WO2012161520A2 - Injectable liquid composition containing docetaxel - Google Patents

Abstract

The present invention relates to an injectable composition containing docetaxel. The injectable composition comprises: docetaxel or pharmaceutically acceptable salts thereof; HP-β-CD; and a solvent, wherein 30 volume % or more of the entire solvent is ethanol and the injectable composition further comprises polyvinyl pyrrolidone for facilitating the dissolution of HP-β-CD. The injectable transparent liquid composition according to the present invention not only has superior preservation stability but also has quite superior stability for perfusate dilution, such that the composition does not cause precipitation when diluted with a perfusate.

Description

Liquid Injectable Compositions Containing Docetaxel

The present invention relates to an injectable composition comprising docetaxel or a pharmaceutically acceptable salt thereof as an active ingredient.

This application claims priority based on Korean Patent Application No. 10-2011-0048225 filed on May 23, 2011, and all the contents disclosed in the specification and drawings of the application are incorporated in this application.

4-acetoxy-2α-benzoyloxy-5β, 20-epoxy-1,7β, 10β-trihydroxy-9-oxo-tax-11-ene-13α-yl (2R, 3S) -3-tertiary- Docetaxel, a butoxycarbonylamino-2-hydroxy-3-phenylpropionate, is used as an anticancer agent as a semisynthetic taxoid derivative.

This docetaxel is very soluble in water and poorly soluble in water with a solubility of about 6-7 ug / mL. These poorly water-soluble properties make it difficult to prepare injectable compositions for administration to the human body, as well as very poor stability in water.

In the case of docetaxel preparation, it is currently administered by diluting a specific concentration ratio in the perfusate. Due to the solubility characteristics of the above-mentioned docetaxel, there is a possibility that precipitation may occur when dilution with the perfusate does not mix a large amount with the perfusion solution at a time. There is the inconvenience of diluting and administering at intervals.

Therefore, the problem to be solved by the present invention is to provide a liquid injectable composition of docetaxel or a pharmaceutically acceptable salt thereof that not only has excellent storage stability, but also maintains stability, such as no precipitation is formed when dilution with the perfusate. .

In order to solve the above problems, the present invention is a transparent liquid injectable composition comprising docetaxel or a pharmaceutically acceptable salt thereof, HP-β-CD and a solvent, wherein at least 30% by volume of the total solvent is ethanol, Provided is a transparent liquid injectable composition comprising polyvinylpyrrolidone to promote dissolution of HP-β-CD.

In the present invention, HP-β-CD, which acts as a solubilizer of docetaxel, in particular, plays a role of securing solubility of docetaxel when diluted with perfusion solution, exhibits a very low solubility of about 20 mg / ml or less in anhydrous ethanol. Therefore, in order to add HP-β-CD in an amount sufficient to guarantee dilution stability, a considerable amount of ethanol should be used, but such a very large volume of injectable compositions is difficult to dilute in perfusate and to administer. . As a result, there is a need for a means that increases the solubility of HP-β-CD in ethanol solvent systems, but more importantly, does not negatively affect the solubility and stability of docetaxel. The inventors have, through various studies, solved this problem by using polyvinylpyrrolidone (PVP) together in an injectable composition comprising docetaxel or a pharmaceutically acceptable salt thereof and HP-β-CD under an ethanol solvent system. That was an amazing invention.

The transparent liquid injectable composition of the present invention comprises docetaxel or a pharmaceutically acceptable salt thereof, preferably docetaxel as an active ingredient, and has a concentration of docetaxel in the composition of 2-30 mg / ml. Anhydrous and trihydrate may be used as the docetaxel.

The transparent liquid injectable composition of the present invention uses ethanol as a main solvent to dissolve docetaxel, which is insoluble in water. In other words, 30-100% by volume of the total solvent is ethanol. In addition, in consideration of the solubility of other excipients such as HP-β-CD and stability upon dilution with the perfusate, an ethanol aqueous solution containing an appropriate amount of water (purified water) is more preferable.

When ethanol aqueous solution is used as the solvent, too much purified water or too much ethanol in the solvent will adversely affect the stability of the formulation, so the solvent of the composition according to the present invention has a ethanol content of 50-85% by volume Aqueous ethanol solution is preferred, ethanol aqueous solution with 65-80% by volume of ethanol is more preferred, and ethanol aqueous solution with 75-80% by volume of ethanol is most preferred. The specificity of this content range is very exceptional to those of ordinary skill in the art.

