WO2018164513A1 - Stable preparation containing bortezomib and preparation method therefor - Google Patents

Abstract

The present invention provides a bortezomib liquid preparation comprising: bortezomib or a pharmaceutically acceptable salt thereof; one or more sugar alcohols selected from the group consisting of mannitol, erythritol, sorbitol, isomalt, maltitol, xylitol and trehalose; and a solvent formed by mixing propylene glycol and polar solvents including water. The bortezomib liquid preparation of the present invention can be easily and commercially prepared, can prevent microbial contamination occurring during freeze-drying or reconstitution, exhibits an effect of improved administration convenience and stability, and since a sugar alcohol and propylene glycol are used, the ortezomib liquid preparation has no property abnormalities, such as discoloration or precipitate generation, in comparison with a conventional bortezomib-containing injectable liquid preparation, and meets standards.

Description

Stable formulation comprising bortezomib 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 liquid formulation containing bortezomib having excellent stability and a method for preparing the same.

Bortezomib used in relapsing multiple myeloma binds the boron atoms of the compound to the catalytic sites of the proteasome, ultimately inducing proteasome inhibition and reduced degradation of the pro-apoptotic factor. It is then believed to trigger apoptosis of the treated cells.

Currently, bortezomib {(N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid} has been developed as Velcade ^™ to treat several neoplastic diseases, in particular relapsing multiple It is a 26S proteasome inhibitor approved for use in the treatment of relapsed multiplemyeloma and mantle cell lymphoma.

The Belcade ^TM is reconstituted in the form of a lyophilized formulation that must be reconstituted prior to administration, i.e., 0.9% sodium chloride solution upon administration to the patient, with dilution concentrations of 2.5 mg / ml (iv) and 1.0 mg / ml (sc). It is commercially available in the form of a lyophilized powder (3.5 mg) form.

However, formulations in the form of lyophilized powders are complicated to manufacture and costly to process. In addition, there is a risk of contamination by microorganisms in the reconstitution of the lyophilized formulation, pharmacists, doctors, nurses, etc. involved in the preparation of the drug is a formulation that is likely to be exposed to cell disruption. Therefore, in the case of cytotoxic anticancer agents such as bortezomib, there is a need for the development of ready-to-use liquid formulations that can be stored for a long time rather than lyophilized formulations.

However, the biggest problem with liquid formulations is their stability during the storage period. Due to this stability problem, many injections are used in the form of lyophilized preparations which are dissolved and used immediately before injection. Bortezomib or its pharmacologically acceptable salts, which have begun to be provided as lyophilized formulations, also have a stability problem in that they can not be stored for a long time at room temperature due to an increase in unknown soft substances when prepared in aqueous solution. Bortezomib also has a long solubility in water (25 ° C.) of only 0.076 mg / ml in liquid form. However, Bortezomib is very unstable in liquid state, so even in the case of the currently lyophilized formulation, it is to be used within 8 hours after reconstitution with 0.9% NaCl. Due to this stability problem, it is currently being used as a lyophilized formulation in clinical practice.

Instability of bortezomib in this liquid state has been reported in several documents. The same applies to bortezomib, but compounds containing aminoalkylboronic acids, due to the instability of the free alpha-amino groups, cause spontaneous 1,3-rearrangement to give homologous amines, which break down boric acid and alcohols. Will be created. This instability results in an oxidative reaction that readily breaks longer and weaker CB bonds than CC bonds. This instability causes the bortezomib in the aqueous solution for injection to become essentially unstable. For example, in ethanol: normal saline solution (2:98, pH 2.8), Bortezomib (0.5 mg / ml) was 20% degraded within 6 months when stored at 25 ° C. In addition, PEG300 is known to cause a self-oxidation reaction to produce peroxides, and the degradation of Bortezomib in PEG300: EtOH: H ₂ O (40:10:50) solvents was assumed to be by peroxides.

In other studies, bortezomib is susceptible to oxidative degradation under a number of experimental conditions, and oxidation of alkyl boranes, which form esters of boric acid, can also be combined with alkyl peracids, alkyl peroxides, or oxygen radical species. (Brown HC. 1972. Boranes in organic chemistry. Ithaca, NY: Cornell University Press.) Initial oxidation may be due to peroxide or molecular oxygen, light metal ions, and Alkali conditions generally promote oxidation. Thus, these conditions are not considered to be beneficial for the stability of bortezomib or any other alkyl boronic acid derivatives (Hussain MA, Knabb R, AungustBJ, Kettner C.1991. Anticoagulant activity of a peptide boronicacid thrombin inhibitor by various routes of administration in rats.Peptide 12: 1153-1154).

