TWI660727B - Stable formulation comprising bortezomib, and its preparation method - Google Patents

Abstract

The present invention provides a liquid formulation of bortezomib, comprising bortezomib or a pharmaceutically acceptable salt thereof; at least one sugar alcohol selected from the group consisting of: mannitol, erythritol, Sorbitol, isomalt, maltitol, xylitol and trehalose; and solvents containing a mixture of propylene glycol and a polar solvent including water. The bortezomib formulation of the present invention is easy to prepare in a commercial manner, can prevent microbial contamination that may occur during lyophilization and reduction, and has improved administration convenience and stability. Furthermore, the bortezomib formulation contains sugar alcohol and Propylene glycol, and therefore different from conventional bortezomib-containing injectable liquid formulations, does not exhibit abnormal appearance, such as discoloration or precipitation, and meets the criteria.

Description

Bortezomib-containing stable formulation and preparation method thereof

The present invention relates to a stable formulation containing bortezomib and a method for preparing the same, and more particularly, to a highly stable liquid formulation containing bortezomib and a method for preparing the same.

Bortezomib is used in recurrent multiple myeloma. It is believed that the boron atom in bortezomib binds to the catalytic site of the proteasome, which eventually leads to the reduction of proteasome inhibition and degradation of pro-apoptotic factors, which in turn triggers treatment. Apoptosis of cells.

Currently, bortezomib (N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid), which is sold as Velcade ^TM , is approved for the treatment of various neoplastic diseases, and is especially used for 26S proteasome inhibitor for the treatment of recurrent multiple myeloma and mantle cell lymphoma.

Velcade ^TM must be administered prior to sale by the reduction of the formulation was lyophilized form, i.e. in the form of formulations sold as a lyophilized powder (3.5 mg), 0.9% sodium chloride solution before administration to the reduction to a patient, and It is diluted at a final concentration of 2.5 mg / ml (intravenous) or 1.0 mg / ml (subcutaneous).

However, the preparation of lyophilized powder formulations is complex and expensive. In addition, lyophilized formulations have the risk of being contaminated with microorganisms during the reduction, and pharmacists, physicians, nurses, and the like associated with the prescription of medicines containing such formulations are likely to be exposed to substances that destroy cells. Therefore, for cytotoxic anticancer agents such as bortezomib, there is a need to develop ready-to-use liquid formulations that can be stored for long periods of time rather than lyophilized formulations.

On the other hand, the biggest problem with liquid formulations is stability during storage. Due to this stability issue, a large number of injectable formulations are used in the form of lyophilized formulations, which dissolve immediately before injection. Even bortezomib or its pharmaceutically acceptable salt, which has recently been provided as a lyophilized formulation, has a problem in that the unknown impurities therein increase when it is prepared in the form of an aqueous solution, making it impossible to store at room temperature for a long period of time. In addition, the solubility of bortezomib in water (25 ° C) is only 0.076 mg / ml, and therefore it takes a long time to make it liquid. However, bortezomib is extremely unstable in liquid form, and for this reason, it is recommended that currently available lyophilized formulations containing bortezomib be used within 8 hours after its reduction with 0.9% NaCl. Due to this stability issue, bortezomib is currently used in clinical applications as a lyophilized formation.

This instability of bortezomib in liquid form has been reported in various literatures. As in the case of bortezomib, compounds including aminoalkylboronic acid undergo spontaneous 1,3-rearrangement to obtain homologous amines due to the instability of the free α-amino group, and degradation produces boric acid and alcohol. Due to this instability, compounds undergo oxidation reactions that tend to break CB bonds that are longer and weaker than the corresponding CC bonds. Due to such instability, bortezomib in aqueous solutions for injection is inherently unstable. For example, in ethanol: standard physiological saline solution (2:98, pH 2.8), bortezomib (0.5 mg / mL) degrades 20% within 6 months when stored at 25 ° C. In addition, it is known that PEG300 undergoes auto-oxidation accompanied by peroxide formation, and it is speculated that the observed degradation of bortezomib in PEG300: EtOH: H ₂ O (40:10:50) solvents may be due to the presence of peroxides. .