However, the present invention is not limited to the above content range. That is, in the present invention, a solvent in which at least 30% by volume of ethanol is ethanol may be used as the solvent, and the concept is more preferable when the ethanol content is in the range of 50-85% by volume. It does not mean to be excluded. That is, when 100% by volume, 99% by volume or 97% by volume of ethanol as a solvent is less stable than the 50-85% by volume range, docetaxel or salt thereof as in the present invention; HP-β-CD; Polyvinylpyrrolidone; And optionally acidifying agents may achieve some of the objects of the present invention.

The transparent liquid injectable composition of the present invention ensures solubility so that docetaxel injectable composition as an active ingredient does not precipitate upon dilution with a perfusate and improves the stability of docetaxel in the perfusate. Includes, the content of such HP-β-CD is preferably 8-100 parts by weight based on 1 part by weight of docetaxel, more preferably 8-50 parts by weight based on 1 part by weight of docetaxel, and 10-25 parts by weight of 1 part by weight of docetaxel. Denial is most desirable. If the content of HP-β-CD is too low, there is a risk of precipitation when dilution with the perfusate. If the content is too high, ethanol must be added to dissolve it, which increases the total volume of the injectable composition. There is this.

The transparent liquid injectable composition of the present invention contains polyvinylpyrrolidone to increase the ethanol solubility of HP-β-CD without adversely affecting the stability of docetaxel. By using such polyvinylpyrrolidone with HP-β-CD, the amount of ethanol for dissolving HP-β-CD can be drastically reduced.

The content of the polyvinylpyrrolidone is preferably 0.05-3 parts by weight, more preferably 0.05-1.5 parts by weight with respect to 1 part by weight of HP-β-CD. If too little polyvinylpyrrolidone is used, the role of improving solubility of HP-β-CD is weak. If too much polyvinylpyrrolidone is used, there is a concern that the content of the solvent should be increased to dissolve polyvinylpyrrolidone. .

In addition, in order to further enhance stability, the transparent liquid injectable composition according to the present invention preferably contains a pH adjuster which is an acidifying agent in order to further secure stability, particularly when the transparent liquid injectable composition contains purified water as part of a solvent. More preferably, the pH of the composition is 5 or less, and more preferably 3 to 5, containing a pH adjuster.

These acidifiers include maleic, fumaric, benzoic, ascorbic, succinic, methanesulphonic, benzenesulphonic, toluenesulphonic, acetic, oxalic, trifluoroacetic, trifluoro Methinesulphonic, propionic, tartaric, salicylic, citric, gluconic, lactic, mandelic, cinnamic, aspartic, stearic, palmitic, formic, glycolic, glutamic, benzene Organic acids such as sulfonic acids or inorganic acids such as hydrochloric, hydrobromic, hydrofluoric, hydroiodic, sulfuric, phosphoric, nitric acid may be used, citric acid, fumaric acid, lactic acid, tartaric acid. , Succinic acid, maleic acid, acetic acid, tartaric acid, oxalic acid, phosphoric acid, hydrochloric acid and the like are preferred, and citric acid is even more preferred.

The transparent liquid injectable composition containing docetaxel or a pharmaceutically acceptable salt thereof according to the present invention not only has excellent storage stability, but also has excellent stability of dilution of perfusate, such as no precipitation occurs when dilution with perfusion liquid, It can be diluted directly in the perfusion solution without use.

Hereinafter, examples and the like will be described in detail to help the understanding of the present invention. However, embodiments according to the present invention can be modified in many different forms, the scope of the invention should not be construed as limited to the following examples. Embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

Example 1 HP-β-CD Solubility Evaluation

HP-β-CD is well soluble in water but very poorly soluble in ethanol. To address this, PVP was used to test the increase of HP-β-CD solubility in ethanol solvent.

HP-β-CD and PVP were put together in 1 ml of absolute ethanol and vortexed and shaken for 10 minutes. After 24 hours, dissolution and precipitation were confirmed. The results are shown in Table 1 below.

