Bortezomib aqueous solution with improved stability, and preparation method therefor

Abstract

The present invention relates to a bortezomib aqueous solution with improved stability, and a preparation method therefor, and, more specifically, to a bortezomib aqueous solution and a preparation method therefor, the solution eliminating the inconvenience of reconstitution, which is a problem of conventional bortezomib products of freeze-dried formulations, and, furthermore, having improved stability without a loss in drug efficacy.

Description

Bortezomib aqueous solution with improved stability and method for preparing the same

[0001] The present invention relates to a bortezomib aqueous solution with improved stability and a method for manufacturing the same, and more particularly, to a bortezomib aqueous solution with improved stability and a method for manufacturing the same, which eliminates the inconvenience of reconstitution, which is a problem of existing bortezomib products in the form of freeze-dried formulations, and further, without reducing the efficacy of the drug.

[0002] Bortezomib (BTZ) is a proteasome inhibitor with the following chemical structure and is approved for use as monotherapy and combination therapy for the treatment of multiple myeloma and mantle cell lymphoma.

[0003]

[0004] The proteasome, a part of the cellular machinery, performs numerous functions within cells, including regulating the concentration of various proteins that regulate cell division and survival. Bortezomib's effect is based on selective inhibition of the chymotrypsin-like activity of the 26S proteasome, ultimately leading to proteasome inhibition and decreased degradation of pro-apoptotic factors, which triggers cell apoptosis. Studies have shown that cancer cells are more sensitive to proteasome inhibitors than normal cells. In multiple myeloma, it acts by blocking the activation of adhesion molecules that allow plasma cells to settle in the bone marrow.

[0005] Bortezomib, provided as an active ingredient (API), is a trimer (bortezomib boroxine, structure shown below) under dehydrated conditions, which is air-sensitive. Furthermore, bortezomib readily oxidizes in air, generating alcohol and boric acid, limiting its pharmaceutical use.

[0006]

[0007] Bortezomib liquid formulations are highly unstable because free bortezomib in aqueous solution is highly susceptible to oxidation. Therefore, Velcade, an existing bortezomib product, ® VELCADE® Inj is supplied as a lyophilized formulation and must be reconstituted with 0.9% saline injection before administration. It has a shelf life of up to 3 years at 30°C in an unopened container, but after reconstitution with saline injection, it must be used within 8 hours at 25°C.

[0008] Freeze-dried products have a complex manufacturing process, requiring significant time and cost. Furthermore, reconstitution with saline solution poses a risk of contamination and exposure to the drug dispenser. Therefore, cytotoxic anticancer drugs such as bortezomib require ready-to-use (RTU) liquid formulations rather than lyophilized products. However, due to the storage stability issue, the biggest problem with liquid formulations, lyophilized formulations are still used. Furthermore, even when bortezomib or its pharmacologically acceptable salts are provided as lyophilized formulations, aqueous formulations can increase the formation of unknown toxic substances, posing stability issues that hinder long-term storage at room temperature. Due to these stability issues, lyophilized formulations continue to be used clinically.

[0009] The purpose of the present invention is to eliminate the inconvenience of reconstitution, which is a problem of the existing bortezomib product in the form of a freeze-dried formulation, and to provide a bortezomib aqueous solution with improved stability without reducing the efficacy of the drug, and a method for manufacturing the same.

[0010] One aspect of the present invention provides a pharmaceutical composition comprising bortezomib and mannitol as initial ingredients in a pharmaceutically acceptable aqueous medium, wherein the amount of mannitol as an initial ingredient in the aqueous medium is greater than 10 parts by weight based on 1 part by weight of bortezomib as an initial ingredient in the aqueous medium.

[0011] Another aspect of the present invention provides a method for preparing a pharmaceutical composition, comprising the step of introducing and mixing bortezomib and mannitol into a pharmaceutically acceptable aqueous medium, wherein the amount of mannitol introduced into the aqueous medium is greater than 10 parts by weight based on 1 part by weight of bortezomib introduced into the aqueous medium.