In other studies, it has been reported that bortezomib is susceptible to oxidative degradation under a variety of experimental conditions, and that the oxidation of alkylborane (which forms the ester of boric acid) can also be due to the reaction with alkyl peracids, alkyl peroxides, or Reaction of Oxygen Free Radical Substances (Brown HC. 1972. Boranes in organic chemistry. Ithaca, NY: Cornell University Press). Initial oxidation can be attributed to peroxides or molecular oxygen and light metal ions and alkaline conditions that generally promote oxidation. Therefore, these conditions are not considered to be beneficial to the stability of bortezomib or any other alkylboronic acid derivative (Hussain MA, Knabb R, Aungust BJ, Kettner C. 1991. Anticoagulant activity of a peptide boronicacid thrombin inhibitor by various routes of administration in rats. Peptide 12: 1153-1154).

US Patent Nos. 7,119,080; 6,713,446; 6,958,319; 6,747,150 and 6,297,217 disclose the formation of boric acid functional groups and mannitol diesters after lyophilization. From the ester thus formed, active boric acid is obtained when the medicine is reduced in physiological saline for injection. Similarly, attempts to form esters of boric acid with alpha-hydroxyl and beta-carboxylic acids such as citric acid, and bulking agents and buffers are disclosed in WO 2009/154737.

To avoid the stability issue of bortezomib in solution form, the compounds can be lyophilized and reduced before injection. However, although this method tends to address issues related to the stability of bortezomib, unused reducing solutions must be injected within hours or days (see, for example, Stability of unused reconstituted bortezomib in original manufacturer vials; J Oncol Pharm Pract. 2010 October 6 or Stability of bortezomib 1-mg / mL solution in plastic syringe and glass vial; Ann Pharmacother. 2005 Sep; 39 (9): 1462-6). Similarly, in the case of reduction, bortezomib mannitol is only suitable for administration within 8 hours when stored at room temperature.

Other known methods include isolating specific polymorphic forms with improved stability as described in WO2008075376A1 and lyophilized forms with tromethamine as described in WO2010089768A2. Other formulations with selected organic solvents and other ingredients are described in WO2010039762A2. Unfortunately, all or almost all such known compositions fail to provide significant stability against bortezomib, especially if the formulation is a liquid formulation.

Therefore, despite the many bortezomib formulations known in the art, all or almost all of them have the problem of limited stability when bortezomib is in solution. As a result, the products currently in use do not provide flexibility in administration and are particularly unlikely to be used in multi-dose liquid formulations with extended stability. In addition, these formulations contain a large amount of a dissolution aid such as propylene glycol, which may cause side effects in the body. Therefore, there remains a need to provide improved alternative bortezomib formulations that have greater stability while also containing highly biocompatible components.

Against this background, the present inventors have conducted extensive research, and as a result, a liquid formulation of bortezomib having high stability and containing a solvent mixture having high biocompatibility due to a large proportion of polar solvents has been prepared.

It is an object of the present invention to provide stable bortezomib formulations.

In particular, it is an object of the present invention to provide ready-to-use injectable bortezomib formulations.

To solve the above problems, the present invention provides a liquid formulation comprising bortezomib as the active ingredient: bortezomib or a pharmaceutically acceptable salt thereof; a solvent comprising a mixture of propylene glycol and a polar solvent including water; And at least one sugar alcohol selected from the group consisting of mannitol, erythritol, sorbitol, isomalt, maltitol, xylitol and trehalose.

In the present invention, the ratio of bortezomib or its pharmaceutically acceptable salt: sugar alcohol (w / w) may be 1:10 to 60, preferably 1:20 to 60.

