CZ300677B6 - Pharmaceutical composition containing docetaxel and intended for preparation of fusion solution, process of its preparation and use - Google Patents

Abstract

In the present invention, there is disclosed a pharmaceutical composition containing docetaxel and intended for the preparation of especially a fusion solution for administering thereof to patients wherein the pharmaceutical composition contains a concentrate including a pharmaceutically effective amount of docetaxel, a suitable solvent being represented by ethanol, a surfactant being represented by polyethylene(20) sorbitan monooleate, a pharmaceutically effective amount of citrate buffer; and optionally a co-solvent consisting of an aqueous solution of a pharmaceutically effective amount of polyethylene(20) sorbitan monooleate and optionally ethanol and/or a pharmaceutically effective amount of citrate buffer. The pharmaceutical composition according to the present invention is characterized by an extraordinary chemical and physical stability. The invention also relates to a process for preparing the above-described pharmaceutical composition and its use.

Description

Technical field

The present invention relates to a novel pharmaceutical composition comprising a taxane derivative of docetaxel, in particular for the preparation of an infusion solution, a process for its manufacture and use. This composition is characterized by exceptional chemical and physical stability.

BACKGROUND OF THE INVENTION

Docetaxel is an anti-cancer chemotherapeutic from the taxane family. It is prepared synthetically, starting from 10-deacetylbaccatin 111 from yew needles (Taxus baccata), see EP 0 253 738 and EP 0 336 841 (Aventis Pharma). Alternative preparations from other natural taxanes are also known, the starting material being, for example, 9-dihydro-1,3-acetyl baccatin from yew

Taxus canadensis (EP 0639 186, Abbott Lab.).

Docetaxel is active in vivo against a wide variety of tumors. It is mainly used in breast and ovarian and lung cancer. Its efficacy has also been described later for the treatment of hepatocellular carcinoma (EP 1214 061, Aventis Pharma) and other cancers. The mechanism of action of docetaxel involves inhibiting mitosis by affecting cellular microtubules, which prevent it from breaking down into the tube by breaking proteins.

Taxane compounds (taxanes) generally exhibit limited solubility in water. Compositions intended for the preparation of a solution suitable for injection usually therefore contain a surfactant and ethanol. Ethanol is the best biocompatible solvent for bringing docetaxel and other taxane active ingredients into solution.

Docetaxel was first disclosed as a new, biologically active substance in French patent FR 2 601 675 (EP 0 253 738). The patent also claimed a composition comprising docetaxel for parenteral, especially intravenous administration. For such a composition, it has been proposed to use excipients, namely emulsifiers, dispersants or wetting agents, in particular propylene glycol, vegetable oils and injectable organic esters. In the example mentioned in the aforementioned patent, docetaxel was dissolved in a 1: 1 volume ratio mixture of ethoxylated castor oil and ethanol, and the resulting mixture was then diluted 1: 9 with saline. The composition was applied within 1 hour of dilution.

In general, the taxanes, and in particular taxol (paclitaxel) in solution, are discussed in the publication published in the Journal of the National Center Inst. 82 (15), 1990, 1247-59 (E.K. Rowinsky et al.). It discloses a taxol-containing composition that is dissolved in a mixture of 50% dehydrated alcohol and 50% ethoxylated castor oil (CremophorEL). Similarly, Chemical Abstract 106 (22), 1987 (Abstract No. 182 581c) discloses a co-solvent system consisting of poly45 ethylene polypropylene glycol block copolymer (Pluronic L64), ethanol and polyoxyethylene (20) sorbitan monooleate, with which taxol forms a stable formulation, applicable after dilution with water.

However, the use of surfactants (eg, Cremophor) in an amount necessary to dissolve a sufficient dose of the active substance, however, causes adverse effects in patients such as vascular enlargement, dyspnea, lowered blood pressure and anaphylactic shock (see EC Rowinsky et al. Journal. of

National Cancer Inst. 82 (15), 1990, 1247-59 and R. B. Weiss et al., J. Clin. Oncol. 8, 1263-1268 (1990).

In addition, injectable pharmaceutical compositions in a surfactant containing small amounts of ethanol may be dissolved in the infusion solution only with extremely vigorous stirring, but may not be available at the clinic. According to EP 0 671 912 (Aventis Pharma), this disadvantage is overcome by preparing an intermediate solution consisting of docetaxel in a surfactant and an aqueous solution with an additive facilitating the dissolution of the intermediate solution in an aqueous infusion solution.

Stable pharmaceutical compositions containing docetaxel for intravenous administration can also be prepared using phospholipids (see EP 0 758 231, Aventis Pharma). Their advantage is the almost complete absence of pharmaceutically unsuitable organic solvents.

