KR101807462B1 - Stable formulation comprising bortezomib, and its preparation method - Google Patents

Abstract

The present invention relates to a bortezomib liquid formulation which contains a solvent formed by mixing: 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 polar solvent containing propylene glycol and water. The bortezomib liquid formulation of the present invention can be easily applied to commercial production, prevents microbial fouling that occurs during freeze-drying or reconstitution, and shows the functional effects of increasing convenience of administration and stability. Further, by using sugar alcohols and propylene glycol, the bortezomib liquid formulation of the present invention does not exhibit discoloration or formation of precipitate, compared to a conventional bortezomib-containing injectable liquid preparation, and is appropriate for the standard.

Description

[0001] The present invention relates to a stable preparation comprising bortezomib and a preparation method thereof,

The present invention relates to a stable preparation containing bortezomib and a preparation method thereof, and more particularly, to a liquid preparation containing bortezomib having excellent stability and a method for producing the same.

Bortezomib, used in recurrent multiple myeloma, is characterized by the fact that the boron atom of the compound binds to the catalytic site of the proteasome, ultimately leading to proteasome inhibition and degradation of the pro-apoptotic factor , Which in turn is thought to trigger apoptosis of the treated cells.

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

The Velcade ^TM is in the form of freeze-dried preparation to be reconstituted prior to administration, that is, and reconstructed with 0.9% sodium chloride solution, upon administration to a patient, diluted concentration of 2.5 mg / ml (iv) with 1.0 mg / ml (sc) to a final concentration (3.5 mg) in the form of a freeze-dried powder.

However, formulations in the form of lyophilized powders are complex in their manufacturing process and require high processing costs. In addition, there is a risk of contamination by microorganisms upon reconstitution of the lyophilized preparation, and pharmacists, doctors, nurses, and the like involved in the preparation of the drug are likely to be exposed to the cell destruction materials. Therefore, in the case of cytotoxic anticancer drugs such as bortezomib, it is necessary to develop a ready-to-use liquid formulation which can be stored for a long period of time rather than a freeze-dried formulation.

However, the biggest problem of liquid formulations is stability during storage period. Due to this stability problem, many injections are used in the form of lyophilized preparations which are used by dissolving immediately prior to injection. Even in the case of bortezomib or its pharmacologically acceptable salt, which is started to be provided as a lyophilized formulation, the preparation of an aqueous solution increases the amount of unknown suppositories and has a problem of stability that can not be stored at room temperature for a long period of time. Because of this stability problem, it is currently being used as a lyophilized formulation in clinical practice.

The instability of bortezomib in such a liquid state has been reported in various literatures. In the case of bortezomib, however, compounds containing aminoalkylboronic acids are subject to spontaneous 1,3-rearrangement due to the instability of the free alpha-amino groups, providing homologous amines and by decomposition thereof, boric acid and alcohols Respectively. This instability leads to an oxidative reaction that easily destroys longer and weaker CB bonds than CC bonds. This instability is responsible for the inherent instability of bortezomib in aqueous stock solutions. For example, among ethanol: normal saline solution (2:98, pH 2.8), bortezomib (0.5 mg / ml) was 20% degraded within six months when stored at 25. In addition, the self-PEG300, creating a peroxide-known to cause an oxidation _{reaction, PEG300: EtOH: H 2 O} (40:10:50) decomposition of Börte jomip in solvents been assumed by the peroxide.

In other studies, bortezomib is vulnerable to oxidative degradation under a number of experimental conditions, and the oxidation of alkylborane (which forms an ester of boric acid) also inhibits the formation of 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, and may be caused by mild metal ions, and Alkali conditions generally promote oxidation. Therefore, these conditions are considered unlikely to be advantageous for 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).

U.S. Patent Nos. 7119080, 6713446, 6958319, 6747150, and 6297217 disclose the diester formation of boronic acid functional groups with mannitol after lyophilization. From the ester thus formed, the active boronic acid is obtained upon reconstitution of the drug product in the saline solution for injection. Similarly, attempts to form esters of beta-carboxylic acids and alpha-hydroxy boronic acids, such as citric acid 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 approach tends to resolve the problems associated with bortezomib stability, but the reconstituted unused solution must be injected within hours or days (see, for example, 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, bortezomib ester of mannitol is only suitable for being administered within 8 hours if stored at room temperature.

Further known methods include separation 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 ingredients is disclosed in WO2010039762A2. Unfortunately, all or nearly all of these known compositions do not provide significant stability to bortezomib, especially when the formulation is a liquid formulation.

