• 专利附录
  • 专利说明
  • 权利要求
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    • 专利摘要:

    公开号:DK200700153U1
    申请号:DK200700153U
    申请日:2007-05-24
    公开日:2007-06-22
    发明作者:Ibrahim Houssam；Gray Martin；Blundell Ross
    申请人:Debiopharm Sa；
    IPC主号:
    专利说明:

    DK 2007 00153 U3
    The present invention relates to a kit consisting of an aqueous oxaliplatin solution and a container containing it.
    Oxaliplatin (INN; also called / -ΌΗΡ), a complex derivative of platinum (CAS RN: 61825-94-3) described by Kidani et al. in J. Med. Chem., 1978, 21.1315, is an antineoplastic agent used intravenously, and especially in the treatment of metastatic colorectal cancer. Currently, it is used within the hospital area in lyophilized form and the preparation is restored in its liquid form just prior to administration thereof, which is commonly performed as short-term infusion.
    Oxaliplatin in lyophilized form is formulated with a large amount of lactose (by weight factor 9 relative to the oxaliplatin). It is then a whitish powder or cake. During its reconstitution, it is recommended to use such an amount of either glucose-containing solution or water of so-called injection solution quality (PI) that the oxaliplatin concentration in the preparation thus obtained is about 5.0 mg / ml.
    Recently, a pharmaceutically stable oxaliplatin preparation was described by Ibrahim et al. in WO 96/04904, which was ready for parenteral administration as an infusion, consisting of an aqueous oxaliplatin solution at a concentration of about 2 mg / ml containing no other adjuvants. It is recommended therein that such a liquid preparation be stored in a neutral glass bottle for drug use.
    This preparation gives the hospital staff the great advantage, partly that no more bottles have to be handled, containing either a powder or a cake which is cytotoxic or the necessary solvents during the reconstitution of the drug preparation, and that any risk of mistakenly avoiding use a reconstitution solution containing chloride ions, such as a sodium chloride solution normally used for this type of action, which has the serious consequence of degrading the active substance.
    Oxaliplatin liquid preparations of the types described above can also be stored in flexible infusion bags. Mauvemay stated in WO 00/21527 that no degradation was observed over a period of at least one year, provided that a polyvinyl chloride-free (PVC-free) material was used as the specific plastic material which was present in direct contact with the oxaliplatin liquid preparation,
    Anderson et al. observed for them a tendency for these same aqueous solutions to degrade over time. They suggested IWO 99/43355 that, in order to overcome this phenomenon, an amount of stabilizing agent, such as oxalic acid, could be added to these solutions and they recommended storing the compositions thus obtained in sealed containers such as ampoules, syringes or flexible infusion bags. . However, this suggestion is not entirely satisfactory, as oxalic acid is generally attributed to a toxic effect (see The Merck Index, 11th edition, 1989, page 1093).
    The health authorities attach great importance to the fact that drug preparations are administered only to patients with few side effects, which could even prove harmful to the patient.
    Consequently, in long and demanding toxicity trials, if the active ingredient (s) is present in a drug preparation in the presence of certain by-products or quality-degrading products, they require that these by-products do not have a deleterious effect.
    For a drug preparation containing an active substance and to be administered to a patient at a daily dose of between 100 mg and 2 g, they generally tolerate the presence of uncharacterized impurities only if each of these impurities does not exceed an amount of about 0 mg. , 2% by weight relative to the weight of the active substance.
    The commonly recommended dosage used as a guideline for treating a patient by administering oxaliplatin in a treatment using a short-term infusion lasting between 2 and 6 hours ranges from about 85 mg to about 130 mg oxaliplatin per day. m2 body surface area. When a mean body surface area value of 1.7 m2 is used, this is combined into a daily administration of a dose of between 145 mg and about 220 mg of oxaliplatin.
    As a starting point, the above dose to be administered is used and, given the total number and amount of quality degrading products present in an oxaliplatin-containing drug preparation, the total measured impurity level should not exceed 2.0 % by weight of oxaliplatin weight after storage for a period of at least 10 months.
    Therefore, there was a need to find new remedies for these degradations that were found over a long period of time when an oxaliplatin preparation in aqueous solution is to be stored in glass bottles, where such measures are necessary to use only bottles of materials, which are widely available on the market and partly exclude the use of chemical stabilizers which may prove to have a deleterious effect.
