 ° C., the appearance of a black precipitate insoluble in water is observed.

Example 3 Comparative treatment test at temperatures of approximately 120 ° C. and approximately 110 ° C.

Different solutions of oxaliplatin at a concentration of 10 mg / ml obtained as above, and previously degassed with argon, were subjected to wet heat treatment operations at temperatures of 120 ° C and 110 ° C respectively.

The results observed at the end of the treatment after returning to ambient temperature are described in Tables 2 and 3. Table 2

Table 3

At the respective temperatures of 120 ° C and 110 ° C, the appearance of a black precipitate insoluble in water is observed.

Example 4 Comparative Test for the Treatment of a Supersaturation Solution at a Temperature of 120 ° C A supersaturated aqueous solution of oxaliplatin, containing 10 mg of oxaliplatin per 10 mg of water was prepared without the addition of a co-solvent by subjecting it to a temperature of approximately 80 ° C. at atmospheric pressure for a few minutes.

After returning to room temperature, this preparation was subjected to a moist heat heating operation at a temperature of 120 ° C.

The results are described in Table 4.

Table 4

At the temperature of 120 ° C., the appearance of a black precipitate insoluble in water is observed.

Example 5: Treatment test at temperatures of approximately 80 ° C and 70 ° C

Solutions of oxaliplatin at concentrations of 10 mg / ml and 12 mg / ml respectively and containing one of the following hydroxylated derivatives: 1, 2-propane-diol, glycerol and maltitol were subjected to a treatment operation with the humid heat at respective temperatures of 70 ° C and 80 ° C.

The results observed 24 hours after the end of the treatment and return to ambient temperature are described in Table 5. Table 5

At respective temperatures of 70 ° C and 80 ° C, the appearance of a black precipitate insoluble in water is not observed.

Example 6: Test for the treatment of a supersaturation solution at temperatures of about 80 ° C.

An aqueous solution of oxaliplatin as prepared in Example 4 was subjected to a humid heat heating operation at a temperature of 80 ° C. The results are described in Table 6. Table 6

At the temperature of 80 ° C., no precipitate was observed.

EXAMPLE 7 Operation of Sterilizing Oxaliplatin Solutions at a Concentration of 10 mg / ml by Treatment with Moist Heat at a Temperature of 80 ° C

Different solutions of oxaliplatin at a concentration of 10 mg / ml, obtained by implementing the method described in Example 1 and by applying the relative amounts of the various constituents as indicated in Table 7, were prepared.

They were then subjected to humid heat sterilization operations by proceeding with three successive heating cycles at a temperature of

80 ° C followed by a return to ambient temperature of approximately 20 ° C. The respective durations of the different phases of these cycles are indicated in the Table

7.

The solutions thus treated were maintained, before observation, for

72 hours at refrigerator temperature. The results are described in Table 7. Table 7

water for injections At the end of each sterilization treatment, a sterilization test was carried out on each of the preparations according to the protocol recommended in Chapter 2.6.1. STERILITY from the European Pharmacopoeia, 3 ^rd edition, this by applying the membrane filtration method.

It turned out that all the results were satisfactory. No contaminating trace of microorganism was found.

From the foregoing results, it follows that pharmaceutical preparations of oxaliplatin for parenteral administration, at a concentration greater than or equal to 7 mg / ml, can be obtained, by being sterile and free from black insoluble precipitate, by sterilization by carrying out successive heatings at temperatures of 80 ° C.

Claims

claims

1. Stable pharmaceutical preparation of oxaliplatin for parenteral administration in which the oxaliplatin is in solution in a solvent at a concentration of at least 7 mg / ml and which has been subjected to a moist heat treatment operation with water vapor in a saturated state and under pressure at a high temperature not exceeding 110 ° C.

2. Stable pharmaceutical preparation of oxaliplatinum according to claim

1, characterized in that said solution has been subjected to a wet heat treatment operation at an elevated temperature between 110 ° C and about 70 ° C.

3. Stable pharmaceutical preparation of oxaliplatin according to claim

1, characterized in that said solution has been subjected to a humid heat treatment operation at an elevated temperature of approximately 80 ° C.

4. Stable pharmaceutical preparation of oxaliplatinum according to claim 1, characterized in that said wet heat treatment operation is carried out during at least two cycles consisting of a heating phase at said high temperature and then a return and rest phase at room temperature.

5. Stable pharmaceutical preparation of oxaliplatin according to claim

4, characterized in that said heating phase at high temperature has a duration of approximately 30 minutes and the return and rest phase at ambient temperature has a duration of approximately 24 hours.

6. Stable pharmaceutical preparation of oxaliplatin according to claim

1, characterized in that the solvent of the said solution in which the oxaliplatin is found comprises a sufficient amount of at least one hydroxylated derivative chosen from 1, 2-propanediol, glycerol, maltitol, sucrose and inositol.

7. A stable pharmaceutical preparation of oxaliplatin according to claim 6, characterized in that said solvent further comprises water.

8. A method for obtaining the pharmaceutical preparation of oxaliplatin of claim 1, implementing a wet heat treatment operation with a saturated water vapor and under pressure in an autoclave at an elevated temperature not exceeding 110 ° C.

9. Method according to claim 8, characterized in that it further comprises, prior to said wet heat treatment operation, the implementation of the following steps: a) contacting at a temperature below 80 ° C of an amount of oxaliplatin with a sufficient amount of said solvent in order to obtain an oxaliplatin concentration of at least 7 mg / ml; and b) establishing the mixture obtained in step a) at a temperature between 15 ° C and 30 ° C.