U.S. Pat.Nos.7119080,6713446,6958319,6747150, and 6297217 disclose diester formation with mannitol of boronic acid functional groups after lyophilization. From the ester thus formed, active boronic acid is obtained upon reconstitution of the drug product in saline for injection. Similarly, attempts to form esters of boronic acid with beta-carboxylic acids such as citric acid and alpha-hydroxy with bulking agents and buffers are disclosed in WO 2009/154737.

To avoid problems with the stability of Bortezomib in solution, the compound can be lyophilized and reconstituted prior to injection. However, this method tends to solve the problems associated with Bortezomib stability, but the reconstituted unused solution should be injected within hours or days (see, eg, Stability of unused reconstituted bortezomib in original manufacturer vials; J Oncol Pharm Pract. 2010 Oct 6, or Stability of bortezomib 1-mg / mL solution in plastic syringe and glass vial; Ann Pharmacother. 2005 Sep; 39 (9): 1462-6). Similarly, if reconstituted, the Bortezomib ester of mannitol is only suitable for administration within 8 hours if stored at room temperature.

Further known methods include isolation of specific polymorphic forms with improved stability as disclosed in WO2008075376A1, and lyophilized forms with tromethamine as disclosed in WO2010089768A2. Another formulation with selected organic solvents and other components is disclosed in WO2010039762A2. Unfortunately, all or almost all of these known compositions do not provide significant stability to Bortezomib, especially when the formulation is a liquid formulation.

Thus, despite the large number of formulations for Bortezomib known in the art, all or almost all such formulations have limited stability when Bortezomib is in solution. As a result, recently used products do not provide flexibility of dosing, and in particular do not allow for multi-dose formulations with extended stability. It also contains an excess of dissolution aids such as propylene glycol, which can cause side effects on the body. Thus, there is still a need to provide improved alternative bortezomib formulations containing more stable and at the same time highly biostable components.

Under these circumstances, the present inventors have conducted extensive research, and have prepared a bortezomib liquid formulation having excellent stability while using a mixed solvent having a high biocompatibility with a high proportion of polar solvents.

It is an object of the present invention to provide a stabilized bortezomib formulation.

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

In order to solve the above problems, the present invention is a solvent, mannitol, erythritol, sorbitol, isomalt composed of a polar solvent comprising bortezomib or a pharmaceutically acceptable salt thereof, propylene glycol and water as an active ingredient To provide a bortezomib liquid formulation comprising at least one sugar alcohol selected from the group consisting of, maltitol, ziritol, and trehalose.

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

The solvent system of the present invention may be 40 vol% or more, more specifically 40 vol% to 60 vol% of a polar solvent comprising water, and even in the case of containing a polar solvent, more specifically water in such a content, When the formulation according to the invention is stored for 3 months at 25 ° C./RH 60%, the degradation rate of bortezomib can be reduced to a total of 2.5% or less, preferably 2% or less.

The bortezomib liquid formulation may include any one or more selected from the group consisting of butylated hydroxyanisole, sodium hydrogen carbonate, and acetylcysteine as an antioxidant, and preferably butylated hydroxyanisole, and It may include any one or more selected from the group consisting of acetylcysteine. Most preferably, acetylcysteine.

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

According to one embodiment of the invention, the preparation is more preferably in a ready-to-use sealed container as a liquid preparation that can be stored in solution.

The concentration of the ready-to-use injection is preferably 1 mg / ml to 5 mg / ml.

In addition, the amount of oxygen in the headspace in the container is preferably 3 v / v% or less with respect to the volume of the headspace, the oxygen amount can be adjusted by replacing the oxygen in the headspace with an inert gas. The inert gas may be nitrogen or argon.

Bortezomib formulations such as above can maintain up to 2% total degradation of bortezomib when stored at 25 ° C./RH 60% for 3 months.

Hereinafter, the present invention will be described in detail.

Bortezomib formulations of the invention comprise Bortezomib or a pharmaceutically acceptable salt thereof as the active ingredient. The Bortezomib according to the present invention includes a pharmacologically effective drug or a pharmacologically effective drug by a chemical or enzymatic method in the body, and specifically, the Bortezomib drug itself or a pharmaceutically acceptable salt thereof may be used. .