    On the basis of this, the object of the present invention is to provide a kit consisting partly of an oxaliplatin drug preparation in aqueous solution and partly of a glass bottle containing said preparation, where it is necessary that said preparation inter alia meets the above criteria for purity and / or stability in relation to storage life of at least 10 months.
    Said bottle consists of a glass normally used for storing liquid drug preparations for parenteral use. It can be provided by a so-called "press-and-blow" process or a "blow-and-blow" process. The glass of choice is preferably a so-called type I glass as defined by the United States Pharmacopeia (United States Pharmacopeia 25- NF 20, 2002) and the European Pharmacopoeia (Pharmacopée Européenne, 4th edition 2002), It is even more preferred that it is a so-called clear or colorless colored glass, or a Type II glass as defined by the same pharmacopoeia can be used. .
    This type of glass is especially recommended for its chemical resistance, especially its hydrolytic resistance, and its very long chemical durability. It is particularly suitable for contact with drug preparations that are acidic, neutral or basic.
    This type of glass is based on borosilicate. Specifically, and given by way of example, Table 1 (extract from Technical Methods Bulletin No. 3, Glass Containers for Small Volume Parenteral Products: Factors for Selection and Test Methods for Identification, Parenteral Drug Association, 1982) lists the chemical composition , expressed as a percentage by weight, of any commercially available Type I glass.
    4 DK 2007 00153 U3
    The loss 1
    Item designation for type I jars Chemical Kimble Kimble Kimble Wheaton Wheaton Wheaton Wheaton compound phrase KG-33 KG-35 N51A NS-33 NS-51 NSV Type I Flint Si02 80 69 71 81 73 73 70 B2O3 13 13 11 13 10 10 10 AI2O3 3 6 7 2 6 6 6 Fe2 O3 0 0 0 0 0 0 0 0 ZnO 0 0 0 0 0 0 0.5 CM OR 0 0 0 0 0 0 0 MnO 0 0 0 0 0 0 0 BaO 0 2 2 0 2 2 2 CaO 0 1 1 0 1 0.5 1 MgO 0 0 0 0 0 0 0.5 Na 2 O 4 8 6 4 6 7 9 K 2 0 1 2 0 1 1 1
    As can be seen, this loss suggests that none of the constituents to be included in the composition of the glass should chemically disrupt the organometallic platinum complex which is ten! present in the solution.
    Despite this, applicant has found, as did Anderson et al. has done in the past that sometimes significant breakdowns occurred.
    However, in the present case, the oxaliplatin preparations in aqueous solution in which this degradation occurred were stored for a few months at laboratory temperature in glass bottles, especially in Type I glass bottles.
    After several experiments with the stability of oxaliplatin preparations in aqueous solution without containing stabilizing agent, such as oxalic acid, and holding different loading conditions, the applicant was able to surprisingly find that the stability of these preparations depended on the geometry of the bottles.
    Specifically, it was able to show that using bottles of different form and for each of these forms, different volume contents, there was a mutual relationship between, on the one hand, the "contact surface area of the aqueous oxaliplatin solution". on the other hand, the degree of stability of the oxaliplatin solution, which is characterized by measuring the level of all impurities present in different drug formulations contained and stored in different bottles.
    In the remainder of the present application, the term "surface area" will mean the contact surface area of the aqueous oxaliplatin solution with a glass bottle of a certain volume content and will be expressed in mm2, and the term "volume" will mean the filling volume of the bottle with the oxaliplatin solution and will be expressed as mm3.
    The kit of the present invention consisting partly of an oxaliplatin drug composition in aqueous solution and partly a glass bottle containing said composition is peculiar in that the surface area / volume ratio is less than 0.26, preferably the surface area / volume ratio is less than 0.20.
    Furthermore, applicant has been able to establish that the surface area / volume ratio followed the following relation:
    Ro + A * c I MAX
    where
    Ro represents the theoretical maximum surface area / volume ratio for which no impurity would be quantifiable (i.e., for W = 0%) using analytical techniques normally recommended by the pharmacopoeia. A is a constant expressed in ml / (mg c) represents the oxaliplatin concentration expressed in mg / ml, and
    Imax represents the acceptable, uncharacterized maximum level of total impurities in weight.
