KR20100126059A - Pharmaceutical composition comprising docetaxel - Google Patents

Abstract

PURPOSE: A pharmaceutical composition containing docetaxel is provided to suppress lymphocyte level reduction and ensure stability. CONSTITUTION: A pharmaceutical composition contains docetaxel, hydroxypropyl-beta-cyclodextrin, and manniotol. The composition contains 10-80 weight parts of hydroxypropyl-beta-cyclodextrin, 3-15 weight parts of mannitol. The composition further contains pharmaceutically acceptable ingredients.

Description

Pharmaceutical composition containing docetaxel {PHARMACEUTICAL COMPOSITION COMPRISING DOCETAXEL}

The present invention relates to pharmaceutical compositions obtained by lyophilizing a solution comprising docetaxel, hydroxypropyl-beta-cyclodextrin and mannitol, and to injectable compositions obtained by reconstitution and / or dilution thereof.

Docetaxel is the European Taxus It is a semisynthetic taxoid synthesized through esterification of baccatin III, a kind of taxoid extracted from the conifers of baccata . This induces the polymerization of tubulin and depolymerization of microtubules, which is twice as effective as micronatural taxanes, and has similar or more severe cytotoxicity to paclitaxel and cancer cells. It is known to have an effect of inhibiting growth and promoting cell death. Known under the trade name Taxotere®, it is generally used to treat breast cancer, non-small cell lung cancer, gastric cancer, ovarian cancer, head and neck cancer, and esophageal cancer, but may also be used for other types of cancer. Taxoteel may generally be administered intravenously.

However, since docetaxel generally has a very low solubility in water, it is difficult to formulate it into an aqueous solution. Therefore, many studies have been made to increase the solubility of poorly soluble docetaxel.

Taxotel, currently on the market, comes with a container containing the stock solution and 13% (W / W) ethanol dissolved in Polysorbate 80, which is a pre-mix with a solubility of 10 mg / ml. The solution is prepared by diluting (Pre-Mix) and diluting it in physiological saline again. The injection solution thus prepared should have a concentration of 0.3-0.9 mg / ml of docetaxel in the dilute perfusate. A concentration above 0.9 mg / ml may cause the formation of precipitates. In addition, the use of polysorbate 80 may cause hypersensitivity reactions, and ethanol is contained, which may cause side effects due to alcohol.

It has been found that the solubility of docetaxel is adequately improved when using cyclodextrins, in particular β-cyclodextrin, instead of the above surfactants. In International Patent WO 99/24073, the aqueous solubility of docetaxel using cyclodextrin (acetyl gamma cyclodextrin (Ac-gamma-CD) or hydroxypropyl-beta-cyclodextrin (HP-beta-CD, hereinafter referred to as HPBCD)). Increased. However, the invention is also likely to remain ethanol used in the process of dissolving docetaxel, the dilution of the prepared liquid composition is a precipitate is formed when the concentration of docetaxel is low.

However, β-cyclodextrin is a very stabilized solubilizer, but does not metabolize upon administration by injection and forms a complex with cholesterol and accumulates in the kidney, thereby exhibiting kidney toxicity. Sulfobutylether β-cyclodextrin / HPBCD, which improves the toxicity of the β-cyclodextrin, has a creatine clearance of 30 mL / min. HPBCD has been banned in patients with the following conditions, and HPBCD has been shown to reduce drug cholesterol, decrease water consumption in rats, increase relative weight of kidneys, and develop vacuoles in the renal cortical cells. Side effects have been reported (Gould S and Scott RC, 2-Hydroxypropyl-β-cyclodextrin (HP-β-CD): A toxicology review, Food Chem. Toxicol., 2005, 43 , 1451-9).

In addition, conventional docetaxel preparations are known to lower the level of lymphocytes or cause fluid retention to cause side effects such as peripheral edema.