Another solution is a pharmaceutical composition in which docetaxel is conjugated to a water-soluble polymer or a water-soluble chelating agent (EP 0 932 399, PG-TXL Company, L.P.).

Another possibility to convert the water-insoluble docetaxel into a solution for intravenous administration is by dissolving it in vegetable oil, diluting it with water and incorporating it into liposomes, or associating it with carriers such as ecyclodextrins or polyethylene glycols (EP 0 667 771, Aventis Pharma).

A fat emulsion with phospholipids and an emulsifying protein also useful for incorporating docetaxel into a liposome emulsion is also disclosed in EP 1 585 504 (Azaya Therapeutics, Inc.). EP 1 305 006 (Pharmasol G.m.b.H.) discloses oil-in-water and water-in-oil emulsions free of organic solvents useful for forming docetaxel into an injectable solution. Further compositions in the form of a fat emulsion are disclosed in patent application WO 2005/065676 (Otsuka Pharma Facto25 ry Inc,). Another application by the same Applicant discloses a composition comprising docetaxel in a solution of ethanol and polyethylene glycol, which is further mixed with an infusion solution (JP 2005/225818).

The problem of converting generally water-insoluble substances (including docetaxel) into solution is also discussed in EP 1 510 206 (Novagali Pharma S.A.), which discloses anhydrous oil formulations which spontaneously form nanoemulsions. In addition to the active agent, they include vitamin E, a co-solvent and a surfactant; optionally a second biologically active compound. Another solution for substances with low solubility in water is described in EP 1 246 608 (ImaRx Therapeutics, Inc,). The claimed injectable formulation contains, in addition to the active compound, polyvinylpyrrolidone, a fatty acid, and a surfactant.

EP 1 560 577 (Bristol-Myers Squibb Company) discloses sulfur-containing docetaxel derivatives which are formulated for intravenous administration using ethanol, polyoxyethylated castor oil and a mixture of antioxidants.

The only drug registered to date containing docetaxel, Taxotere®, is described in EP 0 522 936 (Aventis Pharma). The pharmaceutical composition comprises a solution of docetaxel in a surfactant (selected from polyoxyethylene sorbitan fatty acid esters, polyoxyethylene glycol esters, or polyethylene glycol esters and hydrogenated castor oil) with a small amount of ethanol. This mother liquor is subsequently diluted with saline or glucose solution for administration. The resulting infusion solution exhibits physical stability in the order of several months in the absence of ethanol. The same ethanol solution (having a content of less than 0.01 ml / l to 0.05 ml / l) has a stability of from 8 to 45 hours (see EP 0 522 936, Aventis).

A similar injectable solution is claimed by another patent of Aventis Pharma (EP 0 671 912) relating to taxane compounds including docetaxel. The pharmaceutical composition consists of a solution of docetaxel in a surfactant (selected from polyoxyethylene sorbitan fatty acid esters or polyoxyethylene glycol esters and fatty acid glycerides) with a small amount of ethanol and a diluent. It consists of an organic compound of molecular weight

The weight of the composition is less than 200, or a mineral salt, and prevents the formation of a gel phase after mixing the above solution with an aqueous solution.

Another embodiment has been proposed for formulating intravenously administered pharmaceutical compositions containing taxane derivatives with a sulfur atom. EP 1 558 241 (Bristol-Myers Squibb) discloses a solution comprising two containers, one containing the active compound in a solvent in the presence of a buffer and the other containing a co-solvent in the presence of a buffer. The contents of both containers are mixed prior to application of the composition. Such compositions exhibit increased stability during storage and subsequent dilution with water since they do not degrade the taxane derivative by the peroxide impurities of the polyoxyethylated castor oil as a cosolvent.

A preferred composition of the composition of the above invention comprises 0.001 to 20 mg / ml of active ingredient and 5-95% (v / v) ethanol in an aqueous solution of tartrate buffer in the first container and 1-95% (v / v) polyoxyethylated castor. oil in an aqueous solution of the tartrate buffer in the second reservoir.

A solution of the pharmaceutical composition of acceptable stability and solubility can be prepared simply by using a 75% ethanol in buffer solution. However, for administration to patients, due to the high ethanol content, it must be diluted with saline or glucose solution (see page 11 of the patent). This process causes precipitation which is removed by the addition of a co-solvent, preferably polyoxyethylated castor oil. According to Table V on page 13, the stability of the injectable solution containing such a co-solvent is much lower than in the absence thereof.

