JP2018168088A - Bortezomib liquid formulation - Google Patents

Abstract

To provide a bortezomib formulation having excellent stability while containing water.SOLUTION: The bortezomib formulation contains bortezomib, propylene glycol, and an ascorbic acid, and water.SELECTED DRAWING: None

Description

  The present invention relates to a composition (pharmaceutical composition) containing bortezomib.

  Bortezomib is a proteasome inhibitor having the following structure. As a pharmaceutical product, “3 mg for Velcade injection” is commercially available from Janssen Pharma Co., Ltd. as a freeze-dried preparation, for use as an anticancer agent.

Such a VELCADE injection preparation requires a dissolution operation when used, but such a dissolution operation increases the risk of exposure of the anticancer drug to the medical staff. Therefore, a liquid formulation of bortezomib is desired.

  However, bortezomib is inherently low in stability, and a solution containing bortezomib forms a related substance or the like derived from bortezomib, which may cause problems that are not pharmaceutically acceptable.

Under such circumstances, development of a stable bortezomib solution is desired, and several formulations have been reported.
For example, JP 2013-522320 A (Patent Document 1) discloses a substantially non-aqueous liquid preparation containing bortezomib and propylene glycol and having a total water content of 15% by volume or less. Yes.

  However, with the liquid preparation of this document, a liquid preparation with a high water concentration cannot be obtained.

Special table 2013-522320 gazette

An object of the present invention is to provide a novel bortezomib preparation (liquid preparation).
Another object of the present invention is to provide a bortezomib preparation (liquid preparation) excellent in stability.

  As described above, in the liquid preparation of Patent Document 1, the concentration of water cannot be effectively increased. Moreover, according to examination of this inventor, in the liquid formulation of patent document 1, it seems that a specific related substance may produce in large quantities.

  Under such circumstances, as a result of intensive research, the present inventor can obtain a novel liquid preparation containing water by combining at least two specific components (ie, propylene glycol and ascorbic acids) with bortezomib. In addition, such liquid preparations, surprisingly, have high stability even when the water content is relatively large, and furthermore, efficiently suppress the production of specific related substances. As a result, the inventors have further studied and completed the present invention.

  That is, the composition (or formulation or pharmaceutical composition) of the present invention contains bortezomib, propylene glycol, ascorbic acids, and water. Such a composition may usually be liquid (solution).

  In such a composition, the proportion of propylene glycol may be, for example, 60% by volume or less, and the proportion of ascorbic acids may be about 0.01 to 10 mg with respect to 1 mg of bortezomib.

  In the composition of the present invention, the ratio of water may be, for example, more than 15% by volume, or 0.2 mL or more with respect to 1 mL of propylene glycol.

The composition of the present invention may further contain glycerin. In such a composition containing glycerin, the ratio of glycerin may be, for example, about 3 to 80% by volume.
Moreover, in the composition containing such glycerin, the ratio of propylene glycol may be about 0.05 to 10 mL with respect to 1 mL of glycerin.

Exemplary compositions of the present invention include:
In addition, including glycerin,
The ratio of bortezomib is 0.5 mg / mL or more,
The proportion of propylene glycol is 40% by volume or less,
The ratio of ascorbic acids is 0.05 to 4 mg with respect to 1 mg of bortezomib,
The proportion of water is 16-50% by volume,
The composition etc. whose ratio of glycerol is 10-70 volume% are contained.

  In the present invention, the stability of the composition (or bortezomib in the composition) can be improved or improved by adding propylene glycol and ascorbic acid in combination to the composition containing bortezomib and water.

  Therefore, the present invention includes an additive for improving or improving the stability of a composition containing bortezomib and water, the additive containing propylene glycol and ascorbic acids.

  The present invention also relates to a method for improving or improving the stability of a composition containing bortezomib and water, the method comprising adding an additive containing propylene glycol and ascorbic acids to the composition (adding said composition) To improve or improve the stability of the above.

  In such an additive or method, the additive may further contain glycerin.