The solvent system in the present invention may contain a polar solvent including water in an amount of 40 vol% or more, more particularly 40 vol% to 60 vol%, and even when the solvent system contains the above-specified polar solvent, especially water, The total degradation of bortezomib in the formulation can be reduced to 2.5% or less, preferably 2% or more when stored at 25 ° C and 60% relative humidity (RH) for 3 months. small.

The liquid formulation of bortezomib may further comprise any one or more antioxidants selected from the group consisting of butylated hydroxyanisole, sodium bicarbonate, and acetamylcysteine, and preferably, it may include Any one or more selected from the group consisting of butylated hydroxyanisole and acetocysteine. Optimally, it may comprise acetamylcysteine.

In addition, the preferred pH range of the bortezomib liquid formulation is 4.0 to 6.0, and most preferably 4.0 to 5.0.

According to an embodiment of the invention, the formulation is a liquid formulation that can be stored in a solution, which is more preferably contained in a sealed container in a ready-to-use form.

The concentration of bortezomib in the ready-to-use injectable formulation is preferably 1 mg / ml to 5 mg / ml.

In addition, depending on the volume of the head space of the container, the amount of oxygen in the head space is preferably 3 vol% or less. The amount of oxygen can be controlled by replacing the oxygen in the headspace with an inert gas. The inert gas may be nitrogen or argon.

When the bortezomib formulation as described above is stored at 25 ° C. and 60% relative humidity for 3 months, the total degradation of bortezomib can be maintained at 2% or less.

Hereinafter, the present invention will be described in detail.

The bortezomib formulation according to the present invention contains bortezomib or a pharmaceutically acceptable salt thereof as an active ingredient. The bortezomib according to the present invention includes a pharmaceutically active drug or a drug that becomes pharmacologically active through a chemical or enzymatic process in vivo. In particular, the bortezomib used in the present invention may be the bortezomib drug itself or a pharmaceutically acceptable salt thereof.

As used herein, the term "bortezomib" refers to a compound named N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid, and the term refers particularly to the formula 1 and 26S proteasome inhibitor approved for the treatment of recurrent multiple myeloma and mantle cell lymphoma. Equation 1

As used herein, the term "pharmaceutically acceptable salt" refers to a salt prepared according to conventional methods known in the art, and this method of preparation is known to those skilled in the art. Pharmaceutically acceptable salts include, but are not limited to, salts derived from pharmacologically or physiologically acceptable inorganic acids, organic acids, and bases. Examples of suitable acids include hydrochloric acid, bromic acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid , Toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases include, but are not limited to, salts of alkali metals such as sodium and potassium and salts of alkaline earth metals such as magnesium.

As used herein, the term "sugar alcohol" refers to erythritol, mannitol, maltitol, isomalt, sorbitol, xylitol, trehalose and the like as an excipient, and These formulations are often used in the study of injectable formulations.

Excipients used in conventional injectable formulations are mannitol, sorbitol, sucrose, trehalose, lactose, glucose, erythritol, maltitol, maltose, xylitol, sodium gluconate, Magnesium gluconate, calcium gluconate, iron gluconate, white sugar, starch, corn starch, potato starch, sodium carboxymethyl cellulose, ethyl cellulose, cyclodextrin, dextrose, hydroxypropyl β- Cyclodextrin and its analogs.

The formulation according to the invention may comprise, as an excipient, a sugar alcohol selected from the group consisting of: mannitol, erythritol, sorbitol, isomalt, trehalose, maltitol, xylitol and the like mixture. More preferably, it may include a sugar alcohol selected from the group consisting of mannitol, erythritol, isomalt, and maltitol. Optimally it may comprise mannitol.

The bortezomib formulation according to the present invention uses the sugar alcohols described above, making it possible to stably store bortezomib or a pharmaceutically acceptable salt thereof for a long period of time.

In the bortezomib formulation according to the present invention, the ratio of the concentration of bortezomib or its pharmaceutically acceptable salt: sugar alcohol is preferably 1:10 to 60 (w / w), more preferably 1: 20 to 60. In this case, each concentration can be expressed in units of mg / mL.