It has now been found that a docetaxel-containing concentrate dissolved in polyoxyethylene (20) sorbitan monooleate (polysorbate 80) and ethanol with the addition of citrate or other physiologically acceptable buffer exhibits surprisingly high chemical and physical stability. The established stability of several years has not been described for similar pharmaceutical compositions. The high stability was also confirmed by the premix obtained by diluting the concentrate with a cosolvent (co-solvent). The concentrate can advantageously be stored for a long period of time for commercial purposes and, even after a long storage period, will provide a stable infusion solution after addition of the cosmos and after dilution by the medical personnel as usual.

SUMMARY OF THE INVENTION

It is an object of the present invention to provide a stable pharmaceutical composition containing docetaxel suitable for the preparation of infusion solutions which exhibits enhanced chemical resistance, comprising a concentrate consisting of:

(a) a pharmaceutically effective amount of docetaxel;

(b) an organic solvent which is thanol,

(c) polyoxyethylene (20) sorbitan monooleate surfactants; and

d) a pharmaceutically acceptable amount of a buffer;

and optionally a co-solvent comprising:

e) an aqueous solution of a pharmaceutically acceptable amount of polyoxyethylene (20) sorbitan monooleate and optionally ethanol as an organic solvent and / or a pharmaceutically acceptable amount of a buffer.

A feature of the pharmaceutical composition of the present invention is that it is in the form of a premix comprising a mixture of a concentrate and a cosolvent.

-3GB 300677 B6

Further, a feature of the pharmaceutical composition of the present invention is that it is in the form of a premix suitable for administration.

A feature of the pharmaceutical composition of the present invention is also that it is in the form of a premix which is adapted for administration by the addition of an aqueous infusion solution selected from 0.9% aqueous NaCl and 5% aqueous glucose.

It is also a feature of the pharmaceutical composition of the present invention that a suitable buffer is a citrate buffer.

The present invention further provides a pharmaceutical composition comprising a concentrate consisting of:

(a) docetaxel trihydrate in an amount of between 1,5 and 8,5% (w / w) corresponding to an amount of between 15 and 85 mg / ml of anhydrous docetaxel;

(b) absolute ethanol in an amount of 3 to 57% (w / w);

c) polyethylene (20) sorbitan monooleate in an amount of from 30 to 87.5% (w / w); and

d) 1 to 25% (w / w) buffer for 47 to 71 mmol.r ¹ citric acid monohydrate and 0.17 to 1.36 mM ^"1 trisodium citrate dihydrate;

and optionally a cosolvent comprising from e) polyethylene (20) sorbitan monooleate in an amount of 5 to 35% (w / w), and optionally

f) from 1 to 10% (w / w) of absolute ethanol and / or a pharmaceutically effective amount of a buffer.

A preferred embodiment is a pharmaceutical composition of the present invention, which comprises a concentrate consisting of:

(a) docetaxel trihydrate in an amount of between 1,5 and 8,5% (w / w) corresponding to an amount of between 15 and 85 mg / ml of anhydrous docetaxel;

(b) absolute ethanol in an amount of between 3 and 49,5% (w / w);

(c) polyethylene (20) sorbitan monooleate in an amount of from 48 to 58% (w / w); and

d) from 1 to 25% (w / w) of a buffer having a concentration of 47 to 71 mmol / ^{l of} citric acid monohydrate and 0.17 to 1.36 mmol / ^{l of} trisodium citrate dihydrate; and optionally a cosolvent comprising

(e) polyethylene (20) sorbitan monooleate in an amount of 5 to 35% (w / w) and, where appropriate,

i) from 1 to 10% (w / w) of absolute ethanol and / or a pharmaceutically effective amount of a buffer.

The present invention further provides a stable pharmaceutical composition comprising docetaxel for the preparation of infusion solutions comprising a concentrate comprising a pharmaceutically effective amount of docetaxel in a mixture of ethanol, polyethylene (20) sorbitan monooleate, and a buffer.

Furthermore, a feature of the pharmaceutical composition of the present invention is that the buffer is a citrate buffer.

The present invention further provides a pharmaceutical composition comprising a concentrate comprising:

(a) docetaxel trihydrate in an amount of 1,5 to 4,0% (w / w) corresponding to an amount of 15,0 to 40,0 mg / ml of anhydrous docetaxel;

(b) absolute ethanol in an amount of 3 to 57% (w / w);

(c) polyethylene (20) sorbitan monooleate in an amount of from 30 to 94.5% (w / w); and

d) 1 to 25% (w / w) of buffer at a concentration 47 to 71 mM of ^one of citric acid monohydrate and 0.17 to 1.36 mmol.! ' ¹ trisodium citrate dihydrate

A preferred embodiment is a pharmaceutical composition of the present invention comprising a concentrate consisting of:

(a) docetaxel trihydrate in an amount of 1,5 to 4,0% (w / w) corresponding to 15,0 to 40,0 mg / ml of anhydrous docetaxel;

(b) absolute ethanol in quantities of 3 to 37,5% (w / w);

c) polyethylene (20) sorbitan monooleate in an amount of from 60 to 70% (w / w); and d) 1 to 25% (w / w) of a buffer of 47 to 71 mmol / ^{l of} citric acid monohydrate and 0.17 to 70% w / w. ¹ 1.36 mM of trisodium citrate dihydrate.