As described above, despite efforts to ameliorate the problems of conventional docetaxel-containing formulations, formulations containing docetaxel, in particular docetaxel formulations comprising docetaxel and HPBCD, still have low stability, side effects due to ethanol residue used as cosolvent And drug toxicity side effects.

The present inventors have studied to solve the above problems, as a result of mixing the mannitol in docetaxel and HPBCD and lyophilized to prepare a lyophilized composition, and confirmed that the composition solved the above-mentioned problems to complete the present invention. .

That is, the present invention has an effect of alleviating pharmacotoxicity, which suppresses weight loss and decrease of lymphocyte count, compared to preparations consisting only of docetaxel and HPBCD, and not only excellent stability (storage stability and dilution stability), but also quiet. It is an object to provide a pharmaceutical composition comprising docetaxel, which does not use ethanol as a medium, has low hygroscopicity and forms a good lyophilized cake, and an injectable composition obtained by reconstitution and / or dilution thereof.

In order to achieve the above object, the present invention

(A) Docetaxel;

(B) Hydroxypropyl-beta-cyclodextrin; And

(C) mannitol

It provides a pharmaceutical composition, preferably lyophilized pharmaceutical composition comprising a.

The present invention also provides a docetaxel-containing injectable composition obtained by reconstitution and / or dilution of the pharmaceutical composition in an aqueous solvent.

Also,

1) mixing docetaxel, cyclodextrin and mannitol in distilled water;

2) preparing a lyophilized composition by stirring and dissolving the mixed solution and lyophilizing; And

3) preparing the injectable composition by reconstituting and / or diluting the lyophilized composition in distilled water, dextrose solution or saline solution

It provides a method for producing a docetaxel-containing injectable composition comprising a.

The lyophilized docetaxel-containing pharmaceutical composition of the present invention does not have components such as ethanol in the composition, and thus does not cause side effects, and inhibits drug toxicity and has an effect of inhibiting weight loss and lymphocyte count reduction when injected. . In addition, it has a low hygroscopicity, forms a good cake, and has excellent stability at the low generation of impurities. Thus, it can be stored for a long time and the content of the active ingredient is maintained for a long time even in a reconstituted solution. The effect of temperature and humidity is minimized.

The present invention provides a pharmaceutical composition prepared by further adding mannitol to docetaxel and doxytaxel and hydroxypropyl-beta-cyclodextrin to be dissolved in distilled water and lyophilized. Compared with formulations consisting only of docetaxel and hydroxypropyl-beta-cyclodextrin, it has the effect of inhibiting drug toxicity, inhibiting weight loss and decreasing lymphocyte levels, and storing and reconstituting the composition. And / or have high stability in preparing the injection solution by dilution, do not use ethanol as a cosolvent, and form a good lyophilized cake.

Hereinafter, the present invention will be described in detail.

Docetaxel-containing injectable composition of the present invention,

1) mixing docetaxel, hydroxypropyl-beta-cyclodextrin and mannitol in distilled water;

2) dissolving the mixed solution by stirring and lyophilizing after sterile filtration to prepare a lyophilized composition; And

3) preparing the composition for injection by diluting the lyophilized composition in distilled water, dextrose solution or physiological saline

It is prepared by a method for producing a docetaxel-containing injectable composition comprising a.

Docetaxel, the active ingredient of the pharmaceutical composition of the present invention, is commercially available and may be used in the form of anhydride or hydrate, but is not limited thereto.

The hydroxypropyl-beta-cyclodextrin of the present invention acts as a solvent and excipient of docetaxel, preferably 10 to 80 parts by weight, more preferably 20 to 60 parts by weight based on 1 part by weight of the docetaxel. . When used in excess of 80 parts by weight, the viscosity of the formulation is so high that it is not easy to filter in the filtration step, when used in less than 10 parts by weight, there is a disadvantage that it is difficult to ensure adequate solubility and stability. The hydroxypropyl beta cyclodextrin (HPBCD) is preferably a molecular substitution (MS) of 0.2 to 1.0, more preferably 0.4 to 0.8. Here, the term "molecular substitution" is a molar substitution, and means the molar average number of substituents per glucose unit.