The present invention includes a container (or preparation) in which the composition is enclosed (or sealed). In such a container, the void in the container may be filled with an inert gas. In the container of the present invention, the oxygen concentration relative to the entire volume in the container may be 2.5% by volume or less.
The present invention also includes a method for administering the composition, and treating (or improving) cancer (multiple myeloma, plasma cell myeloma, etc.) using the composition (by administering the composition). ) Is also included. The form of administration may be injection (intravenous infusion).

According to the present invention, a novel bortezomib preparation (liquid preparation) can be provided. Such a preparation is excellent in stability. Therefore, according to the present invention, a stable bortezomib liquid formulation that does not impair quality (and appearance) even after long-term storage can be efficiently obtained.
In addition, the preparation of the present invention can achieve high stability even if it contains a relatively large amount of water. Therefore, in the present invention, surprisingly, both high water concentration and excellent stability can be achieved.
By containing a large amount of water [and thus reducing liquid components other than water (for example, propylene glycol, etc.), the amount of the organic solvent to be administered to the subject patient can be reduced, and the patient's QOL can be improved.
Furthermore, in the preparation of the present invention, the production of a specific related substance can be efficiently suppressed. In a conventional liquid formulation of bortezomib, a specific related substance may be specifically produced. In the present invention, such a specifically produced related substance can be suppressed. In many cases, the effects of large amounts of specific related substances are not yet known. Bortezomib is safer and more reliable by suppressing the generation of specific related substances as well as the total amount of related substances. A formulation can be provided.

  The composition of the present invention contains at least bortezomib, propylene glycol, ascorbic acids, and water.

[Bortezomib]
Bortezomib is a compound having the above structure. In the composition of the present invention, bortezomib may be included as a compound having the above structure, or may be included as an ester of boronic acid (for example, mannitol ester).

  Bortezomib may be contained in the composition in the form of a salt, a hydrate or the like.

[Ascorbic acids]
Ascorbic acids include ascorbic acid (L-ascorbic acid and the like), ascorbic acid derivatives, salts thereof (particularly pharmacologically acceptable salts), hydrates thereof and the like.

The ascorbic acid derivative is not particularly limited. For example, ascorbic acid ester {for example, ester of ascorbic acid and carboxylic acid [for example, fatty acid ester (for example, ascorbyl mono- or distearate, ascorbyl mono- or dipalmitate, mono- or Saturated or unsaturated C _1-40 carboxylic acid ester such as ascorbyl dioleate, more preferably saturated or unsaturated C _1-20 carboxylic acid ester, etc.], ester of ascorbic acid and phosphoric acid (ascorbic acid mono to triphosphoric acid) ester, etc.)}, ascorbic acid ethers {e.g., ascorbic acid alkyl ethers (e.g., ascorbic acid methyl ether, ascorbic acid C _1-10 alkyl ethers, such as ascorbic acid ethyl ether), etc.}, Asukoru Glycosides phosphate (e.g., ascorbic acid glucoside), and the like.

  In the salt of ascorbic acid or ascorbic acid derivative, examples of the salt include metal salts [eg, alkali metal salts (eg, lithium salt, sodium salt, potassium salt, etc.), alkaline earth metal salts (eg, magnesium salt, calcium, etc.) Salt), Group 13 metal salts (for example, aluminum salts), transition metal salts (for example, salts of zinc, iron, cobalt, copper, etc.)], ammonium salts, amine salts [for example, alkylamine salts (for example, , Trimethylamine salt, trialkylamine salt of triethylamine salt), alkanolamine salt (for example, monoethanolamine salt, triethanolamine salt), cyclic amine salt (for example, pyridine salt, substituted pyridine salt)], amino acid salt (for example, , Salts with histidine, arginine, etc.). The salt may be a single salt or a double salt. Moreover, you may form the salt with the same or different acid or base.

  Typical ascorbic acids include ascorbic acid, metal ascorbate (eg, alkali or alkaline earth metal salts of ascorbic acid such as sodium ascorbate, potassium ascorbate, magnesium ascorbate, calcium ascorbate), phosphorus ascorbate Acid ester, ascorbic acid phosphate metal salt (for example, alkali or alkaline earth metal salt of ascorbic acid phosphate such as sodium ascorbate phosphate and magnesium ascorbate phosphate).

  Ascorbic acids may be used alone or in combination of two or more.