As used herein, the term "bortezomib" is a compound having the name "(N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid", specifically, Denotes a 26S proteasome inhibitor approved for use in the treatment of recurrent multiple myeloma and mantle cell lymphoma.

As used herein, the term "pharmaceutically acceptable salts" refers to salts prepared according to methods conventional in the art, and such methods are known to those skilled in the art. Specifically, the pharmaceutically acceptable salts include, but are not limited to, salts derived from the following pharmacologically or physiologically acceptable inorganic and 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, methanesulfuric acid Phonic acid, formic acid, benzoic acid, malonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Salts derived from suitable bases may include, but are not limited to, alkali metals such as sodium or potassium, alkaline earth metals such as magnesium.

As used herein, the term “sugar alcohol” includes excipients such as erthritol, mannitol, maltitol, isomalt, sorbitol, xylitol, trehalose and the like, and is an excipient commonly used in injection formulation research.

Excipients conventionally used in injectable preparations include mannitol, sorbitol, sucrose, trehalose, lactose, glucose, erthritol, maltitol, maltose, xylitol, sodium gluconate, magnesium gluconate, calcium gluconate, iron gluconate, White sugar, starch, corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose, cyclodextrin, dextrose, hydroxypropyl beta cyclodextrin and the like.

In the present invention, an excipient may include a sugar alcohol selected from the group consisting of mannitol, erthritol, sorbitol, isomalt, trehalose, maltitol, xylitol, and mixtures thereof. More preferably, it may include a sugar alcohol selected from the group consisting of mannitol, erythritol, isomalt and maltitol. Most preferably, it may include mannitol.

Bortezomib formulations of the present invention, using the above "sugar alcohol", it is possible to stably store Bortezomib or a pharmaceutically acceptable salt thereof for a pharmaceutically long term.

In the present invention, the Bortezomib formulation is preferably when the concentration ratio of Bortezomib or its pharmaceutically acceptable salt: sugar alcohol is 1: 10 ~ 60 (w / w), in particular, the concentration ratio is 1: 20 ~ 60 More preferred. In this case, the unit of each concentration may be mg / mL.

In addition, stabilizers and antioxidants conventionally used in injectable preparations include beta carotene, glycine, gallic acid, thimerosal, EDTA, parahydroxybenzoic acid ester derivatives, phenol derivatives ( phenol derivatives, alcohols, retinol, tocopherol, TPGS, acetic anhydride, sodium carboxylate, lauryl sulfate, cysteamine ), Cystine, cysteine, amino acids, organic acids such as ascorbic acid, sulfide compounds, sulfite, sulfite, butylated hydroxyani Butylated hydroxyanisole, butylated hydroxytoluene, and the like.

In the present invention, the antioxidant may include any one or more selected from the group consisting of butylated hydroxyanisole, sodium hydrogen carbonate, and acetylcysteine. More preferably, at least one selected from the group consisting of butylated hydroxyanisole, and acetylcysteine. Most preferably, acetylcysteine.

As used herein, the term "acetylcysteine" is a compound having the name of N-acetyl-L-Cysteine (N-Acetyl-L-Cysteine, NAC, C5H9NO3S, CAS number616-91-1), Borte of the present invention By compound used as an antioxidant in zomib formulations. In the present invention, "acetylcysteine" and "N-acetyl-L-cysteine" are used interchangeably.

In the present invention, the Bortezomib formulation may preferably be a liquid formulation that can be stored in solution, and more preferably, may be a liquid formulation for injection in a sealed container ready-to-use. .

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

Bortezomib formulations of the present invention may further include pharmaceutically acceptable excipients, and examples thereof include lactose, dextrose, cyclodextrin and derivatives thereof, sucrose, glycerol, sodium carbonate, citric acid, mannitol and the like.

In the present invention, the bortezomib formulation may include a solvent composed by mixing a polar solvent such as propylene glycol and water. It is preferable that the said polar solvent corresponds to the solvent of the injection approved by FDA.

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 solution can be adjusted using an acid such as hydrochloric acid or a base such as sodium hydroxide.

Bortezomib formulation of the present invention may be prepared by purging with an inert gas such as nitrogen or argon and then filtered.

In addition, the Bortezomib formulations of the invention may be packaged in suitable containers known in the art. For example, suitable containers may be glass vials, vials, cartridges, pre-filled injections and the like, preferably glass vials. More preferably, it may be a light shielding glass vial.