Table 1 Unit: mg HP-β-CD PVP Liquid phase One 20 0 Dissolution 2 30 0 Sedimentation 3 20 30 Dissolution 4 40 30 Dissolution 5 50 60 Dissolution 6 70 60 Dissolution 7 100 60 Dissolution 8 200 100 Dissolution 9 200 150 Dissolution 10 200 200 Dissolution 11 300 120 Dissolution 12 300 150 Dissolution 13 300 200 Dissolution 14 400 120 Dissolution 15 400 150 Dissolution 16 400 200 Dissolution

As shown in Table 1, it was dissolved only in anhydrous ethanol to a concentration of 20mg / ml showed a very low solubility, but by dissolving PVP together to obtain a result that can increase the HP-β-CD solubility in anhydrous ethanol.

Example 2 Dilution Stability Test

The following tests were run to assess whether HP-β-CD affects dilution stability.

Commercial docetaxel injectable drug Taxotere ^™ is diluted in 0.9% saline or 5% dextrose solution to make docetaxel at a concentration of 0.74 mg / mL or less and is then injected within 4 hours. Therefore, at least docetaxel should not precipitate for 4 hours at concentrations below 0.74 mg / mL in the perfusate.

As shown in Table 2, the dilution stability test was tested by varying the amount of HP-β-CD and the amount of PVP. Specifically, after dissolving HP-β-CD and PVP, docetaxel and citric acid were dissolved.

TABLE 2 Unit: mg F0 F1 F2 F3 F4 F5 F6 F7 F8 Docetaxel 20 20 20 20 20 20 20 20 20 HP-β-CD 300 400 300 195 226 154 218 217 PVP 200 200 300 94 113 154 146 146 Citric acid 2 Ethanol Anhydrous 1ml 1ml 1ml 1ml qs 1ml qs 1ml qs 1ml qs 1ml qs 1ml

HP-β-CD: Hydroxylpropyl-beta-cyclodextrin

PVP: Polyvinylpyrrolidone

q.s 1 ml: fill to the final volume of 1 ml

Dilution stability was evaluated as follows and the results are shown in Table 3 below. The injectable compositions of F0 to F8 and Taxotere (one vial) were diluted in a 5% dextrose solution at a concentration of 0.74mg / ml and observed for precipitation for 4 hours. According to the degree of precipitation production of the final administration composition, it was measured by dividing into more (3), moderate (2), less (1) and none (0).

TABLE 3 At start 1 hours 2 hours 3 hours 4 hours F0 3 3 3 3 3 F1 0 0 0 0 0 F2 0 0 0 0 0 F3 0 0 0 0 0 F4 0 0 0 0 0 F5 0 0 0 0 0 F6 0 0 0 0 One F7 0 0 0 0 O F8 0 0 0 0 0 Taxotere 0 0 0 0 0

As shown in Table 3, F0 using only anhydrous ethanol showed a phenomenon that precipitation occurs as soon as the dilution proceeds. However, formulations containing HP-β-CD were assured for dilution with perfusate.

The amount of HP-β-CD was about 7.7 parts by weight based on 1 part by weight of docetaxel, but precipitation started at 4 hours in F6, but no precipitation occurred by F4 (about 10 parts or more). It was found to be about 8 parts by weight or more relative to 1 part by weight.

HP-β-CD, which acts as a solubilizer for docetaxel in the present invention, exhibits a very low solubility of about 20 mg / ml or less in anhydrous ethanol. Therefore, in order to add HP-β-CD in an amount sufficient to ensure dilution stability, a considerable amount of ethanol should be used, but such a bulky injectable composition is practically very difficult to be diluted in perfusion solution. . As a result, a means for increasing the solubility of HP-β-CD in an ethanol solvent system is essential. In the present invention, PVP is used together with an injectable composition including docetaxel and HP-β-CD under an ethanol solvent system. Could solve the problem.

Example 3 Further Study of Stability of Docetaxel-Dissolved Compositions

Purified Water Utilization Evaluation

In order to confirm the effect of citric acid, an example of ethanol and pH adjusting agent on the storage stability of docetaxel, a formulation such as Table 4 was prepared, followed by an acceleration (40 ° C., 75%) stability for one month with some prescriptions according to Table 2 above. Confirmed.