[Glycerin]
The composition of the present invention may contain glycerin. By combining propylene glycol and glycerin, the stability of bortezomib in a liquid preparation containing water may be improved.

[Ratio of each component]
In the composition (solution) of the present invention, the ratio (concentration) of bortezomib is, for example, 0.01-100 mg / mL (for example, 0.05-50 mg / mL), preferably 0.1-30 mg / mL (for example, 0.2-20 mg / mL), more preferably 0.5-10 mg / mL (e.g. 0.7-5 mg / mL), especially 0.8-3 mg / mL (e.g. 0.9-2 mg / mL) Usually 0.5 mg / mL or more (for example, 0.7 mg / mL or more, 0.8 mg / mL or more, 0.9 mg / mL or more, 0.95 mg / mL or more, 1 mg / mL or more) Etc.).

In the composition of the present invention, the ratio of propylene glycol (concentration or ratio to the whole liquid component constituting the composition) is, for example, 90% by volume or less (for example, 80% by volume or less), preferably 70% by volume or less (for example, , 60% by volume or less), more preferably 50% by volume or less, particularly 40% by volume or less (for example, 35% by volume or less).
The lower limit value of the proportion (concentration) of propylene glycol is not particularly limited. For example, 1 volume%, 2 volume%, 3 volume%, 5 volume%, 8 volume%, 10 volume%, 12 volume%, 15 Volume%, 18 volume%, 20 volume%, 22 volume%, 25 volume%, etc. may be sufficient.

  The proportion of propylene glycol may be, for example, 3 mL or less, preferably 2 mL or less, more preferably 1.5 mL or less, particularly 1 mL or less, with respect to 1 mg of bortezomib.

  In the composition of the present invention, the ratio (concentration) of ascorbic acids is, for example, 0.001 to 100 mg / mL (for example, 0.005 to 50 mg / mL), preferably 0.01 to 10 mg / mL (for example, 0 0.03-5 mg / mL), more preferably 0.05-4 mg / mL (e.g. 0.07-3 mg / mL), especially 0.1-2 mg / mL (e.g. 0.12-1.5 mg / mL). About 0.15 to 1.2 mg / mL (for example, 0.18 to 1.1 mg / mL, 0.2 to 1.05 mg / mL, etc.).

  The ratio of ascorbic acids is, for example, 0.001 to 100 mg (for example, 0.005 to 50 mg), preferably 0.01 to 10 mg (for example, 0.03 to 5 mg), more preferably 0, per 1 mg of bortezomib. 0.05 to 4 mg (for example, 0.07 to 3 mg), particularly about 0.1 to 2 mg (for example, 0.12 to 1.5 mg), usually 0.15 to 1.2 mg (for example, 0 to .18-1.1 mg, 0.2-1.05 mg, etc.).

  The ratio of ascorbic acids is, for example, 0.1 to 30 mg (for example, 0.2 to 25 mg), preferably 0.3 to 20 mg (for example, 0.35 to 15 mg), and more preferably, with respect to 1 mL of propylene glycol. About 0.4-10 mg (for example, 0.45-7 mg) may be sufficient, and 0.5-5 mg (for example, 0.6-4 mg, 0.7-3.5 mg) may be sufficient normally.

In the composition of the present invention, the ratio of water (concentration or ratio to the whole liquid component constituting the composition) may be selected from a range of, for example, 5% by volume or more (for example, 8% by volume or more). It may be at least 15% by volume (for example, at least 12% by volume), preferably at least 15% by volume, more preferably at least 18% by volume. % Or more, 17 volume% or more, 18 volume% or more).
In addition, although the upper limit of the ratio (concentration) of water is not specifically limited, For example, 90 volume%, 80 volume%, 70 volume%, 60 volume%, 50 volume%, 40 volume%, 35 volume%, 30 volume %, 25% by volume, and the like.

  The ratio of water may be, for example, 0.1 mL or more, preferably 0.2 mL or more, more preferably about 0.3 mL or more, and 0.4 mL or more (for example, 0.5 mL) with respect to 1 mL of propylene glycol. Or more).