The stabilizers and antioxidants used in conventional injectable formulations are β-carotene, glycine, gallic acid, thimerosal, EDTA, paraben derivatives, phenol derivatives, alcohols, retinol , Tocopherol, TPGS, acetic anhydride, sodium carboxylate, dodecyl sulfate, cysteamine, cystine, cysteine, amino acids, organic acids such as ascorbic acid, sulfide compounds, sulfites, Butylated hydroxyanisole, butylated hydroxytoluene, and the like.

The present invention may include, as an antioxidant, any one or more selected from the group consisting of butylated hydroxyanisole, sodium bicarbonate, and acetocysteine. More preferably, it may comprise one or more selected from the group consisting of butylated hydroxyanisole and acetocysteine. Optimally, it may comprise acetamylcysteine.

As used herein, the term "ethanylcysteine" refers to a compound named N-ethanyl-L-cysteine (NAC, C ₅ H ₉ NO ₃ S, CAS No. 616-91- 1) It is used as an antioxidant in the bortezomib formulation of the present invention. In the present invention, "ethanylcysteine" and "N-ethanyl-L-cysteine" are used interchangeably with each other.

In the present invention, the bortezomib formulation is preferably a liquid formulation that can be stored in a solution, and more preferably, it can be an injectable liquid formulation contained in a sealed container for immediate use.

In the present invention, the bortezomib formulation may include a pharmaceutically acceptable carrier and a pH adjusting agent.

The bortezomib formulation according to the present invention may further include a pharmaceutically acceptable excipient, and examples of the pharmaceutically acceptable excipient include lactose, dextrose, cyclodextrin and its derivatives, sucrose , Glycerol, sodium carbonate, citric acid, mannitol and the like.

In the present invention, the bortezomib formulation may comprise a solvent system comprising a mixture of propylene glycol and a polar solvent such as water. The polar solvent is preferably an FDA-approved injectable solvent.

In the present invention, the pH of the bortezomib injectable liquid formulation may preferably be about 4.0 to 6.0, more preferably about 4.0 to 5.0. The pH of the liquid formulation can be adjusted using acids such as hydrochloric acid or bases such as sodium hydroxide.

The bortezomib formulations of the invention can be prepared by purging with an inert gas such as nitrogen or argon, followed by filtration.

Furthermore, the bortezomib formulations of the present invention may be packaged in suitable containers known in the art. For example, the container may be a glass vial, a glass bottle, a cartridge, a pre-filled syringe, or the like, and preferably, the container may be a glass vial. More preferably, the container may be a light-resistant glass vial.

The injectable liquid formulation of bortezomib according to the invention is dispensed in a previously washed and sterilized container, and the container is sealed with a Teflon plug whose surface does not react with the liquid formulation. If necessary, the space between the injectable liquid formulation and the plug is filled with an inert gas. The stopper is attached using a crimping device, and then, if necessary, the vial filled with the injectable liquid formulation is heated and sterilized.

In the present invention, stability tests are performed on bortezomib formulations containing various additives or excipients. As a result, it was found that most additives or excipients do not improve the stability of the formulation but cause problems such as precipitation or discoloration.

However, unexpectedly, the present inventors found that when a solvent including propylene glycol is used as a solvent and a sugar alcohol is used as an excipient, the total impurity content of the formulation within 3 months under the condition of 25 ° C / RH60% stability Keeping it at 2% or less, without discoloration or precipitation, indicates that the formulation has stability that meets the standards. In addition, propylene glycol and sugar alcohol are both commonly used materials and are also advantageous in commercial terms due to their lower prices.

According to the present invention, it is possible to provide a bortezomib formulation that is easy to prepare commercially, can prevent microbial contamination that may occur during lyophilization and reduction, and has improved ease of administration and stability. In addition, by using sugar alcohols and propylene glycol, the present invention can provide stable bortezomib formulations, which are different from conventional bortezomib-containing injectable liquid formulations, which do not show abnormalities such as discoloration or precipitation and meet the standards.