In addition, the mannitol of the present invention acts to alleviate the drug toxicity of docetaxel and HPBCD and to increase the stability of the docetaxel-containing composition. The content of the mannitol is preferably used 3 to 15 parts by weight, more preferably 4 to 8 parts by weight based on 1 part by weight of docetaxel. If the mannitol is less than 3 parts by weight, the particle shape of the cake formed by lyophilization is closer to the wax phase, the uniformity of the particles is worsened and the reconstitution of the formulation takes longer. The shape of the cake formed by this is bad, the hygroscopicity is high and there is a disadvantage that can not inhibit the drug toxicity. In addition, when 4 to 8 parts by weight of mannitol is used per 1 part by weight of docetaxel, it exhibits an effect of alleviating drug toxicity, which is remarkably suppressed in weight loss and decrease in lymphocyte count, and also the particle properties of the cake formed by lyophilization. And the hygroscopicity was also confirmed to be excellent.

The docetaxel, hydroxypropyl-beta-cyclodextrin and mannitol are placed in water, preferably distilled water for injection, and in consideration of the solubility of docetaxel, 1.5 mg / ml to 30 mg / ml, preferably 5 mg It is preferred to dissolve to / ml to 15 mg / ml. When prepared at a concentration of less than 1.5 mg / ml there is a disadvantage in that the productivity of one batch that can be produced using the same freeze dryer during freeze-drying, there is a disadvantage to increase the production cost, if it exceeds 30 mg / ml Since the solubility of docetaxel is not improved and the viscosity is increased, there is a commercially difficult point in the subsequent sterilization process.

 At this time, the stirring of the mixture is carried out at a temperature range of 5 ° C to 70 ° C, preferably 10 ° C to 40 ° C until the mixture is completely dissolved. A general docetaxel preparation requires an organic solvent or a solubilizer when dissolving docetaxel, but is not necessary in the present invention. The docetaxel solution thus prepared was sterilized and filtered, and the filtered docetaxel-containing solution was lyophilized at low temperature for freeze-drying, and then lyophilized under reduced pressure at -50 ° C to -80 ° C to prepare a white to pale yellow lyophilized formulation. can do. The actual lyophilization step in the present invention includes a main drying step and a post-drying step. In a preferred embodiment, the main drying step is carried out at a temperature of -45 ° C to -23 ° C under a pressure of 10 to 100 mbar. In a preferred embodiment, the subsequent post-drying step is carried out at a temperature of 45 ° C. under a pressure of 0.0001 mbar. After lyophilization, N2 is used to depressurize the lyophilizer. It is then desirable to sterilize the bottle containing the docetaxel lyophilisate under nitrogen atmosphere.

The docetaxel injectable composition of the present invention reconstitutes the lyophilized docetaxel preparation obtained by the above process into any one selected from the group consisting of a suitable solvent, such as saline solution, aqueous glucose solution or distilled water for injection. And / or diluted. The docetaxel lyophilisate according to the invention is preferably dissolved at room temperature. The isotonicity of the resulting solution by dissolution can be controlled through the volume of the aqueous medium used for dissolution. The docetaxel injectable composition of the present invention is preferably used in the form of an intravenous injection. At this time, it is preferable to first prepare the lyophilized composition in the form of reconstitution and dilution to a clinically administrable concentration. When the lyophilized docetaxel composition is reconstituted, the concentration of docetaxel is 1.5 mg / ml to 30 mg / ml, preferably 5 mg / ml to 15 mg / ml, and the docetaxel is diluted to a clinically administrable concentration. Can be prepared to include 0.2 mg / ml to 2.0 mg / ml, preferably 0.3 mg / ml to 0.9 mg / ml.