When the composition of the present invention contains glycerin, the proportion of glycerin (concentration or the proportion of the whole liquid component constituting the composition) is, for example, 90% by volume or less (for example, 85% by volume or less), preferably 80% by volume. Or less (for example, 75 volume% or less), more preferably 70 volume% or less (for example, 65 volume% or less), particularly 60 volume% or less (for example, 55 volume% or less).
The lower limit of the ratio (concentration) of glycerin is not particularly limited. For example, 1% by volume, 2% by volume, 3% by volume, 5% by volume, 8% by volume, 10% by volume, 15% by volume, and 20% by volume. %, 25% by volume, 30% by volume, 35% by volume, 40% by volume, 45% by volume, and the like.

  When the composition of the present invention contains glycerin, the proportion of propylene glycol is, for example, about 0.05 to 10 mL, preferably 0.1 to 8 mL, and more preferably about 0.2 to 3 mL with respect to 1 mL of glycerol. 1 mL or less [e.g., 0.9 mL or less (e.g., 0.1 to 0.85 mL), 0.8 mL or less (e.g., 0.2 to 0.75 mL), 0.7 mL or less (e.g., 0 .3-0.65 mL) etc.].

[Other ingredients]
The composition of the present invention may further contain other components (bortezomib, propylene glycol, ascorbic acids, water and other components not belonging to the category of glycerin) as necessary. Other components are not particularly limited, for example, pH adjusters, buffers, isotonic agents, solubilizers, stabilizers, antioxidants, surfactants, antifoaming agents, solubilizers, solubilizers Agents, dispersants, preservatives and the like.
You may use another component individually or in combination of 2 or more types.

[Aspect and properties of composition]
The composition of the present invention contains liquid components such as water and propylene glycol (and glycerin), and is usually liquid (liquid agent).

  The pH of such a composition (liquid composition, liquid preparation) of the present invention is not particularly limited, but is, for example, 3.0 to 7.0, preferably 3.5 to 7.5, and more preferably 4.5. It may be about ~ 6.5.

  The oxygen concentration in the composition (liquid agent) is not particularly limited, but may be as low as possible (for example, 10% by volume or less), for example, 5% by volume or less (for example, 3% by volume or less), preferably May be 2.5% by volume or less, more preferably 2% by volume or less.

  The oxygen concentration (dissolved oxygen concentration) in the composition can be adjusted (reduced) by a conventional method (such as bubbling with an inert gas).

  The composition of the present invention can be selected depending on the administration method, but in particular, it may be in the form of an injection (or intravenous infusion). Specific administration methods include intravenous injection (intravenous injection), subcutaneous injection, and the like. More specifically, it may be administered intramuscularly, intraarterially, intraperitoneally, submeningially, intraventricularly, intraurethrally, intrasternally, intracranial, etc., or by intravenous infusion.

  The concentration of each component in the liquid preparation can be selected from the same range as described above. In particular, when administering by intravenous infusion, an intravenous infusion solution is prepared by mixing and dissolving the composition in an infusion solution. Also good. In this embodiment, the ratio when the composition is mixed with the infusion solution is appropriately selected according to the body surface area, age, sex, application location, disease state, etc. of the subject or the like to whom the intravenous solution is administered. There is no particular limitation.

  Examples of the infusion include, but are not limited to, physiological saline solution, sugar aqueous solution (such as glucose aqueous solution and fructose aqueous solution), sugar alcohol aqueous solution (such as D-sorbitol aqueous solution and xylitol aqueous solution), amino acid aqueous solution, Ringer's solution and the like.

The composition of the present invention may be usually enclosed in a container during storage or the like.
Therefore, the present invention includes a container containing the composition inside. In such a container, the composition may usually be enclosed or sealed.

  As a container, it can select suitably according to an administration mode etc., For example, a bottle (vial bottle), an ampule, a syringe etc. are mentioned.

  The container may be externally packaged (for example, packaged with a plastic film).

  The interior of the container may be composed only of the composition (liquid agent) or may have a void (space). Such voids are particularly preferably filled (or substituted) with an inert gas (such as nitrogen gas).

  Furthermore, it is preferable that the dissolved oxygen contained in the composition (solution) contained in the container is as small as possible.

  Typically, the oxygen concentration with respect to the entire volume in the container is, for example, preferably 10% by volume or less, for example, 5% by volume or less (for example, 3% by volume or less), preferably 2.5% by volume or less, More preferably, it may be 2% by volume or less.