Hereinafter, the present invention will be described in more detail with reference to examples. It should be understood, however, that these examples are for illustrative purposes only and are not intended to limit the scope of the invention.

Formulation examples 1 to 24

Liquid formulations were prepared according to the composition shown in Table 1 below. An acetate buffer was prepared, and propylene glycol and acetate buffer were mixed at a ratio of 60:40 (%) to 40:60 (%), and the mixture was used as a solvent. Dissolve mannitol as an excipient. However, in Formulation Example 4, water for injection (WFI) was used instead of the acetate buffer, thereby preparing a solvent mixture containing propylene glycol. In Formulation Examples 1, 2, 5, and 6, nitrogen substitution was performed.

In addition, a liquid formulation was prepared according to the composition shown in Table 2 below. Propylene glycol and acetate buffer mixed at a ratio of 60:40 (%) to 40:60 (%) were used as solvents, and mannitol, erythritol, maltitol, trehalose, sorbitol, isopropyl alcohol Maltitol or xylitol is dissolved in the solvent as an excipient. Nitrogen replacement was performed, and a light-resistant vial was used as a container for storing a sample.

The results of the stability evaluations of Formulation Examples 1 to 6 are shown in Table 3 below. The stability test conditions are 5 ° C and 25 ° C / RH60%. After 21 days of storage in a closed chamber, the total impurity content of each formulation was evaluated.

Compared to the total impurities (%) of Formulation # 002 without mannitol, the total impurities (%) of Formulation # 001 containing mannitol is reduced by about 50%.

When comparing Formulation # 005 and Formulation # 006, the total impurities (%) of Formulation # 005 containing 3 times the amount of mannitol are reduced by about 50% compared to the total impurities (%) of Formulation # 006. .

When comparing Preparation # 001 and Preparation # 003, the total impurity (%) of the headspace of the container replaced with nitrogen # 003 is significantly lower than the total impurities (%) of the preparation # 001 without nitrogen replacement.

In Formulation # 003 and Formulation # 004, the total impurity content of Formulation # 003 using acetate buffer was lower than the total impurity content of Formulation # 004 using water for injection.

The results of the stability evaluations of Formulation Examples 7 to 24 are shown in Table 4 below. The stability test conditions were ①40 ° C / RH75% and ②60 ° C / RH80%, and the total impurity content of each formulation was evaluated after storage in a closed room for 10 days. Table 4

It can be seen from the stability results in Table 4 above that most of the formulations containing sugar alcohols show excellent stability (as opposed to the stability evaluation results of formulation # 002).

Formulation Examples 25 to 35 prepared liquid formulations according to the composition shown in Table 5 below. Propylene glycol and acetate buffer or water for injection were mixed with each other at a ratio of 60:40 (%), and the mixture was used as a solvent, and mannitol was dissolved in the solvent as an excipient. The formulations were adjusted to different pHs in the pH range 2.0 to 8.0. Table 5

The results of the stability evaluation are shown in Table 6. The stability test conditions are ① 5 ℃ and ② 25 ℃ / RH60%. The formulations were stored under conditions ① and ② for 21 days (# 007 to # 011) or 33 days (# 012 to # 019), and the total impurity content of each formulation was then evaluated. Table 6

It can be seen from the stability results that formulations with a pH in the range of 4.0 to 6.0 show a low impurity content (%), indicating that they are stable.

From the results of formulation # 033 to formulation # 035, it can be seen that the use of acetate buffer is superior to the use of water for injection in terms of total impurities (%).

Formulation examples 36 to 63

Liquid formulations were prepared according to the composition shown in Table 7 below. A mixture of propylene glycol and acetate buffer mixed at a ratio of 40:60 (%) was used as a solvent, and mannitol, maltitol, or isomalt was dissolved in the solvent as an excipient. In addition, ascorbic acid, sodium bisulfite, butylated hydroxyanisole, sodium bicarbonate, sodium metabisulfite, or N-acetamido-L-cysteine is added. Nitrogen replacement was performed, and a light-resistant vial was used as a container for storing a sample.