The present invention further provides a process for the manufacture of a pharmaceutical composition according to the present invention comprising mixing the taxane derivative docetaxel in a solution consisting of ethanol, polyethylene (20) sorbitan monooleate and a buffer with a solution consisting of aqueous ethanol, polyethylene monooleate (20). 20) sorbitan and optionally a buffer, to prepare a premix which is then formulated in a form suitable for administration.

A feature of the method of the present invention is that the premix is formulated for administration by diluting 1 to 2 parts of the premix to 25 parts of the infusion with a sterile aqueous solution for infusion consisting of 0.9% aqueous NaCl solution or 5% aqueous glucose solution.

The present invention further provides a process for the manufacture of a pharmaceutical composition of the present invention comprising dissolving the docetaxel taxane derivative, melting from ethanol, polyethylene (20) sorbitan monooleate, and a buffer, to obtain a concentrate, which is then treated to form a concentrate. forms suitable for administration.

It is a feature of the method of manufacture of the pharmaceutical composition of the present invention that the composition is formulated in a form suitable for intravenous administration.

The present invention also provides the use of a pharmaceutical composition of the invention for the preparation of a medicament in a form suitable for intravenous administration for the treatment of various types of cancer diseases and other diseases manifested by abnormal cell proliferation.

The present invention further provides a tumor growth inhibiting kit comprising a concentrate consisting of a taxane derivative of docetaxel, ethanol as a suitable solvent, polyethylene (20) sorbitan monooleate and a pharmaceutically acceptable amount of buffer, and a cosolvent comprising a pharmaceutically acceptable amount of polyethylene (20) sorbitan monooleate. , ethanol as a solvent, and optionally a pharmaceutically acceptable amount of a buffer, wherein the concentrate and cosol 40 vent are for use in combination to form a premix that is diluted prior to administration to the patient by a sterile aqueous solution for infusion.

The pharmaceutical composition of the invention is prepared by mixing the concentrate and the co-solvent prior to administration to form a premix which is diluted with physiological saline (0.9% aqueous NaCl) or 5% aqueous glucose to prepare a form suitable for administration. immediately before intravenous administration.

In a preferred embodiment, the present invention provides a pharmaceutical composition comprising a docetaxel concentrate in a mixture of ethanol, polyethylene (20) sorbitan monooleate, and a buffer.

To prepare a form suitable for administration, it is diluted immediately with the prescribed amount of a sterile aqueous solution for infusion, i.e. 0.9% aqueous NaCl or 5% aqueous glucose.

-5GB 300677 B6

The composition of the present invention provides a preferred method for administering the active compound docetaxel while maintaining its solubility, significantly increasing the chemical stability of the compound during storage, and the physical stability of the prepared concentrated solutions and premix.

Docetaxel is a cell microtubule stabilizing compound and as such can be used to treat various types of cancer or other diseases manifesting abnormal cell proliferation. The composition of the invention is particularly suitable for use in the manufacture of a medicament for the treatment of patients suffering from cancer or other hyperproliferative inflammatory disease. As used herein, the term "cancerous disease" includes, but is not limited to, soft and hard tissue cancers and blood-related cancers. The term "cancerous disease" refers to diseases of the skin, tissues, organs, bones, cartilage, blood and blood vessels. The term "cancer" further includes both primary and metastatic types of cancer.

The composition of the invention is preferably provided in the form of dosage units in sealed vials, preferably in glass vials.

Ethanol, which is the best biocompatible solvent, is used as a solvent in the composition of the present invention to bring docetaxel and other taxane active ingredients into solution.

The concentration of docetaxel in the claimed formulation is 40 mg per ml concentrate for co-solvent formulations. This concentration allows the preparation of a premix containing 10 mg docetaxel per ml. The premix is then diluted in an aqueous solution for infusion in the required amount (usually 1 to 2 parts of premix per 25 parts of infusion) and parenterally administered within one hour.

A sorbitol derivative is used as a surfactant in the composition of the invention; it is chemically a sorbitan polyoxyethylene (20) monooleate (i.e. polysorbate 80; this name is used hereinafter) which is a nonionic surfactant, emulsifier.