The pharmaceutical composition according to the invention has the advantage that an aqueous solvent can be used to prepare the injection solution. In preparing a conventional injectable docetaxel solution, only a solvent system containing a high content of an organic solvent such as propylene glycol is used, but the pharmaceutical composition according to the present invention has excellent solubility in an aqueous solvent, so that an organic solvent or a soluble solvent may be used for dissolution. There is no need to use topics.

In addition, the present inventors have confirmed that the pharmaceutical composition obtained by the above manufacturing process has an effect of inhibiting drug toxicity by docetaxel and HPBCD, and also forms a good aspect of the cake, exhibits moisture absorption preventing effect, harsh conditions It was confirmed that stability was improved under the following conditions.

In addition, the pharmaceutical composition of the present invention, in addition to the above components, pharmaceutically acceptable components such as stabilizers, dissolution aids, mold release agents, emulsifiers, antioxidants, pH adjusting agents, buffers, isotonic agents, analgesics, wetting agents, preservatives, etc. It may be formulated in a range that does not impair the object and effect of the present invention, but is not limited thereto.

[Example]

Hereinafter, although an Example and an experimental example are given and this invention is demonstrated more concretely, these are for illustrating this invention and the scope of the present invention is not limited by these.

Comparative example  1 and 2.

After anhydrous docetaxel and HPBCD were weighed and mixed as shown in Table 1, a part of distilled water was added and stirred until completely dissolved at 30 ° C., and the final volume was adjusted to 1 mL with the remaining amount of distilled water under continuous stirring. The docetaxel solution was sterilized using a 0.2 μm membrane filter and the sterilized solution was filled into sterile dried glass vials under sterile conditions. Under normal lyophilization conditions, the sterilized solution filled in the vial was completely dried to remove water until it became an amorphous powder to obtain a composition. Glass vials containing the lyophilized powder were sealed with sterile dried rubber stoppers.

Example  1 to 13.

A composition comprising docetaxel was obtained in the same manner as in Example 1 except that anhydrous docetaxel, HPBCD and mannitol were weighed and mixed.

Experimental Example  1. Animal testing

Weight change and lymphocyte sensitization were investigated to determine whether the composition comprising the docetaxel of the present invention has an effect of alleviating the cytotoxicity and lymphatic toxicity of docetaxel and HPBCD. SD rats of the same gender, similar age and weight were used for the investigation, and they consumed similar diets and tap water. All animals were placed in polycarbonate cages. The animals were divided into five groups, five in each group:

Group I (control): normal saline (0.9%)

Group II free of mannitol (Comparative Example 1 + distilled water for injection)

Group III: containing 4% w / v mannitol (Example 2 + distilled water for injection)

Group IV: containing 8% w / v mannitol (Example 6 + distilled water for injection)

Group V: containing 15% w / v mannitol (Example 11 + distilled water for injection)

In one example, the mannitol-free composition of Group II is reconstituted to a docetaxel content of 10 mg / ml of the lyophilized composition prepared in Comparative Example 1 with distilled water for injection. The remaining groups III to V were also prepared in the same manner as in Group II using Examples 2, 6 and 11.

1-1. Mannitol  Cytotoxicity Mitigation of Containing Compositions

Immediately prior to intravenous infusion, the reconstituted docetaxel composition of Group II-V (10 mg / ml) was diluted to 1 mg / ml with physiological saline (0.9%) and 10.08 mg as the equivalent of docetaxel to each rat. Inject to a dose of / kg. The saline solution of group I was injected with the same amount of saline solution used in group II-V. Intravenous infusion was reinjected 1 week after the initial injection, and the weight and weight change of SD rats were checked daily and averaged (%) for 12 days, and are shown in Tables 2 and 3, FIGS. 1 and 2.

As shown in Tables 2 and 3 and FIGS. 1 and 2, the rats of group I (physiological saline-administered group) gained weight, and the rats of group II (no mannitol) lost weight.

On the other hand, rats injected with the compositions of groups III and IV (with mannitol 4% and 8% added) were found to initially lose weight and increase in weight, and rats in group V gained weight rather than group II rats. Decreased further.