The liquid formulation for injection of bortezomib of the present invention is dispensed in a pre-washed sterilized container, and the surface of the cap suitable for the container is sealed with a teflon plug which is inert to the liquid formulation for injection of bortezomib. At this time, if necessary, the space between the injectable liquid formulation and the stopper is filled with an inert gas. After the stopper is attached using a crimper, the vial filled with the liquid for injection is sterilized if necessary.

In the present invention, stabilization tests of Bortezomib formulations of injectable formulations were carried out on various additives or excipients. As a result, in the case of the majority of additives or excipients, not only the stability was improved but also the problem of precipitation or discoloration was confirmed.

Surprisingly, however, the inventors of the present invention used a solvent containing propylene glycol as a solvent and a sugar alcohol as an excipient, the total softening material was maintained at 2% or less and discolored for 3 months at 25 ° C / RH60% stability conditions. Or it was found that no sediment will occur to have stability that meets the criteria. In addition, both propylene glycol and sugar alcohols are generally used, and there is also an advantage of low commercial unit price.

The present invention can provide a Bortezomib formulation which is easy to manufacture commercially, can prevent microbial contamination accompanying freeze-drying or reconstitution, and has improved dosage convenience and stability. In addition, by using sugar alcohol and propylene glycol, it is possible to provide a stabilized bortezomib formulation that meets the criteria without abnormalities such as discoloration or deposit generation as compared to conventional bortezomib-containing injectable liquid formulations.

Hereinafter, the configuration and effects of the present invention through the embodiments will be described in more detail. These examples are only for illustrating the present invention, but the scope of the present invention is not limited by these examples.

[ Formulation example  1 to 24]

To prepare a liquid formulation according to the prescription shown in Table 1 below. After preparing an acetate buffer, the composition ratio of propylene glycol and acetate buffer solution was mixed at 60:40 (%) to 40:60 (%) and used as a solvent. An excipient was prepared by dissolving mannitol. However, in Preparation Example 4, a mixed solvent including propylene glycol was prepared by replacing acetate buffer with water for injection (WFI). Nitrogen substitution was performed about Formulation Examples 1, 2, 5, and 6.

In addition, liquid formulations were prepared according to the formulations set forth in Table 2 below. As a solvent, the composition ratio of propylene glycol and acetate buffer solution was used in a mixture of 60:40 (%) to 40:60 (%), and as excipients, mannitol, erythritol, maltitol, trehalose, sorbitol, isomalt or Prepared by dissolving xylitol. Nitrogen substitution was performed, and a light shielding vial was used as a container for storing the sample.

Table 3 shows the results of the stability evaluation for Formulation Examples 1 to 6. Stability test conditions are ① 5 ° C and ② 25 ° C / RH60%. After storage for 21 days in the chamber (closed), the total cast material was evaluated.

Compared to # 002 without the addition of mannitol, the total% of%% of 001 added mannitol was reduced by about 50%.

Compared with # 005 and # 006, the total% of the% related soft substance of # 005 with 3 times more mannitol was reduced by about 50% than # 006.

When comparing # 001 and # 003, it was confirmed that # 003, which was nitrogen-substituted in headspace, was significantly lower in total lead (%) than # 001 which was not nitrogen-substituted.

In # 003 and # 004, the total analog of # 003 with acetate buffer was lower than that of # 004 with water for injection.

The stability evaluation results for Formulation Examples 7 to 24 are shown in Table 4. The stability test conditions were ① 40 ° C./RH75%, ② 60 ° C./RH 80%, and were stored in the stability chamber for 10 days and then evaluated for the total flexible material.

Looking at the stability results of Table 4, it can be seen that the overall stability is excellent when the sugar alcohol is included (as opposed to the stability evaluation results of # 002).

[ Formulation example  25 to 35]

To prepare a liquid formulation as prescribed in the following Table 5. Propylene glycol and acetate buffer or water for injection were mixed in a composition ratio of 60:40 (%) and used as a solvent, and prepared by dissolving mannitol as an excipient. The pH was set differently for each formulation within the range of pH 2.0 to 8.0.

The stability evaluation results are shown in Table 6 below. Stability test conditions are ① 5 ℃, ② 25 ℃ / RH60%. ① and ② were stored in the chamber (closed) for 21 days (# 007 ~ 011) or 33 days (# 012 ~ 019), and then evaluated for the total flexible material.