Thus, although there are many formulations for bortezomib known in the art, all or almost all such formulations have limited stability when bortezomib is present in solution. As a result, recently used products do not provide flexibility of dosing and do not allow multi-dose formulations with extended stability in particular. In addition, it contains an excessive amount of solubilizing agent such as propylene glycol, which may cause side effects to the body. Thus, there is still a need to provide improved alternative bortezomib formulations that contain more stable and biostable components at the same time.

Under these circumstances, the inventors of the present invention have conducted extensive studies, and as a result, they have found that a bortezomip liquid preparation having excellent stability is obtained by using a mixed solvent having high biocompatibility due to a high polar solvent ratio.

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

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

In order to solve the above-described problems, the present invention provides a pharmaceutical composition comprising as an active ingredient, a solvent composed of bortezomib or a pharmaceutically acceptable salt thereof, a polar solvent containing propylene glycol and water, mannitol, erythritol, sorbitol, isomalt , At least one sugar alcohol selected from the group consisting of maltitol, xylitol, and trehalose.

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

The solvent system of the present invention can be a polar solvent containing water in an amount of 40 vol% or more, more specifically 40 vol.% To 60 vol.%, And even when a polar solvent, more specifically water, If the formulation according to the invention is stored for 3 months at 25 ° C / RH 60%, the degradation rate of bortezomib may be reduced to less than 2% in total.

The bortezomib liquid formulation may contain any one or more selected from the group consisting of butylated hydroxyanisole, sodium hydrogencarbonate, and acetylcysteine as an antioxidant, preferably butylated hydroxyanisole, Acetylcysteine, and the like. And most preferably acetylcysteine.

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

According to one embodiment of the present invention, it is more preferred that the preparation is contained in a ready-to-use sealed container as a liquid preparation which can be stored in a solution state.

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

Also, it is preferable that the oxygen amount in the head space in the vessel is 3 v / v% or less with respect to the head space volume, and the oxygen amount can be controlled by replacing oxygen in the head space with an inert gas. The inert gas may be nitrogen or argon.

Such bortezomib preparations can maintain bortezomib decomposition below 2% total when stored at 25 ° C / RH 60% for 3 months.

Hereinafter, the present invention will be described in detail.

The bortezomib agents of the present invention comprise bortezomib or a pharmaceutically acceptable salt thereof as an active ingredient. The bortezomib according to the present invention may be pharmacologically effective or include a pharmacologically effective drug by an in-body chemical or enzymatic method. Specifically, the bortezomib drug itself or a pharmaceutically acceptable salt thereof may be used .

The term "bortezomib" used in the present invention means a compound having the name "(N- (2-pyrazine) carbonyl-L-phenylalanine-L-leucine boronic acid" Quot; means < / RTI > a 26S proteasome inhibitor approved for use in the treatment of recurrent multiple myeloma and omentum cell lymphoma.

[Chemical Formula 1]

As used herein, the term "pharmaceutically acceptable salt" refers to salts prepared according to methods conventional in the art, and such methods of preparation are known to those skilled in the art. In particular, the pharmaceutically acceptable salts include, but are not limited to, salts derived from inorganic and organic acids and bases, which are pharmacologically or physiologically acceptable. Examples of suitable acids include hydrochloric acid, hydrobromic 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, 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" is an excipient that is commonly used in injection drug formulation studies, including erythritol, mannitol, maltitol, isomalt, sorbitol, xylitol and trehalose.

Conventional excipients used in injectable preparations include mannitol, sorbitol, sucrose, trehalose, lactose, glucose, erythritol, maltitol, maltose, xylitol, sodium gluconate, magnesium gluconate, calcium gluconate, Starch, corn starch, potato starch, sodium carboxymethylcellulose, ethylcellulose, cyclodextrin, dextrose, hydroxypropylbetacyclodextrin, and the like.

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

The bortezomib formulation of the present invention can be stably stored for a prolonged period of time using pharmacologically acceptable salts of bortezomib or its pharmaceutically acceptable salts using the above "sugar alcohols".

In the present invention, the bortezomib agent is preferable when the concentration ratio of bortezomib or pharmaceutically acceptable salt thereof: sugar alcohol is 1:10 to 60 (w / w), and particularly, the concentration ratio is 1:20 to 60 Is more preferable. At this time, the unit of each concentration may be mg / mL.

Examples of the stabilizer and antioxidant that have been conventionally used in the injectable preparations include antioxidants such as beta-carotene, glycine, gallic acid, thimerosal, EDTA, parahydroxybenzoic acid ester derivatives, phenol derivatives, alcohols, retinol, tocopherol, TPGS, acetic anhydride, sodium carboxylate, lauryl sulfate, cysteamine, ), Cystine, cystein, amino acids, organic acids such as ascorbic acid, sulfide compounds, sulfite, butylated hydroxyanilide Butylated hydroxyanisole, butylated hydroxytoluene, and the like.