[0012] The bortezomib aqueous solution provided according to the present invention, unlike conventional bortezomib lyophilized formulations, does not require reconstitution for use and exhibits excellent stability without reducing the efficacy of the drug even under accelerated and harsh storage conditions.

[0013] Figure 1 shows the results of an accelerated stability test (impurity B content) performed in a test example of the present invention.

[0014] Figure 2 shows the results (total impurity content) of an accelerated stability test performed in a test example of the present invention.

[0015] Figure 3 shows the results of a harsh stability test (impurity B content) performed in a test example of the present invention.

[0016] Figure 4 shows the results (total impurity content) of a harsh stability test performed in a test example of the present invention.

[0017] Unless otherwise specified throughout this specification, the terms “include” or “comprising” refer to the inclusion of a certain component (or component) without limitation, and are not to be construed as excluding the addition of other components (or components).

[0018] The present invention is described in more detail below.

[0019] One aspect of the present invention relates to a pharmaceutical composition comprising bortezomib and mannitol as initial ingredients in a pharmaceutically acceptable aqueous medium, wherein the amount of mannitol as an initial ingredient in the aqueous medium is greater than 10 parts by weight based on 1 part by weight of bortezomib as an initial ingredient in the aqueous medium.

[0020] In the present invention, if the amount of mannitol as an initial component in an aqueous medium is 10 parts by weight or less based on 1 part by weight of bortezomib as an initial component in an aqueous medium, the storage stability of the pharmaceutical composition deteriorates.

[0021] According to one specific example, based on 1 part by weight of bortezomib as an initial component in an aqueous medium, the amount of mannitol as an initial component in an aqueous medium may be 11 parts by weight or more, 12 parts by weight or more, 13 parts by weight or more, 14 parts by weight or more, 15 parts by weight or more, 16 parts by weight or more, 17 parts by weight or more, 18 parts by weight or more, 19 parts by weight or more, or 20 parts by weight or more, and may also be 50 parts by weight or less, 45 parts by weight or less, 40 parts by weight or less, 39 parts by weight or less, 38 parts by weight or less, 37 parts by weight or less, 36 parts by weight or less, 35 parts by weight or less, 34 parts by weight or less, 33 parts by weight or less, 32 parts by weight or less, 31 parts by weight or less, or 30 parts by weight or less, but is not limited thereto.

[0022] In one specific example, the bortezomib may be bortezomib boroxine in trimer form.

[0023] In one specific example, the mannitol may be D-mannitol.

[0024] In one embodiment, the pharmaceutically acceptable aqueous medium may be distilled water for injection, 0.9% (w / v) saline, or a combination thereof.

[0025] In one specific embodiment, the pharmaceutical composition of the present invention may be vacuum degassed after mixing the initial components and the aqueous medium.

[0026] In one specific example, the mixing of the initial components and the aqueous medium may be performed at a temperature of 20°C or higher.

[0027] More specifically, the mixing temperature of the initial components and the aqueous medium may be 20°C or higher, 22°C or higher, 25°C or higher, 27°C or higher, or 30°C or higher, and may also be 50°C or lower, 48°C or lower, 45°C or lower, 43°C or lower, or 40°C or lower, but is not limited thereto.

[0028] In one specific example, the vacuum degassing may be performed at a vacuum of 0 to 200 mTorr at -50°C to 20°C for 2 to 6 hours, but is not limited thereto.

[0029] In one specific example, the vacuum degassing may be performed sequentially through two or more steps.

[0030] In one embodiment, the vacuum degassing may be performed on a cooled-frozen pharmaceutical composition.

[0031] The above cooling-freezing refers to the process of continuously cooling a mixture of initial components and an aqueous medium to lower its temperature below the mixing temperature and finally freezing it.

[0032] In one specific example, the cooling-freezing may be performed at 15°C to -60°C for 1 to 6 hours, but is not limited thereto.

[0033] In one specific example, the cooling-freezing may be performed sequentially through two or more steps.

[0034] In one embodiment, the pharmaceutical composition of the present invention may further comprise a pH adjusting agent.