In the stability results, it was confirmed that the total flexible material (%) in the formulation of the pH range 4.0 to 6.0 is low.

The results of # 033 ~ # 035 show that the use of acetate buffer is more advantageous than the use of water for injection in terms of the total% flexible.

[ Formulation example  36 to 63]

To prepare a liquid formulation as shown in the following Table 7. Propylene glycol and acetate buffer were used as a solvent in a composition ratio of 40:60 (%) and prepared by dissolving mannitol, maltitol or isomalt as excipients. In addition, ascorbic acid, sodium bisulfite, butylated hydroxyanisole, sodium bicarbonate, sodium pyrosulfite or N-acetyl-L-cysteine was added. Nitrogen substitution was performed, and a light-shielding vial was used as a container for storing.

The stability test results for the above described compositions are shown in Table 8. Stability test conditions are ① 5 ℃, ② 25 ℃ / RH60%. For # 036 to # 063, total lead was assessed after 30 days of storage in a stable chamber.

From the stability results of Table 8, it was confirmed that the sample using ascorbic acid (# 036, # 043, # 050, # 057) as the antioxidant in all sugar alcohol formulations showed the highest total level of analog (%). . In addition, peak quantification was not possible in all samples when sodium bisulfite (# 037, # 044, # 051, # 058) and sodium pyrosulfite (# 040, # 047, # 054, # 061) were used. This may be due to a chemical reaction with the active ingredient bortezomib.

However, samples using butylated hydroxyanisole, sodium hydrogen carbonate, or acetylcysteine showed a total softening material of approximately 1% or less at 25 ° C / RH60%, which is a long term condition.

In conclusion, it is preferable to use butylated hydroxyanisole, sodium hydrogen carbonate, or acetylcysteine as the antioxidant, more preferably, butylated hydroxyanisole or acetylcysteine.

[ Control  64 and 65]

In Table 9, # 064 is made of a Velcade ^ⓡ state (Janssen Korea ㈜) and # 065 is Velcade ⓡ main reconstruct (Janssen Korea ㈜) (reconstitution) ready-to-use type injection (ready-to-use) by the freeze-dried formulation It is.

The stability test results for the above described compositions are shown in Table 10. Stability test conditions are ① 5 ℃, ② 25 ℃ / RH60%. ① and ② were stored in a stable chamber for 3 months, and then evaluated for total flexible substances.

Claims (12)

1. Bortezomib or a pharmaceutically acceptable salt thereof;

   One or more sugar alcohols selected from the group consisting of mannitol, erythritol, sorbitol, isomalt, maltitol, xyitol, and trehalose; And

   Bortezomib liquid formulation containing a solvent comprising a polar solvent containing propylene glycol and water.
2. The bortezomib liquid formulation according to claim 1, wherein the bortezomib or a pharmaceutically acceptable salt thereof: sugar alcohol has a ratio of 1 to 10 to 60.
3. The bortezomib liquid formulation according to claim 2, wherein the ratio (w / w) is 1:20 to 60.
4. The bortezomib liquid formulation of claim 1, wherein the sugar alcohol is any one selected from mannitol, erythritol, isomalt, and maltitol.
5. According to claim 1, Bortezomib liquid formulation of the mixed solvent containing propylene glycol 40 to 60% vol of the total solvent.
6. The bortezomib liquid formulation of claim 1, wherein the pH of the bortezomib liquid formulation is 4.0 to 6.0.
7. The bortezomib liquid formulation of claim 1, wherein the bortezomib liquid formulation comprises at least one selected from the group consisting of butylated hydroxyanisole, sodium hydrogen carbonate, and acetylcysteine as an antioxidant.
8. The formulation of Bortezomib according to claim 1, wherein the formulation is in a sealed container ready-to-use.
9. 10. The liquid formulation of claim 8, wherein the concentration of the ready-to-use injection is 1 mg / ml-5 mg / ml.
10. 9. The Bortezomib liquid formulation according to claim 8, wherein the amount of oxygen in the headspace in the container is 3 v / v% or less with respect to the headspace volume.
11. 11. The bortezomib liquid formulation of claim 10, wherein the amount of oxygen is controlled by replacing oxygen in the headspace with an inert gas.
12. 12. The bortezomib liquid formulation of claim 11, wherein the inert gas is nitrogen or argon.