This surfactant was chosen because of its good dissolution capacity for docetaxel and its ability to keep it in aqueous solution for a long time without precipitation. Pharmaceutical formulations containing poiysorbate 80 appear to be more advantageous for parenteral administration than formulations containing ethoxylated castor oil due to the different farm35 of the co-kinetic behavior of poiysorbate 80. This compound is much more rapidly eliminated from the plasma of patients by carboxylesterase hydrolysis (see AJ Titi and Col Clin Pharmakokinetics 2003, 42 (7), 665-685).

The composition of the present invention comprises 30 to 30 polysorbate 80 in the concentrate

87.5% by weight and preferably from 48 to 58% by weight based on the weight of the concentrate. In the co-solvent, it comprises an amount of 5 to 35% by weight and preferably from 16 to 20% by weight, based on the weight of the co-solvent. Thus, per milligram of docetaxel in a form suitable for administration (in an infusion solution) accounts for 13 to 46 mg of poisorbate 80 and preferably 20.0 to 30.0 mg. After preparation of the premix and dilution thereof, the highest concentration of poysysorbate in the form suitable for administration is 2.0% by weight, but is usually in the range of 1.0 to 1.6% by weight based on the weight of the resulting infusion solution as a form suitable for administration.

In a preferred embodiment, the cosolvent-free composition of the present invention comprises in the concentrate of the concentrate polysorbate 80 in an amount of 30 to 96% by weight, preferably 60 to 70% by weight of the composition. Thus, as with the two-component formulation of the composition, per milligram of docetaxel in a form suitable for administration is 13 to 46 mg of polysorbate 80 and preferably 20 to 30 mg. Once the premix has been prepared and diluted, the highest concentration of poiysorbate 80 is again in a form suitable for administration of 2.0% by weight, but usually

C

It ranges from 1.0 to 1.6% by weight relative to the weight of the resulting infusion solution as a form suitable for administration.

It has been found that, for optimal stability of the composition, the composition must contain a pharmaceutically acceptable buffer predominantly of an acidic component. A preferred buffer is citrate buffer prepared using an excess of citric acid. Such a buffer preferably comprises 1000 to 1500 mg citric acid monohydrate and 5 to 100 mg trisodium citrate dihydrate per 100 ml solution.

A preferred composition of the invention comprises a concentrate consisting of 10 a) docetaxel trihydrate in an amount of from 1.5 to 8.5% (w / w), corresponding to an amount of from 15 to 85 mg / ml of anhydrous docetaxel;

(b) absolute ethanol in an amount of 3 to 57% (w / w);

(c) surfactants in an amount of 30 to 87,5% (w / w); and

d) 1 to 25% (w / w) of a buffer having a concentration of 47 to 71 mmol.T ^{1 of} citric acid monohydrate and 0.17 to 1.36 mmol.l ^{-1 of} trisodium citrate dihydrate;

and optionally a cosolvent consisting of

(e) surfactants in an amount of 5 to 35% (w / w), and optionally i

f) from 1 to 10% (w / w) of absolute ethanol and / or a pharmaceutically effective amount of a buffer.

A preferred embodiment of the composition of the present invention is only a concentrate consisting of:

(a) docetaxel trihydrate in an amount of 1,5 to 4,0% (w / w) corresponding to an amount of 15,0 to 40,0 mg / ml of anhydrous docetaxel;

(b) absolute ethanol in an amount of 3 to 57% (w / w);

(c) surfactants in an amount of 30 to 94,5% (w / w); and

d) an amount of from 1 to 26% (w / w) of a buffer having a concentration of 47 to 71 mmol.T ¹ citric acid monohydrate and 0.17 to 1.36 mmocl ^-1 trisodium citrate dihydrate.

Particularly preferred compositions of the present pharmaceutical composition are detailed in Table I.

The following examples are provided to illustrate the invention without limiting it in any way.

Overview of the drawings

Figures 1A-1D show a graph of the content of impurities produced by the breakdown of docetaxel in a sample of the concentrate of the pharmaceutical composition of Example 1 versus time. The y-axis shows the amount of total impurities (symbol ▲) and the amount of two selected impurities with the fastest increase (symbol ♦ for impurity 1 and for impurity 2) in% by weight relative to the weight of the sample. The time in hours is plotted on the x-axis.

Figure 1A shows the above dependence at 25 ° C;

Figure 1B shows the above dependence at 40 ° C;

Figure 1C shows the above dependence at 55 ° C; and Figure 1D shows the above dependence at 70 ° C.