Table 4 Unit: mg F9 F10 F11 Docetaxel 20 20 20 HP-β-CD 800 800 800 PVP 60 60 60 Citric acid 2 10 Purified water qs 4ml qs 4ml qs 4ml

q.s 4ml: An appropriate amount of purified water was added to a total volume of 4 mL.

The stability evaluation results are shown in Tables 5 and 6 below. In order to evaluate the stability, the results of epi-docetaxel showing the largest increase rate as the single flexible material among the flexible materials were used and are shown in Table 5 below. Visual observation results are shown in Table 6 below.

Table 5 pH Initial 1week 2week 3week 4week F1 5.65 0.04 0.1 0.17 0.23 0.29 F2 6.37 0.03 0.10 0.16 0.29 0.29 F3 5.64 0.04 0.09 0.14 0.21 0.26 F7 5.66 0.03 0.10 0.18 0.25 0.33 F8 3.48 0.03 0.05 0.04 0.04 0.05 F9 - 0.11 2.30 5.27 7.20 8.41 F10 - 0.11 0.17 0.23 0.32 0.37 F11 - 0.11 0.17 0.18 0.21 0.23 Taxotere - 0.04 0.06 0.08 0.10 0.12

As shown in Table 5, when F9 was added to purified water instead of anhydrous ethanol, a single flexible material increased to 8.41% in 4 weeks. F8 with pH adjuster did not increase mono-flexic material, and F10 and F11, which used purified water as solvents, also contained pH adjuster, so the rate of increase of flexible substances was relatively slow compared to F9. As a result of measuring the pH, the pH was higher than pH 5 without the pH adjusting agent and lower than pH 5 containing the pH adjusting agent. That is, it can be seen that the composition containing the pH adjusting agent to adjust the pH below 5 has excellent stability.

Table 6 Initial 1w 2w 3w 4w F1 Transparency Transparency Transparency Transparency Transparency F2 Transparency Transparency Transparency Transparency Transparency F3 Transparency Transparency Transparency Transparency Transparency F7 Transparency Transparency Transparency Transparency Transparency F8 Transparency Transparency Transparency Transparency Transparency F9 Transparency Sedimentation Sedimentation Sedimentation Sedimentation F10 Transparency Sedimentation Sedimentation Sedimentation Sedimentation F11 Transparency Sedimentation Sedimentation Sedimentation Sedimentation Taxotere Transparency Transparency Transparency Transparency Transparency

As shown in Table 6, F10, F11, and F12 without anhydrous ethanol produced precipitates in one week, resulting in inadequate properties. Thus, ethanol with high solubility of docetaxel was preferred for phase stability.

These results suggest that ethanol is preferred to water as a solvent, considering the storage stability of the docetaxel injectable composition.However, as mentioned above, ethanol is a stabilizer of HP-β-CD that acts as a stabilizer when distillate is perfused. Negatively affect solubility.

Evaluate Use of Ethanol and Purified Water Mixtures

Purified water has a negative effect on the storage stability of docetaxel by reducing the solubility of docetaxel and increasing the amount of the flexible substance. However, the pH control agent may improve the stability to some extent, and since such purified water may help to improve the solubility of other excipients such as HP-β-CD, ethanol is used as the main solvent and Co using purified water as a cosolvent. We tried to develop a -solvent system. That is, stabilization was attempted using an appropriate ratio of ethanol and water.

Docetaxel-containing injectable compositions were prepared according to the formulations in Table 7 below, and the accelerated (40 ° C., 75%) stability of the composition was evaluated for 1 month. The results are shown in Table 8-10. Table 8 shows the results of the increase of Epi-docetaxel (RRT 1.31), Table 9 shows the results of the increase of the flexible material (RRT 0.74) whose structure is not confirmed, Table 10 shows the results of appearance observation.