The results of the stability tests of the compositions described above are shown in Table 8. The stability test conditions are 5 ° C and 25 ° C / RH60%. The formulations # 036 to # 063 were stored in a closed room for 30 days, and the total impurity content of each formulation was then evaluated.

table 8

As can be seen from the stability results in Table 8 above, formulation samples (# 036, # 043, # 050, and # 057) containing ascorbic acid as an antioxidant in addition to sugar alcohols showed the highest total impurity content (%). In addition, for samples of formulations containing sodium bisulfite (# 037, # 044, # 051, and # 058) and samples of formulations containing sodium metabisulfite (# 040, # 047, # 054, and # 061), peaks could not be detected Quantitative. This seems to be attributable to the chemical reaction with the active ingredient bortezomib.

However, under long-term conditions of 25 ° C / RH60%, samples containing butylated hydroxyanisole, sodium bicarbonate, or acetamylcysteine showed a total impurity content of about 1% or less.

The conclusion is that it is preferred to use butylated hydroxyanisole, sodium bicarbonate or acetamylcysteine as the antioxidant, and more preferably, butylated hydroxyanisole or acetamylcysteine is preferred .

Comparative Examples 64 and 65 In Table 9, Formulation # 064 is a Velcade ( ^R) injection (Janssen Korea Ltd.) sold as a lyophilized formulation, and Formulation # 065 is a ready-to-use injection prepared by reducing Velcade ( ^R ) injection. Formulation (Janssen Korea Ltd.). Table 9

The results of the stability tests of the formulations shown in Table 9 above are shown in Table 10. The stability test conditions are ① 5 ℃ and ② 25 ℃ / RH60%. Under conditions ① and ②, the formulations were stored in a closed room for 3 months, and the total impurity content of each formulation was then evaluated. Table 10

Claims (12)

A liquid formulation of bortezomib comprising bortezomib or a pharmaceutically acceptable salt thereof; one or more excipients selected from the group consisting of: mannitol, erythritol, Sorbitol, isomalt, maltitol, xylitol and trehalose; and solvents containing a mixture of propylene glycol and a polar solvent including water. The liquid formulation of bortezomib as claimed in claim 1, wherein the ratio of bortezomib or a pharmaceutically acceptable salt thereof: excipient (w / w) is 1:10 to 60. A liquid formulation of bortezomib as claimed in claim 2, wherein the ratio (w / w) is 1:20 to 60. The liquid formulation of bortezomib according to claim 1, wherein the excipient is any sugar alcohol selected from the group consisting of mannitol, erythritol, isomalt and maltitol. The liquid formulation of bortezomib as claimed in claim 1, wherein the propylene glycol is contained in the mixture solvent in an amount of 40 to 60 vol% based on the total volume of the solvent. The liquid formulation of bortezomib as claimed in claim 1, wherein the pH of the liquid formulation of bortezomib is 4.0 to 6.0. The liquid formulation of bortezomib according to claim 1, wherein the liquid formulation of bortezomib comprises any one or more antibodies selected from the group consisting of butylated hydroxyanisole, sodium bicarbonate, and acetamylcysteine Oxidant. A liquid formulation of bortezomib as claimed in claim 1, wherein the formulation is contained in a sealed container in a ready-to-use form. The liquid formulation of bortezomib as claimed in claim 8, wherein the concentration of bortezomib in the ready-to-use form is 1 mg / ml to 5 mg / ml. For example, the liquid formulation of bortezomib of claim 8, wherein the amount of oxygen in the headspace of the container is 3v / v% or less based on the volume of the headspace. A liquid formulation of bortezomib as claimed in claim 10, wherein the amount of oxygen is controlled by replacing the oxygen in the headspace with an inert gas. The liquid formulation of bortezomib as claimed in claim 11, wherein the inert gas is nitrogen or argon.