[0035] In one specific example, the pH adjusting agent is potassium hydroxide, sodium bicarbonate (NaHCO3), sodium borate, sodium carbonate, sodium hydroxide (NaOH), glycerol, sorbitol, mannitol, glucose, sodium chloride, citric acid, sodium citrate, potassium citrate, lithium citrate, tartaric acid, sodium tartrate, potassium tartrate, calcium tartrate, lithium tartrate, phosphoric acid, sodium dihydrogenphosphate, sodium monohydrogenphosphate, lithium phosphate, potassium phosphate, calcium phosphate, malic acid, hydrochloric acid, nitric acid, acetic acid, sodium acetate, potassium acetate, calcium acetate, sulfuric acid, sodium sulfate, It may be selected from the group consisting of potassium sulfate, boronic acid, sodium boronic acid, maleic acid, lithium malate, sodium malate, potassium malate, calcium malate, succinic acid, lithium succinate, sodium succinate, calcium succinate, potassium succinate, lactic acid, sodium lactate, potassium lactate, calcium lactate, triethanolamine, diisopropanolamine, and combinations thereof, but is not limited thereto.

[0036] In one specific embodiment, the pH adjusting agent may be mixed with the aqueous medium together with the initial components, or added to a mixture of the initial components and the aqueous medium, and the resulting mixture may be subjected to the vacuum degassing described above, or may be subjected to cooling-freezing and vacuum degassing.

[0037] In one specific embodiment, the pharmaceutical composition of the present invention may have an acidic pH.

[0038] In one specific embodiment, the pH of the pharmaceutical composition of the present invention may be, but is not limited to, 3.0 to 5.5, more specifically 3.5 to 5.0, and even more specifically 4.0 to 4.5.

[0039] The pharmaceutical composition of the present invention may further include one or more conventional additives acceptable for aqueous liquid pharmaceutical compositions in addition to the components described above, within the scope that can achieve the purpose of the present invention.

[0040] In one specific embodiment, the pharmaceutical composition of the present invention may be an injection.

[0041] In one specific embodiment, the pharmaceutical composition of the present invention is for the treatment of cancer, more specifically for the treatment of multiple myeloma and / or mantle cell lymphoma.

[0042] Another aspect of the present invention relates to a method for preparing a pharmaceutical composition, comprising the step of introducing and mixing bortezomib and mannitol into a pharmaceutically acceptable aqueous medium, wherein the amount of mannitol introduced into the aqueous medium is greater than 10 parts by weight based on 1 part by weight of bortezomib introduced into the aqueous medium.

[0043] In the method for manufacturing the pharmaceutical composition of the present invention, the bortezomib, mannitol, and pharmaceutically acceptable aqueous medium, the amount of mannitol added in the aqueous medium, and the mixing thereof are as described above.

[0044] In one specific example, bortezomib and mannitol may be introduced and mixed into a pharmaceutically acceptable aqueous medium together with a pH adjusting agent, or a pH adjusting agent may be added to the mixture of bortezomib and mannitol and a pharmaceutically acceptable aqueous medium.

[0045] In the method for manufacturing the pharmaceutical composition of the present invention, the pH adjusting agent is as described above.

[0046] In one specific embodiment, the method for preparing the pharmaceutical composition of the present invention may further include a step of vacuum degassing a mixture comprising the bortezomib, mannitol, and a pharmaceutically acceptable aqueous medium.

[0047] In the method for manufacturing the pharmaceutical composition of the present invention, the vacuum degassing is as described above.

[0048] In one specific embodiment, the method for preparing the pharmaceutical composition of the present invention may further include, prior to the vacuum degassing step, a step of cooling-freezing a mixture comprising bortezomib, mannitol, and a pharmaceutically acceptable aqueous medium.

[0049] In the method for manufacturing the pharmaceutical composition of the present invention, the cooling-freezing is as described above.

[0050] Hereinafter, preferred examples are presented to aid understanding of the present invention. However, the following examples are intended only to illustrate the present invention and are not intended to limit the present invention to these examples.