    6 DK 2007 00153 U3
    The preparation will be described in more detail by the following examples and the drawing, in which: - Figure 1 shows the level of uncharacterized total impurities in weight in an aqueous oxaliplatin preparation, at a concentration of 5 mg / ml after 4 months storage as a surface area / volume - Figure 2 indicates the level of uncharacterized total impurities in weight in an aqueous oxaliplatin preparation, at a concentration of 7 mg / ml after 4 months of storage as a function of surface area / volume ratio, - Figure 3 shows an aggregation of the curves shown in Figures 1 and 2 - Figure 4 indicates the level of uncharacterized total weight impurities in an aqueous oxaliplatin preparation, at a concentration of 5 mg / ml after 1 month of storage as a function of surface area / volume ratio, Figure 5 indicates the level of uncharacterized total impurities by weight in an aqueous oxaliplatin preparation, at a concentration of 5 mg / ml after 5.5 months, Figure 6 indicates the level of uncharacterized total weight impurities in an aqueous oxaliplatin preparation, at a concentration of 5 mg / ml after 10 months of storage as a function of surface area / volume ratio.
    1: Preparation and storage of the samples
    To carry out this experiment, four series of bottles were used, consisting of a colorless type 1 glass, all of which had a cylindrical shape but different volumes. Table 2 collects for each series of bottles their so-called "usable" contents, their so-called "edge" contents, the inner diameter of the bottles, their neck diameter and their height.
    Table 2
    Series Applicable Room Content (ml) Edge Room Content (ml) Inner Diameter (mm) Neck Diameter (mm) Height (mm) 1 5 7 23.50 20.0 40.0 2 10 17 29.90 20.0 60.0 3 20 22 29.90 20.0 60.0 4 50 60 42.47 20.0 70.0 7 DK 2007 00153 U3. These bottles, which were used for the first time, were initially subjected to three cycles of washing and rinsing with hot water heated to about 50 ° C and so-called P1 quality water before drying.
    Three oxaliplatin storage solutions were prepared at concentrations of respectively. 2 mg / ml, 5 mg / ml and 7 mg / ml in the normal way using P1 grade water as solvent. No stabilizer was used.
    Aliquots of these preparations were pooled and then, under aseptic loading conditions, transferred to different bottles to reach each level corresponding to the heights given below. The bottles were then hermetically sealed by folding a lid.
    A first portion of these bottles were placed under stability conditions under normal conditions in a first chamber maintained at a temperature of 25 ° C and at a relative humidity of 60%. These bottles were kept upright and at rest without much stirring in the chamber. times specified below.
    Samples were collected at the indicated times and then analyzed by high performance liquid chromatography according to a conventional method to quantify the level of uncharacterized total impurities, expressed as a percentage by weight, relative to the oxaliplatin levels present in each test specimen.
    2. Results from the test of the stability of oxaliplatin preparations in aqueous solution at a concentration of 5 mg / ml.
    This experiment was carried out on groups of bottles with a usable space content of respectively. 5 ml, 15 ml and 20 ml were filled as described above with aliquots of a stock solution at a concentration of 5 mg / ml and then stored under the above conditions for a period of at least 10 months.
    Collected after periods of respectively. 1 month, and then 2.5 months, 4 months, 5.5 months, 7 months and 10 months after filling.
    8 DK 2007 00153 U3
    Table 3 below collects, for each bottle, each with its volume content, the inside diameter of the bottle, the height of the liquid preparation filling, the volume of the aqueous solution filling and the calculated surface area of the bottle walls in contact with this aqueous composition, and then the surface area / volume ratio. Table 4 collects for each of the bottles the level of total impurities measured at a given time, expressed and expressed as a weight percentage relative to the amount of oxaliplatin present.
    Table 3
    Applicable space content (ml) Inner diameter (mm) Filling height (mm) Filling volume x103 ± 4% (mm3) Contact surface area x102 (mm2) Surface area / volume ratio 5 23.50 10.58 4.59 12.15 0.26 15 29.90 15.55 10.92 21.63 0.20 20 29.90 30.51 21.42 35.67 0.17 50 42.47 35.30 50.00 61.25 0, 12
    Table 4
    Applicable room content Impurity level (weight%) 1 month Impurity level 2.5 months Impurity level 4 months Impurity level 5.5 months Impurity level 7 months Impurity level 10 months 5 ml 2.34 2.55 2.89 2.70 3.19 3.64 15 ml 1.15 1.16 1.23 1.50 1.56 1.59 20 ml 1.06 1.11 1.13 1.38 1.42 1.45
    It should be noted that the bottle of 5 ml volume is not satisfactory because the acceptable uncharacterized maximum level of total impurities, ie. 2.0%, already exceeded when the initial analysis is done 1 month after dissolution.