As a result of the present experiment, it was shown that the use of the composition to which 4% and 8% mannitol was added reduced cytotoxicity of docetaxel, and the composition to which mannitol was added more than 15% had no cytotoxic effect.

1-2. Mannitol  Of containing composition Lymphatic Toxicity  Palliative Test-Hematological Evaluation

About 2 ml of blood was collected from the cornea of the SD rat with capillaries before and after the injection of the same docetaxel injection solution (using the group II-V composition) and the saline solution used in Experimental Example 1-1 and 3 hours after the injection. For hematological evaluation, the blood samples were mixed with EDTA 2sodium and then centrifuged to separate serum samples and stored at −80 ° C. until analysis for serum biochemical measurements by a Heematology analyzer. Lymphocyte levels were compared and shown in Table 4 and FIG. 3, and lymphocyte levels were expressed as the number of lymphocytes contained in 10 ³ cells / ml.

As shown in Table 4 and FIG. 3, the levels of lymphocytes in rat blood of group II (without mannitol) were reduced by at least 20% compared to the control, while the composition of group III and group IV (with mannitol 4% and 8% added) Rats injected with reconstitution showed excellent inhibition of lymphocyte reduction in blood, and some inhibition of lymphocyte reduction was also seen in rats of Group V (addition of mannitol 15%).

Experimental Example  2. Mannitol  By addition Docetaxel  Improvement of Physical Properties of Containing Compositions

A prescription without mannitol (Comparative Example 2) and a formulation containing 3, 4, 6, 8, 9, 12, 15 and 20 parts by weight of mannitol per 1 part by weight of docetaxel (Examples 1, 3, 5, 7, 8 , 10, 12, and 13) were dried on the same lyophilizer for 3 days at -45 ° C and 1 day at 45 ° C, and the cake formation was visually observed and evaluated based on the particle properties and uniformity of the resulting product. The results are shown in Table 5 below.

[Evaluation standard]

1: Very bad / 2: Bad / 3: Average / 4: Good / 5: Very good

(The higher the number of evaluation criteria, the closer the particle shape is to the powder phase and the better uniformity)

As shown in Table 5, the particle shape of the cake in the case of containing mannitol 30, 40, 60 and 80 mg / mL of Examples 1, 3, 5 and 7 was the cake of Example 2, which was freeze-dried only docetaxel and HPBCD. It was found that the particle size was closer to the powder phase than the particle and the uniformity of the particle size was improved.

Experimental Example  3. Mannitol  Stability Improvement by Addition

3-1. Mannitol  According to the content Hygroscopicity  Measure

HPBCD is a hygroscopic material that can absorb moisture in the air when it is stored and delay the reconstitution time or change the properties of the formulation. .

In order to examine the hygroscopic effect of the composition of the present invention, each group shown in Table 6 was placed in an open glass vial of 20 mg each as an equivalent amount of docetaxel, and left at 40 ° C. and 75% (relative humidity, RH) for 70 hours. The moisture content before and after the test was measured using a Karl Fischer moisture analyzer (Metrohm, Switzerland) and is shown in Table 6 and FIG. 4 below.

As shown in Table 6 and FIG. 4, the moisture absorption of the example composition containing mannitol was lower than that of the comparative example of the mannitol-free composition. Therefore, it turns out that the composition of this invention has a low possibility of formation of the block which arises by hardening or aggregation.

3-2. Docetaxel  Stability Improvement of Containing Compositions

Comparative Examples 1, 4, and 11 were placed in glass vials of 20 mg each as a docetaxel equivalent, and left at 60 ° C. and 75% (RH) for 15 days, and the impurities generated before and after the test were measured and generated using HPLC. The content (% by weight) was calculated as the amount of total impurities and is shown in Table 7 and FIG. 5.

As shown in Table 7 and Figure 5, compared to Comparative Example 1, which is a mannitol-free composition, it was found that the generation amount of impurities in Examples 4 and 11 containing mannitol is low. Therefore, when mannitol is used as an excipient, it can be seen that there is an effect of suppressing the generation of impurities.