  In the case where oxygen does not have voids in the container, the dissolved oxygen contained in the composition, and in the case of voids in the container, the total amount of dissolved oxygen contained in the composition and oxygen contained in the voids. It is.

  The oxygen concentration can be adjusted by a conventional method, for example, a method of bubbling an inert gas into the composition and / or the container, a method of degassing the composition and / or the container, or a combination of these. .

  Next, the present invention will be described more specifically with reference to experimental examples and examples. However, the present invention is not limited to these examples, and many modifications are within the technical idea of the present invention. This is possible by those with ordinary knowledge in the field.

[Purity test]
Using the sample solution, measurement by liquid chromatography (UPLC method) was performed under the following conditions.

Detector: UV absorption detector (measurement wavelength: 270 nm)
Column used: Stainless steel tube with an inner diameter of 2.1 mm and a length of 10 cm packed with 1.7 μm of octadecylsilylated silica gel for liquid chromatography Column temperature: constant temperature around 40 ° C. Mobile phase A: exactly 1 mL of phosphoric acid Mobile phase B: accurately 1 mL of phosphoric acid, and acetonitrile accurately to 1000 mL Flow rate: 0.6 mL / min
Injection volume: 10 μL
Mobile phase feeding: The concentration gradient was controlled by changing the mixing ratio of mobile phase A and mobile phase B as follows.

In the calculation, the content of each impurity peak was calculated by the area percentage method.
In addition, the relative substance (impurity) “A” has a ratio of the retention time of the peak to the retention time of the peak corresponding to bortezomib (relative retention time RRT) around 1.4 (about 1.39 to 1.41). ) Is a related substance corresponding to a peak.

(Severe test method)
The sample was stored at 40 ° C./swelling humidity, and various test items were analyzed after 1 week, 2 weeks, or 3 weeks.

[Examples and Reference Examples]
3 mL of a liquid agent (bortezomib aqueous solution) containing 3 mg of bortezomib, each component shown in the table, and water (remainder) was obtained. And the quantity of the related substance was measured about each liquid agent.

  The results are shown in the table together with the composition of each solution. In the table, in the related substances, “−” indicates that the measurement is omitted, and “ND” indicates that the measurement is not detected.

  As is clear from the above table, Examples 1 to 3 in which propylene glycol and ascorbic acid are combined with bortezomib have high stability in a system containing water. Further, such stability can be realized even in a system having a relatively high proportion of water, and is maintained at a relatively high level even after a severe test. Further, in the embodiment, not only the total related substances but also the generation of a specific related substance A can be suppressed.

  According to the present invention, a novel bortezomib preparation (solution) containing water can be obtained.

Claims (11)

  A composition comprising bortezomib, propylene glycol, ascorbic acids, and water.   The composition according to claim 1, wherein the proportion of propylene glycol is 60% by volume or less.   The composition according to claim 1, wherein the ratio of ascorbic acids is 0.01 to 10 mg per 1 mg of bortezomib.   The composition according to claim 1 or 2, wherein the proportion of water is more than 15% by volume.   The composition according to claim 1, wherein the proportion of water is 0.2 mL or more with respect to 1 mL of propylene glycol.   Furthermore, the composition in any one of Claims 1-5 containing glycerol.   Furthermore, the composition in any one of Claims 1-6 which contains glycerol and the ratio of glycerol is 3-80 volume%.   The composition according to any one of claims 1 to 7, further comprising glycerol, wherein the proportion of propylene glycol is 0.05 to 10 mL with respect to 1 mL of glycerol. In addition, including glycerin,
The ratio of bortezomib is 0.5 mg / mL or more,
The proportion of propylene glycol is 40% by volume or less,
The ratio of ascorbic acids is 0.05 to 4 mg with respect to 1 mg of bortezomib,
The proportion of water is 16-50% by volume,
The composition in any one of Claims 1-8 whose ratio of glycerol is 10-70 volume%.   A method for improving or improving the stability of a composition comprising bortezomib and water, wherein an additive comprising propylene glycol and ascorbic acids is added to the composition.   The method according to claim 10, wherein the additive further comprises glycerin.