    Figure 1 indicates the values in the "4 months" column of Table 4 as a function of the surface area / volume ratio.
    9 DK 2007 00153 U3 3. Results of the experiment with the stability of oxaliplatin preparations in vandia solution at a concentration of 7 mA / ml.
    This experiment was carried out as above, with the difference that the bottles were filled with aliquots of a stock solution at a concentration of 7 mg / ml and samples were collected within the same time period.
    Table 5 below collects for each bottle the level of total impurities measured at a given time, expressed and expressed as a weight percentage relative to the amount of oxaliplatin present.
    Table 5
    Applicable room content Impurity level (weight%) 1 month Impurity level 2.5 months Impurity level 4 months Impurity level 5.5 months Impurity level 7 months Impurity level 10 months 5 ml 1.87 2.09 2.33 2.56 2.75 2 98 15 ml 0.96 1.03 1.12 1.19 1.23 1.30 20 ml 0.70 0.81 0.97 1.04 1.07 1.11
    As with the test performed with the aqueous oxaliplatin preparation at a concentration of 5 mg / ml, it is noted that the bottle with 5 ml volume is not satisfactory. However, the acceptable uncharacterized maximum level of total impurities is exceeded just later. The result is that the stability of the solution increases with concentration.
    Figure 2 represents the values in the "4 months" column of Table 5 as a function of the surface area / volume ratio.
    Figure 3 represents an aggregation of the curves of Figures 1 and 2, which allows a better illustration of the fact that the stability of the solution increases with concentration.
    10 DK 2007 00153 U3
    Figures 4 to 6 represent the values in Ί months "," 5.5 months ", and" 10 months "columns according to Table 5 as a function of surface area / volume ratio, 4. Results from the experiment with the lanatide stability of oxaliplatin prairates in aqueous solution at a concentration of 2 mo / ml.
    This experiment was carried out on three batches of bottles of the same usable volume of 50 ml which were filled as described above with aliquots of the same volume of a stock solution at a concentration of 2 mg / ml and then stored under the above conditions under a period of 5 years. At the end of this time, sample items were collected for analysis.
    Table 6 below collects for these bottles of the same applicable compartment content their inner diameter, the height of the liquid preparation filling, the volume of the aqueous solution filling and the calculated surface area of the bottle walls in contact with this aqueous composition, and then the surface area / v-forhoidet. Table 7 collects for each bottle the level of total impurities measured after 5 years.
    Table 6
    Applicable room content (ml) Inner diameter (mm) Filling height (mm) Filling volume x103 ± 4% (mm3) Contact surface area x 102 (mm2) Surface area / volume ratio 50 42.47 35.30 50.00 61 , 0.12
    Table 7
    Lot Impurity level (weight%) 5 years 1 1.47 2 1.56 3 1.55 11 DK 2007 00153 U3 5, Comments and conclusions
    It is noted from the teachings of Figures 1 and 2 that the level of uncharacterized total impurities decreases as the surface area / volume ratio decreases.
    Even from the beginning of storage of the oxaliplatin vials, the stability of the solution is better for a low surface area / volume ratio.
    In addition, a linear relationship between the surface area / volume ratio and the level of impurities is observed.
    Taking into account the above results, the following general equation can be deduced:
    R = Ro + A · c · I
    where you represent the level of uncharacterized total impurities present in the aqueous oxaliplatin preparation at a given concentration.
    Ro represents the theoretical maximum surface area / volume ratio for which no impurity would be quantifiable (i.e., for I max = 0%), using analytical techniques normally recommended by the pharmacopoeia, where this value is dependent on the oxaliplatin concentration in the preparation. , A is a constant expressed in ml / (mg · mm), c represents the oxaliplatin concentration expressed in mg / ml, and R represents the surface area / volume ratio specific to the bottle considered at a given filling.