In the present invention, the antioxidant may include at least one selected from the group consisting of butylated hydroxyanisole, sodium hydrogencarbonate, and acetylcysteine. More preferably, butylated hydroxyanisole, and acetylcysteine. And most preferably acetylcysteine.

As used herein, the term "acetylcysteine" refers to a compound having the name N-Acetyl-L-Cysteine (NAC, C5H9NO3S, CAS number 616-91-1) Means a compound used as an antioxidant in bortezomib preparations. In the present invention, "acetylcysteine" and "N-acetyl-L-cysteine"

In the present invention, the bortezomib agent is preferably a liquid preparation that can be stored in a solution state, and more preferably, it may be a liquid formulation for injection in a sealed container ready-to-use .

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

The bortezomib agent of the present invention may further include a pharmaceutically acceptable excipient such as lactose, dextrose, cyclodextrin and its derivatives, sucrose, glycerol, sodium carbonate, citric acid, mannitol and the like.

In the present invention, the bortezomib agent may include a solvent composed of a mixture of propylene glycol and a polar solvent such as water.

In the present invention, the pH of the liquid formulation for bortezomib can be preferably about 4.0 to 6.0, more preferably about 4.0 to 5.0. The pH of the solution can be adjusted by using an acid such as hydrochloric acid or a base such as sodium hydroxide.

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

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

The liquid formulation for use with the present invention is dispensed in a pre-cleaned container and the surface of the cap suitable for the container is sealed with a Teflon stopper that is inert to the liquid formulation containing the bortezomib. At this time, if necessary, a space between the injectable liquid preparation and the plug is filled with an inert gas. After attaching the stopper using a crimper, the vial filled with injectable liquid formulation is sterilized by heating if necessary.

In the present invention, a stabilization test of the bortezomib formulation of the injection formulation was carried out on various additives or excipients. As a result, it was confirmed that most of the additives or excipients did not improve stability, but rather caused problems such as precipitation and discoloration.

Surprisingly, however, the inventors of the present invention found that when a solvent containing propylene glycol was used as a solvent and sugar alcohol was used as an excipient, the total amount of the flexible substance was maintained at less than 2% for 3 months under the condition of 25 ° C / RH 60% Or sediment is not generated, and thus has stability suitable for the standard. In addition, propylene glycol and sugar alcohol are all commonly used, and their low price is also advantageous in terms of commerciality.

The present invention can provide a bortezomib formulation that is easy to manufacture commercially, can prevent microbial contamination during freeze-drying or reconstitution, and is improved in dosage convenience and stability. Further, by using the sugar alcohol and propylene glycol, it is possible to provide a stabilized bortezomib agent suitable for the standard without any abnormalities such as discoloration or precipitate generation as compared with the conventional liquid agent for bortezomib containing main use.

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

[ Formulation example  1 to 24]

Liquid preparations were prepared according to the prescriptions shown in Table 1 below. Acetate buffer solution was prepared, and then the composition ratio of propylene glycol and acetate buffer was mixed at 60:40 (%) to 40:60 (%) and used as a solvent. The excipient was prepared by dissolving mannitol. However, in Formulation Example 4, a mixed solvent containing propylene glycol was prepared by replacing the acetate buffer solution with water for injection (WFI). Nitrogen substitution was carried out on Formulation Examples 1, 2, 5 and 6.

[Table 1]

Liquid formulations were also prepared according to the prescriptions shown in Table 2 below. As the solvent, the composition ratio of propylene glycol and acetate buffer was used in a ratio of 60:40 (%) to 40:60 (%). As the excipient, mannitol, erythritol, maltitol, trehalose, sorbitol, isomalt Was prepared by dissolving xylitol. Nitrogen substitution was carried out and a shading vial was used as a container for storing the specimen.

[Table 2]

The stability evaluation results for Formulation Examples 1 to 6 are shown in Table 3. The stability test conditions are ① 5 ℃, ② 25 ℃ / RH 60%. After storage in the closed for 21 days, the total flexible material was evaluated.

[Table 3]

Compared to # 002 which did not contain mannitol, the total amount of the suppository (%) of # 001 added with mannitol was reduced by about 50%.

When comparing # 005 and # 006, the total soft matter (%) of # 005 added with 3 times more mannitol was reduced by about 50% than # 006.

When comparing # 001 and # 003, it was confirmed that the total amount of the flexible substance (%) was significantly lower than that of # 001 in which nitrogen in the in-vessel head space was replaced by nitrogen.

In # 003 and # 004, the total flexible material in # 003 using acetate buffer was lower than in # 004 using 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 / RH 75%, (2) 60 ° C / RH 80%, and were evaluated for total flexible materials after being stored in a stability chamber for 10 days.