Figures 2A-2D show a plot of the content of impurities produced by the breakdown of docetaxel in a sample of the concentrate of the pharmaceutical composition of Example 2 versus time. The y-axis shows the amount of total impurities (symbol A) and the amount of two selected

-7GB 300677 B6 impurities with the tendency to increase rapidly (symbol ♦ for impurity 1 and for impurity 2) in% by weight relative to the weight of the sample. The time in hours is plotted on the x-axis.

Figure 2A shows the above dependence at 25 ° C;

Figure 2B shows the above dependence at 40 ° C;

Figure 2C shows the above dependence at 55 ° C; and Figure 2D shows the above dependence at 70 ° C.

Chemical stability of the composition

The chemical stability of the composition of the present invention was tested in its concentrate, i. At different temperatures, the percentages of the sum of impurities and the two selected main impurities were measured with a tendency to the greatest increase resulting from the decomposition of docetaxel versus time. The claimed composition, the compositions of which are given in Table I, was exposed to temperatures of 25,

40, 55 and 70 ° C for up to 120 hours. The percent increases in both the sum of impurities and the two main impurities in the samples were determined by HPLC, see Figures 1A to 1D, 2A to 2D and Tables II and III. The increases were also evaluated by methods of mathematical regression analysis allowing extrapolation to determine the time period for reaching the specified limit concentration of impurities. The compositions tested according to the invention exhibit extremely low impurity increases over time; mathematical extrapolation to room temperature confirmed a high degree of stability beyond two years.

The physical stability of the premixture of the composition of the present invention, as defined by turbidity (precipitation of docetaxel), was at least 2 hours after preparation of the premix (data not shown).

Table I

Composition of the compositions of Examples 1 and 2

Composition of the composition according to Example 1 according to Example 2 Folder name concentrate; co-solvent: concentrate; cosolvent; in mg / ml in g / 20 ml in g / 100 ml in mg / ml in g / 20 ml in g / 100 ml Doeetaxel x 3H2O 42,68 ' 0,8536 ’ 42.68 0.8536 Ethanol abs. 300.0 6.00 2.71 380.0 7.60 Polysorbate 80 570.0 11.40 15.67 465.0 9,30 19.17 Puf? 80.0 1.60 100.0 2.00 Cleaned water to 100 ml to 100 ml

Comment

Corresponds to 40 mg of anhydrous docetaxel.

Corresponds to 0.80 g of anhydrous docetaxel.

 cz, ουυο / / do ^ Buffer composition:

1. Citric acid monohydrate ....... 1300 mg

2. Trisodium citrate dihydrate ........... 40 mg

3. Purified water ................................. up to 100 ml

Example 1

Preparation of concentrate io

Weigh 853.6 mg of docetaxel trihydrate and 6.0 g of absolute ethanol into the flask and shake until the substance is completely dissolved. 11.4 g of polysorbate 80 are then added to the solution and mixed again thoroughly.

An aqueous buffer solution consisting of citric acid monohydrate and trisodium citrate dihydrate at a concentration of 62 mmol / ^{l of} acid and 1.4 mmol of salt was prepared. 1.6 g of this buffer are added to the flask with a solution of ethanol and polysorbate 80 in ethanol and mixed until a homogeneous solution is obtained. The concentrate thus prepared had a concentration of 40 mg docetaxel per ml of solution.

From the prepared concentrate a sample is taken, which is determined by HPLC analysis of impurity profile, 10 ml were taken for preparation of the premix and the residue is divided into four well-sealed containers, stored at the temperatures 25, 40, 55 and 70 ^D C. In the interval 24, At 48, 96 and 120 hours, a sample is taken from each container and the percentage of impurities is determined. The results for the sum of the impurities and the two selected impurities are summarized in Table II and in FIG. 1A to 1D.

Table II: Chemical stability of the concentrate of the composition of Example 1, expressed in wt. relative to the weight of the sample

Time 0 hours 24 hours 48 hours Impurity ^ xC 25 40 55 70 25 40 55 70 Impurity 1 0,084 0,082 0,088 0.108 0.253 0,086 0,094 0,128 0.352 Impurity 2 0.106 0.108 0.109 0,124 0.269 0.109 0,110 0.141 0.431 Sum of impurities 0.504 0.504 0.511 0.549 0,886 0.509 0.521 0.587 1,244

\time Impurity ^^ C 96 hours 120 hours 25 40 55 70 25 40 55 70 Impurity 1 0,086 0.108 0.201 0.389 0,088 0,118 0.214 0.436 Impurity 2 0,110 0,116 0.180 0.803 0,110 0,124 0.204 1,061 Sum of impurities 0.512 0.535 0.699 1,975 0.514 0.559 0.744 2,366

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Preparation of cosolvent

Next, prepare a co-solvent solution: weigh 2.71 g of absolute ethanol, 15.67 g of 5 polysorbate 80 into a clean flask and make up to 100 ml with purified water. Stirring is continued until a homogeneous solution is obtained.