3-3. Docetaxel  Improved stability of injection

The lyophilized powders of Groups 1 and 2 described in the table below were dissolved in distilled water for injection to prepare 10 mg of docetaxel injection solution as the equivalent of docetaxel, and the accelerated test was carried out for 30 days under stability conditions (45 ° C., 75% RH), and the solution The content of docetaxel remaining in is shown in Table 8 and FIG. 6.

As shown in Table 8 and FIG. 6, the preservative effect of docetaxel in the injection solution was superior in the formulation containing mannitol (3%) as compared to the formulation containing only docetaxel / HPBCD.

The test results show that the docetaxel composition of the present invention is pharmacotoxicity is suppressed and lyophilized by adding 3 to 15 parts by weight of mannitol as a component with respect to 1 part by weight of docetaxel as compared to a formulation consisting of conventional docetaxel and HPBCD. It clearly suggests that the cake shape, i.e., the physical properties of the docetaxel-containing composition is improved, and that the stability of the composition is improved.

1 is a graph comparing weight averages of rats receiving injections reconstituted and diluted with Comparative Examples (Docetaxel and HPBCD) and Examples (Docetaxel, HPBCD and Mannitol) of the present invention,

FIG. 2 is a graph comparing changes from initial body weight of rats receiving injections reconstituted and diluted with Comparative Examples (Docetaxel and HPBCD) and Examples (Docetaxel, HPBCD and Mannitol) of the present invention, FIG.

3 is a graph comparing the change in lymphocyte levels in rats before and after administration of injection solutions reconstituted and diluted with Comparative Examples (Docetaxel and HPBCD) and Examples (Docetaxel, HPBCD and Mannitol) of the present invention,

4 is a graph of the hygroscopicity comparison of the lyophilized cake of Comparative Examples (Docetaxel and HPBCD) and Examples (Docetaxel, HPBCD and Mannitol) of the present invention,

5 is a graph of comparison of the harsh state stability in the dry state of the comparative examples (docetaxel and HPBCD) and the examples (docetaxel, HPBCD and mannitol) of the present invention,

Figure 6 is a graph of the acceleration stability in the solution of the comparative examples (docetaxel and HPBCD) and the examples (docetaxel, HPBCD and mannitol) of the present invention.

Claims (8)

(A) Docetaxel; (B) Hydroxypropyl-beta-cyclodextrin; And (C) mannitol Pharmaceutical composition comprising a. The method according to claim 1, 1 part by weight of the docetaxel 10 to 80 parts by weight of hydroxypropyl-beta-cyclodextrin; And 3 to 15 parts by weight of mannitol Characterized in that it comprises a pharmaceutical composition. The method according to claim 1, 1 part by weight of the docetaxel 20 to 60 parts by weight of hydroxypropyl-beta-cyclodextrin; And Mannitol 4 to 8 parts by weight Characterized in that it comprises a pharmaceutical composition. The method according to claim 1, Pharmaceutical composition, characterized in that it further comprises a pharmaceutically acceptable component. The method according to claim 1, The composition is characterized in that the lyophilized form, pharmaceutical composition. A docetaxel-containing injectable composition which can be obtained by reconstituting or diluting the pharmaceutical composition according to any one of claims 1 to 5 in an aqueous solvent or by diluting after reconstitution. The docetaxel-containing injectable composition according to claim 6, wherein the aqueous solvent is any one selected from the group consisting of water, dextrose solution and physiological saline. 1) mixing docetaxel, cyclodextrin and mannitol in distilled water; 2) preparing a lyophilized composition by stirring and dissolving the mixed solution and lyophilizing; And 3) preparing the composition for injection by reconstituting or diluting the lyophilized composition in distilled water, dextrose solution or physiological saline, or diluting after reconstitution. Method for producing a docetaxel-containing injectable composition comprising a.

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