TABLE 7 Unit: mg F12 F13 F14 F15 F16 F17 Docetaxel 20 20 20 20 20 20 HP-β-CD 800 800 800 800 800 800 PVP 60 60 60 60 60 60 Citric acid 2 2 2 2 2 2 Ethanol anhydrous (mL) 0.25 0.5 0.75 0.8 0.85 0.9 Purified water (mL) 0.75 0.5 0.25 0.2 0.15 0.1

Table 8 Initial 1week 2week 3week 4week F12 ND ND 0.06 0.08 0.11 F13 ND ND 0.05 0.08 0.10 F14 ND ND 0.05 0.08 0.10 F15 ND 0.03 0.05 0.08 0.10 F16 ND 0.02 0.05 0.07 0.10 F17 ND 0.02 0.05 0.07 0.08

N.D: not detected

Table 9 Initial 1week 2week 3week 4week F12 ND 0.12 0.15 0.16 0.14 F13 ND 0.07 0.11 0.13 0.12 F14 ND 0.03 0.09 0.06 0.08 F15 ND 0.03 0.05 0.05 0.07 F16 ND 0.03 0.05 0.05 0.06 F17 ND ND 0.03 0.04 0.05

N.D: not detected

Table 10 Initial 1w 2w 3w 4w F12 Polished Polished Polished Polished Polished F13 Transparency Transparency Transparency Transparency Transparency F14 Transparency Transparency Transparency Transparency Transparency F15 Transparency Transparency Transparency Transparency Transparency F16 Transparency Transparency Transparency Transparency Transparency F17 Transparency Transparency Transparency Transparency Transparency

As shown in Table 8-10, in the case of the prescription according to the present invention, a portion of ethanol could be replaced with purified water. However, as shown in Table 9, which is a result of the increase of the unknown flexible material, the higher the purified water content, the more flexible material was produced. As shown in Table 10, F12 having an ethanol: purified water ratio of 25:75 is an opaque solution state in which docetaxel is not transparently dissolved. Ethanol: Purified water was prepared using a solvent in a ratio of 30:70, it was confirmed that the transparent dissolved. Therefore, the ethanol ratio of 30% by volume or more in the solvent seems to have sufficient solubility in the clear solution state. From these results, a composition having a certain degree of stability was developed even in a formulation containing purified water.

Long-term accelerated stability (appearance) evaluation

The prepared formulations were stored under accelerated conditions (40 ° C., 75%) and observed for six months. The results are shown in Table 11 below.

Table 11 Initial 1m 2m 3m 4m 5 m 6m F12 Polished Polished Polished Polished Polished Polished Polished F13 Transparency Transparency Transparency Transparency Transparency Transparency Transparency F14 Transparency Transparency Transparency Transparency Transparency Transparency Transparency F15 Transparency Transparency Transparency Transparency Transparency Transparency Transparency F17 Transparency Transparency Sedimentation Sedimentation Sedimentation Sedimentation Sedimentation F7 Transparency Transparency Transparency Transparency Transparency Transparency Transparency F8 Transparency Transparency Transparency Transparency Transparency Transparency Transparency

As shown in Table 11, when the content of ethanol in the solvent is 50-80% by volume (prescription F13-15) or when only ethanol is used as the solvent (prescription F7 or F8), it is sufficient to provide a clear solution for 6 months. It showed solubility, but the long-term stability was relatively poor when the ethanol content was 25, and 90% by volume.

Claims (9)

Injectable composition comprising docetaxel or a pharmaceutically acceptable salt thereof, HP-β-CD and a solvent, At least 30% by volume of the total solvent is ethanol, and a transparent liquid injectable composition comprising polyvinylpyrrolidone to promote dissolution of HP-β-CD. The transparent liquid injectable composition according to claim 1, wherein the solvent of the composition is an ethanol aqueous solution having a content of 50-85% by volume of ethanol. The transparent liquid injectable composition according to claim 2, wherein the solvent of the composition is an aqueous ethanol solution having an ethanol content of 75-80% by volume. According to claim 1, wherein the content of HP-β-CD is a transparent liquid injectable composition, characterized in that 8 to 50 parts by weight relative to 1 part by weight of docetaxel. According to claim 1, wherein the content of the polyvinylpyrrolidone is a transparent liquid injectable composition, characterized in that 0.05 to 1.5 parts by weight relative to 1 part by weight of HP-β-CD. The transparent liquid injectable composition according to claim 1, wherein the composition contains docetaxel as an active ingredient. The composition of claim 1, wherein the composition further comprises an acidulant. 8. The composition of claim 7, wherein the composition further comprises an acidulant, wherein the pH of the composition is 5 or less. The transparent liquid injectable composition according to claim 7 or 8, wherein the acidifying agent is citric acid.