    Including the results illustrated in Figure 1, the following values can be deduced from the curve: A = 0.01 ml / (mg · m) and Ro = 0.10 for c = 5 mg / ml 12 DK 2007 00153 U3
    Including the results illustrated in Figure 2, the following values can be deduced from the curve: A = 0.009 ml / (mg · m) and Ro = 0.11 for c = 5 mg / ml
    It should also be noted, as can be seen in Figures 4 to 6, that the stability of the composition decreases linearly over time.
    Thus, it becomes possible to select an appropriate surface area / volume ratio, e.g. 0.1 when a given storage period is set, for example 3 years.
    In practice, when the surface area / volume ratio, which must not be exceeded for a given bottle containing an oxaliplatin drug preparation as aqueous solution at a given concentration, is to be determined, the procedure can be carried out as follows:
    At least two bottles of uniform shape are used, but with different volumes (and therefore with different surface area / volume ratios), and they are filled with the aqueous oxaliplatin preparation.
    The surface area / volume ratios are then determined to quantify the respective levels of uncharacterized total impurities after the given storage period, (for example, after 1 month or 4 months). A graph is then prepared on which the measured impurity levels are plotted as a function of the "surface area / volume" ratio and the location at which the x-axis and curve intersect are determined. The value thus obtained indicates the surface area / volume ratio which should not be exceeded.
    Applicant has further found that this production is particularly effective for a filling volume greater than 7 ml. The present preparation is preferably applicable to any oxaliplatin solution contained in a bottle having a usable volume equal to or greater than 10 ml.
    The stored oxaliplatin drug preparations are preferably those in which the oxaliplatin is in aqueous solution at concentrations of between 2 and 7 mg / ml.
    13 DK 2007 00153 U3
    Finally, it should be noted that the applicant performed a stability study under accelerated conditions intended to predict stability over a period of 3 years. With this in focus, bottles were placed in a chamber brought to a temperature of 40 ° C and in an atmosphere with a humidity of 75%. Sample items were collected periodically 5 times and then analyzed.
    The results obtained indicate that oxaliplatin aqueous solution preparations can be stored in the bottles already selected above and under the specified loading conditions for a period of up to at least 36 months, thus meeting the best storage times recognized by the health authorities.
    It goes without saying, however, that the person skilled in the art will know how to utilize the production without being limited by either the concentrations used, or by the shape of the bottle (bottles of parallel-piped or cylindrical bases) or by the types of glass used. in the previous examples. In addition, the preparation can be used on any oxaliplatin drug composition in aqueous solution, where it is possible for the latter to further contain components such as stabilizers (e.g., buffers).
    20
    权利要求:
    Claims (8)
    [1]
    1. A kit consisting of an oxaliplatin drug preparation in aqueous solution and a glass bottle containing it, characterized in that the surface area / volume ratio of the bottle, expressed in mm2 / mm3, is less than 0.26.
    [2]
    Set according to claim 1, characterized in that the surface area / volume ratio of the bottle is less than 0.20.
    [3]
    Set according to any of the preceding claims, characterized in that the bottle is filled with an oxaliplatin preparation in aqueous solution contained in a bottle with a usable volume equal to or greater than 10 ml.
    [4]
    Set according to any one of the preceding claims, characterized in that the bottle is of type I glass.
    [5]
    Use of a glass vial containing an oxaliplatin drug preparation in aqueous solution at a concentration of between 2 mg / ml and 7 mg / ml where the surface area / volume ratio of the bottle, expressed in mm2 / mm3, is less than 0.20 and if usable room contents equal or greater than 10 ml; to maintain said composition for at least 10 months with a total level of impurities not exceeding 2% by weight relative to the weight of oxaliplatin, wherein said "surface" is the contact surface of the aqueous oxaliplatin solution with the bottle and said "volume" is that of the bottle. volume filled with said solution.
    [6]
    Use according to claim 5, wherein the concentration is 2 mg / ml.
    [7]
    Use according to claim 5, wherein the concentration is 5 mg / ml.
    [8]
    Use according to any one of the preceding claims 5 to 7, in which the bottle is made of Type I glass.
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    同族专利:
    公开号 | 公开日
    DK200700153U3|2007-08-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2012-03-23| UUP| Utility model expired|
    优先权:
    申请号 | 申请日 | 专利标题
    DK200700153U|DK200700153U3|2007-05-24|2007-05-24|Use of a bottle containing an oxaliplatin solution|DK200700153U| DK200700153U3|2007-05-24|2007-05-24|Use of a bottle containing an oxaliplatin solution|
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