[0051] [Example]

[0052] Preparation example of the formulation

[0053] As an initial component, bortezomib trimer, bortezomib boroxine (50 mg as bortezomib) and mannitol in the amount shown in Table 1 below were added to 20 mL of 0.9% (w / v) saline injection as an aqueous medium, stirred at 30°C and 500 rpm for 60 minutes, and then 1 N HCl was added to prepare an aqueous solution having a pH of 4.3 to 4.5 and an active ingredient concentration of 2.5 mg / mL.

[0054]

[0055]

[0056] The aqueous solution of Example 1 prepared above was used in the stability test described below without any additional treatment.

[0057] The aqueous solutions of Examples 2 and 3 prepared above were subjected to cooling-freezing and vacuum degassing under the following conditions and then used in the stability test described below.

[0058] The aqueous solution of Comparative Example 1 manufactured above was subjected to nitrogen bubbling and then used in the stability test described below.

[0059] (1) Cooling-freezing conditions

[0060] - Step 1: Lower the temperature to 5℃ for 1 hour.

[0061] - Step 2: Lower the temperature to -40℃ for 2 hours

[0062] (2) Vacuum degassing conditions

[0063] The process was carried out under a vacuum of 100 mTorr at -40°C for 2 hours.

[0064] Example of stability test of formulation

[0065] Each of the aqueous solutions of Examples 1 to 3 and Comparative Example 1 was stored for one month under accelerated conditions (25±2°C / RH60±5%) and harsh conditions (40±2°C / RH75±5%), and then the content of impurity B and total impurity content in the solutions were measured using a flexible substance analysis method, thereby confirming the storage stability of the solutions.

[0066] [Impurity B]

[0067]

[0068] The stability test results are as shown in Table 2 below and are shown in Figures 1 to 4, respectively.

[0069]

[0070]

[0071] As confirmed from the above Table 2 and Figures 1 to 4, the bortezomib aqueous solution of the present invention exhibited excellent stability under accelerated and harsh storage conditions. That is, according to the present invention, while eliminating the inconvenience of reconstitution, which is a problem of the existing bortezomib product in the form of a freeze-dried formulation, a bortezomib aqueous solution with significantly improved stability can be obtained without reducing the efficacy of the drug.

Claims

1. A pharmaceutical composition comprising bortezomib and mannitol as initial ingredients in a pharmaceutically acceptable aqueous medium, Based on 1 part by weight of bortezomib as an initial component in an aqueous medium, the amount of mannitol as an initial component in an aqueous medium exceeds 10 parts by weight. Pharmaceutical composition.

2. A pharmaceutical composition in claim 1, wherein bortezomib is bortezomib boroxine in a trimer form.

3. A pharmaceutical composition in claim 1, wherein the mannitol is D-mannitol.

4. A pharmaceutical composition in paragraph 1, wherein the pharmaceutically acceptable aqueous medium is distilled water for injection, 0.9% (w / v) physiological saline, or a combination thereof.

5. A pharmaceutical composition according to claim 1, wherein the composition is vacuum degassed after mixing the initial components and the aqueous medium.

6. A pharmaceutical composition according to claim 5, wherein vacuum degassing is performed on a cooled-frozen pharmaceutical composition.

7. A pharmaceutical composition according to claim 1, further comprising a pH regulator.

8. A step of introducing and mixing bortezomib and mannitol into a pharmaceutically acceptable aqueous medium, Here, based on 1 weight part of bortezomib administered in an aqueous medium, the amount of mannitol administered in an aqueous medium exceeds 10 weight parts. A method for preparing a pharmaceutical composition.

9. A method for preparing a pharmaceutical composition, further comprising the step of vacuum degassing a mixture containing bortezomib, mannitol, and a pharmaceutically acceptable aqueous medium in paragraph 8.

10. A method for preparing a pharmaceutical composition, wherein, in claim 9, prior to the vacuum degassing step, the method further comprises a step of cooling and freezing a mixture comprising bortezomib, mannitol, and a pharmaceutically acceptable aqueous medium.

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