[Table 4]

From the stability results in Table 4, it can be seen that when the sugar alcohol is included, the overall stability is excellent (in contrast to the stability evaluation result of # 002).

[ Formulation example  25 to 35]

Liquid formulations were prepared as in the prescription shown in Table 5 below. Propylene glycol and acetate buffer or water for injection were mixed at a composition ratio of 60:40 (%) to prepare a solvent, which was 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.

[Table 5]

The stability evaluation results are shown in Table 6 below. The stability test conditions are ① 5 ℃, ② 25 ℃ / RH 60%. ① and ② were stored in a closed chamber for 21 days (# 007 ~ 011) or 33 days (# 012 ~ 019) and then evaluated for total flexible materials.

[Table 6]

From the stability results, it was confirmed that the total soft matter (%) was low and stable in a formulation having a pH ranging from 4.0 to 6.0.

From the results of # 033 to # 035, it can be seen that the use of the acetate buffer is more advantageous than the use of the injection water in terms of the total flexible substance (%).

[ Formulation example  36 to 63]

Liquid formulations were prepared as in the prescription shown in Table 7 below. Propylene glycol and acetate buffer were mixed as a solvent at a composition ratio of 40:60 (%), and mannitol, maltitol or isomalt was dissolved as an excipient. In addition, ascorbic acid, sodium hydrogen sulfite, butylated hydroxyanisole, sodium hydrogen carbonate, sodium pyrophosphate or N-acetyl-L-cysteine were added. Nitrogen substitution was carried out, and a shading vial was used as a container for storage.

[Table 7]

The stability test results for the above-described compositions are shown in Table 8. The stability test conditions are ① 5 ℃, ② 25 ℃ / RH 60%. # 036 to # 063 were evaluated for total flexible materials after storage for 30 days in a stability chamber (closed).

[Table 8]

The stability results in Table 8 confirm that the samples using ascorbic acid (# 036, # 043, # 050, # 057) as antioxidants in all sugar alcohol prescriptions exhibited the highest total level of the flexible substance . In addition, when sodium bisulfite (# 037, # 044, # 051, # 058) and sodium pyrousulfate (# 040, # 047, # 054, # 061) were used, peak quantification could not be performed in all samples. This seems to be due to a chemical reaction with the active substance, bortezomib.

However, specimens using butylated hydroxyanisole, sodium hydrogencarbonate, or acetylcysteine showed total solids content of about 1% or less at 25 ° C / RH 60%, which is a long term condition.

Consequently, it is preferable to use butylated hydroxyanisole, sodium hydrogencarbonate, or acetylcysteine as an antioxidant, more preferably butylated hydroxyanisole or acetylcysteine.

[ Control Example  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.

[Table 9]

The stability test results for the compositions described above are shown in Table 10. The stability test conditions are ① 5 ℃, ② 25 ℃ / RH 60%. (1) and (2) were stored in a stability chamber for 3 months and evaluated for total flexible materials.

[Table 10]

Claims (13)

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
Propylene glycol and a polar solvent containing water. ≪ RTI ID = 0.0 > 18. < / RTI > The bortezomib liquid formulation according to claim 1, wherein the ratio (w / w) of bortezomib or its pharmaceutically acceptable salt: sugar alcohol is 1: 10-60. The bortezomib liquid formulation according to claim 2, wherein the ratio (w / w) is 1:20 to 60. The bortezomib liquid formulation according to claim 1, wherein the sugar alcohol is any one selected from mannitol, erythritol, isomalt, and maltitol. The bortezomib liquid formulation according to claim 1, wherein propylene glycol in the mixed solvent is contained at 40 to 60% vol of the total solvent. The bortezomib liquid formulation according to claim 1, wherein the pH range of the bortezomib liquid formulation is 4.0 to 6.0. The bortezomib liquid pharmaceutical preparation according to claim 1, wherein the bortezomib liquid formulation comprises at least one selected from the group consisting of butylated hydroxyanisole, sodium hydrogencarbonate, and acetylcysteine as antioxidants. The bortezomib liquid formulation of claim 1, wherein the formulation is in a ready-to-use sealed container. The formulation according to claim 8, wherein the concentration of the immediate-use injection is from 1 mg / ml to 5 mg / ml. The bortezomib liquid formulation according to claim 8, wherein the amount of oxygen in the head space in the vessel is not more than 3 v / v% with respect to the head space volume. 11. The bortezomib liquid formulation of claim 10, wherein the amount of oxygen is regulated by displacing oxygen in the headspace with an inert gas. 12. The bortezomib liquid formulation according to claim 11, wherein the inert gas is nitrogen or argon. delete