Preparation of the premix io A premix is prepared by thoroughly mixing 10 ml of concentrate and 30 ml of cosolvent. The premix thus prepared had a concentration of 10 mg docetaxel in 1 ml of solution.

Example 2 15

The work is carried out in the same manner as in Example 1, except that 7.6 g of absolute ethanol, 9.3 g of polysorbate 80 and 2.0 g of buffer of the same composition as in Example 1 are used in the preparation of the concentrate. in this case, it consists of a 19.17% (w / w) polysorbate solution 80.

The results of chemical stability, given by the percentages of the sum of impurities and the two selected impurities in the test samples, are summarized in Table III and in FIG. 2A to 2D.

Table III: Chemical stability of the composition of Example 2, expressed in wt. relative to the weight of the sample

Time Impurity íC 0 hours 24 hours 48 hours 25 40 55 70 25 40 55 70 Impurity 1 0,082 0,085 0,086 0,103 0.242 0,085 0.091 0.120 0.364

Impurity 2 0.109 0.108 0,110 0,122 0.255 0.109 0,112 0.136 0.437 Sum of impurities 0.501 0.504 0.514 0.536 0,900 0.505 0.520 0.590 1,254

Time Do not read ota ^ xC 96 hours 120 hours 25 40 55 70 25 40 55 70 Impurity 1 0,086 0.106 0.155 0.390 0,086 0,111 0.181 0.441 Impurity 2 0.109 0,116 0.176 0,759 0,111 0.121 0.210 1,006 Sum of impurities 0.510 0.529 0,685 1,965 0.511 0.548 0.730 2.303

Industrial applicability

Docetaxel is an antitumor active chemotherapeutic in the taxane family. In vivo, it is effective against a wide variety of tumors. It is mainly used in cases of breast cancer but also in ovarian cancer.

CZ JWJO // bO and lung. Its efficacy for the treatment of hepatocellular carcinoma and other cancers has also been described. The novel pharmaceutical composition containing the taxane derivative of doeetaxel according to the present invention, especially for the preparation of an infusion solution, is characterized by exceptional chemical and physical stability over several years. Preferably, the concentrate can be stored for a long period of time for commercial purposes and, even after a long storage period, provides a stable infusion solution after addition of the cosolvent and after usual dilution by medical personnel. Its commercial preparation will expand the spectrum of available taxane anticancer drugs.

Claims (4)

PATENT CLAIMS 15 1. A stable pharmaceutical composition containing doeetaxel suitable for the preparation of infusion solutions which exhibits enhanced chemical resistance, comprising a concentrate consisting of: (a) a pharmaceutically effective amount of doeetaxel; (b) an organic solvent which is ethanol; (C) polyoxyethylene (20) sorbitan monooleate surfactants; and d) a pharmaceutically acceptable amount of a buffer; and optionally a co-solvent comprising: e) an aqueous solution of a pharmaceutically acceptable amount of polyoxyethylene (2G) sorbitan monooleate and optionally i F) ethanol as an organic solvent and / or a pharmaceutically acceptable amount of a buffer. Pharmaceutical composition according to claim 1, characterized in that it is in the form of a premix comprising a mixture of a concentrate and a cosolvent. 30 3. A pharmaceutical composition according to claim 2 which is in the form of a premix suitable for administration. Pharmaceutical composition according to claim 3, characterized in that it is in the form of a premix which is adapted for administration by the addition of an aqueous solution for infusion selected from the group consisting of: 35 0.9% aqueous NaCl solution and 5% aqueous glucose solution. A pharmaceutical composition according to claim 1 wherein the suitable buffer is citrate buffer. 40 Pharmaceutical composition according to claim 1, characterized in that it comprises a concentrate consisting of: (a) doeetaxel trihydrate in an amount of between 1,5% and 8,5% (w / w) corresponding to an amount of between 15 and 85 mg / ml of anhydrous doeetaxel; (b) absolute ethanol in an amount of 3 to 57% (w / w); (C) polyethylene (20) sorbitan monooleate in an amount of from 30 to 87.5% (w / w); and d) from 1 to 25% (w / w) of a buffer having a concentration of 47 to 71 mmol.l · ¹ citric acid monohydrate and 0.17 to 1.36 mmol / ^l trisodium citrate dihydrate; and optionally a co-solvent comprising: (e) polyethylene (20) sorbitan monooleate in an amount of from 5 to 35% (w / w), and optionally -11 CZ 300677 B6 f) from 1 to 10% (w / w) of absolute ethanol and / or a pharmaceutically effective amount of a buffer. A pharmaceutical composition according to claim 6, comprising a concentrate consisting of; (a) docetaxel trihydrate in an amount of between 1,5% and 8,5% (w / w) corresponding to an amount of between 15 and 85 mg / ml of anhydrous docetaxel; (b) absolute ethanol in an amount of between 3 and 49,5% (limo mass), c) monooleate, polyethylene (20) sorbitan monooleate in an amount of from 48 to 58% (w / w), and also d) 1 to 25% (w / w) of buffer at a concentration 47 to 71 mM of citric acid monohydrate, ¹ and 0 17 to 1.36 mmol.l ^{-1 of} trisodium citrate dihydrate; and optionally a co-solvent comprising: (e) polyethylene (20) sorbitan monooleate in an amount of from 5 to 35% (w / w); (F) from 1 to 10% (w / w) of absolute ethanol and / or a pharmaceutically effective amount of a buffer, 8. A stable pharmaceutical composition comprising docetaxel according to claim 1 comprising a concentrate consisting of a pharmaceutically effective amount of docetaxel in (2) mixtures of ethanol, polyethylene (20) sorbitan monooleate and buffer, 9. A pharmaceutical composition according to claim 8 wherein the suitable buffer is citrate buffer. 25 Pharmaceutical composition according to claim 8, characterized in that it comprises a concentrate consisting of: (a) docetaxel trihydrate in an amount of 1,5 to 4,0% (w / w) corresponding to 15 to 40,0 mg / ml of anhydrous docetaxel; (b) absolute ethanol in an amount of 3 to 57% (w / w); (C) polyethylene (20) sorbitan monooleate in an amount of from 30 to 94.5% (w / w); and d) 1 to 25% (w / w) of a buffer having a concentration of 47 to 71 mmol / ^{l of} citric acid monohydrate and 0.17 to 1.36 mmol / ^{l of} trisodium citrate dihydrate. 11. A pharmaceutical composition according to claim 8 comprising a concentrate consisting of: (a) docetaxel trihydrate in an amount of 1,5 to 4,0% (w / w) corresponding to 15,0 to 40,0 mg / ml of anhydrous docetaxel; (b) absolute ethanol in quantities of 3 to 37,5% (w / w); (c) polyethylene (20) sorbitan monooleate in an amount of from 60 to 70% (w / w); and (D) 1 to 25% (w / w) of a buffer having a concentration of 47 to 71 mmol.l · ¹ citric acid monohydrate and 0.17 to 1.36 mmol.l · ¹ trisodium citrate dihydrate. A process for the preparation of a pharmaceutical composition according to claims 1 to 4, wherein the taxane derivative docetaxel in a solution consisting of ethanol, polyethylene mono-oleate sorbitan (20) and a buffer is mixed with a solution consisting of an aqueous solution of ethanol, polyethylene monoleate. (20) sorbitan and optionally a buffer, to prepare a premix which is then formulated into a form suitable for administration. 13. A method according to claim 12, wherein the premix is formulated in a form suitable for administration by dilution in a ratio of 1 to 2 parts of the premix to 25 parts of the infusion with sterile aqueous. BG solution for infusion, consisting of 0.9% aqueous NaCl solution or 5% aqueous glucose solution. 14. A process for the preparation of a pharmaceutical composition according to claim 8, wherein: 5. The method according to claim 5, wherein the taxane derivative docetaxel is brought into a solution consisting of ethanol, polyethylene (20) sorbitan monooleate and a buffer to obtain a concentrate which is then brought into a form suitable for administration. 15. A method for producing a pharmaceutical composition according to claim 12 or 14, wherein the composition is formulated for intravenous administration. Use of a pharmaceutical composition according to claim 1 or 8 for the preparation of a medicament in a form suitable for intravenous administration for the treatment of various types of cancer diseases and other diseases manifesting abnormal cell proliferation. A kit for inhibiting tumor growth, comprising a stable pharmaceutical composition according to claim 1, comprising a concentrate consisting of a taxane derivative of docetaxel, ethanol as a suitable solvent, polyethylene (20) sorbitan monooleate and a pharmaceutically acceptable amount of a buffer, and a cosolvent; containing pharmaceutically acceptable 20 amounts of polyethylene (20) sorbitan monooleate, ethanol as a solvent, and optionally a pharmaceutically acceptable amount of buffer, the concentrate and the cosolvent being for use in combination to form a premix which is diluted prior to administration to the patient by a sterile aqueous solution for infusion. 4 drawings -13GB 300677 B6