RU2279873C2 - Vinorelbin-containing oral pharmaceutical composition for soft capsule and method for treatment - Google Patents

Abstract

FIELD: medicine, oncology, pharmacy.

SUBSTANCE: invention describes a liquid pharmaceutical composition used in treatment of cancer and comprising vinorelbin as an active component and is useful for incapsulation into soft capsules. The liquid oral pharmaceutical composition useful as a liquid filling agent composition for the dosed formulation as a soft capsule comprises vinorelbin or its pharmaceutically acceptable salt, in particular, vinorelbin tartrate, ethanol, water, glycerol and polyethylene glycol. Also, invention relates to a method for preparing cancer that involves oral administration to a patient a soft capsule comprising the pharmaceutical composition. The liquid composition containing vinorelbin proves the improved solubility and bioavailability for oral administration.

EFFECT: improved and valuable pharmaceutical and medicinal properties of pharmaceutical composition.

13 cl, 7 tbl, 6 ex

Description

The invention relates to the field of orally administered pharmaceutical compositions for treating cancer. Specifically, the invention relates to oral dosage forms containing vinca vinorelbine alkaloid as a pharmaceutically active ingredient.

BACKGROUND OF THE INVENTION

Vinorelbine or 3 ', 4'-didehydro-4' '- deoxy-C'-norvincaleikoblastin is a derivative of the vinca alkaloid compound, which exhibits cytostatic effects by inhibiting tubulin polymerization. Vinorelbine inhibits mitosis in the G2 + M phase. Vinorelbine and its pharmaceutical salt forms, including tartrate salt form, are known both as antineoplastic agents and antimitotic agents and are used in the treatment of large cell lung cancer and metastatic breast cancer.

Vinorelbine is widely used for administration to patients with cancer, as part of parenteral chemotherapy, by intravenous infusion or injection. Although the medicine can be administered in a variety of ways, the intravenous route is one of the most commonly used forms of administration of vinorelbine due to the fact that it is associated with increased bioavailability. Vinorelbine tartrate is currently manufactured by Plantes et Industrie, Gaillac, France.

For the oral route of administration of the drug, oral dosage forms were studied, including soft capsule dosage forms containing vinorelbine. The possible use of dosage forms in the form of soft capsules for the delivery of liquid forms of vinorelbine for the treatment of cancer is investigated in Rowinsky et al., "Pharmacokinetic, Bioavailability, and Feasibility Study of Oral Vinorelbine in Patients with Solid Tumors", J. Clin. Oncol., Vol. 12 (9) (September, 1994), p. 1754-63; Zhou et al., "Relative Bioavailability of Two Oral Formulations of Navelbine in Cancer Patients," Biopharmaceutics & Drug Disposition, Vol. 15 (1994), pp. 577-86; and Jassem et al., "A Multicenter Randomized Phase II Study of Oral vs. Intravenous Vinorelbine in Advanced Non-small-cell Lung Cancer Patients", Annals of Oncology, Vol. 12 (2001), pp. 1375-81.

However, the development of liquid filler compositions suitable as the contents of a soft capsule has proven difficult. In capsule filler compositions that can be used in combination with soft capsules, it is necessary that the active ingredient be dissolved in a mixture with a solvent. In addition, the filler composition, in General, must be chemically compatible with the material of the capsule and to prevent degradation of the material after encapsulation, as well as be inert or reduce adverse chemical interaction with the active ingredient. Ultimately, to ensure applicability, the biological activity of the active ingredient should not be significantly compromised. Accordingly, it may be difficult to develop a balance between all these characteristics, taking into account, at the same time, the chemical nature of the active ingredient.

In the pharmaceutical field, there is a need for orally administered dosage forms containing vinorelbine as an active ingredient. In addition, there is a need for finished capsule filler formulations containing vinorelbine that have improved solubility and stability characteristics and which have effective bioavailability after ingestion.

SUMMARY OF THE INVENTION

The present invention is directed to a pharmaceutical composition containing vinorelbine as an active ingredient that is suitable for encapsulation in soft capsules, and a method for treating cancer by oral administration. Accordingly, the invention provides a liquid filler composition for a dosage form in the form of a soft capsule, said composition comprising:

a) vinorelbine or a pharmaceutically acceptable salt thereof;

b) ethanol;

c) water;

d) glycerin; and

e) polyethylene glycol.

In a preferred embodiment, the tartrate salt form of vinorelbine is used in the composition. In an even more preferred embodiment, the soft capsule composition for encapsulating the excipient comprises a mixture of porcine and bovine gelatin.

The invention also provides a method of treating cancer, comprising orally administering to a patient in need of such treatment a pharmaceutical composition comprising:

a) a pharmaceutically effective amount of vinorelbine or a pharmaceutically acceptable salt thereof;

b) ethanol;

c) water;

d) glycerin; and

e) polyethylene glycol;

where the specified composition is encapsulated in a soft capsule.

DETAILED DESCRIPTION OF THE INVENTION

The term "pharmaceutically acceptable salt" in the context of vinorelbine means an indication that the active ingredient vinorelbine is present in the pharmaceutical composition in its salt form suitable for oral administration. A variety of salt forms known in the art may be used for compounds such as vinorelbine and other derivatives of vinca alkaloids.

The term "pharmaceutically effective amount" in the context of vinorelbine means that the dosage of vinorelbine as an active ingredient is in the range between the minimum amount that provides the desired pharmaceutical effect, but below the amount determined to be toxic to the patient as a whole, exceeding the patient's tolerance levels for the intended treatment, with accommodation of a variety of patient responses. Thus, the pharmaceutical efficacy for vinorelbine can be determined on the basis of in vivo antineoplastic and antimitotic activity.

The invention includes an improved orally administrable pharmaceutical composition comprising vinorelbine suitable for encapsulation in a soft capsule dosage form. It has been found that a liquid filling composition containing vinorelbine as an active ingredient can be formulated to provide improved solubility and bioavailability for oral administration, while at the same time balancing the chemical properties of the various ingredients by a method suitable for encapsulation in a soft capsule material.

Vinorelbine and its salt forms for preparing the filler composition of the present invention can be obtained by organic synthesis from natural starting materials or purchased directly from the manufacturer.

The amount of vinorelbine, namely, the pharmaceutically effective amount of vinorelbine or its pharmaceutically acceptable salt, which can be used in the pharmaceutical composition of the present invention, may vary, provided that the amount and concentration of the active ingredient can be dissolved in the excipient composition, providing the total volume of the dosage form suitable for oral administration. The pharmaceutical composition of the present invention may include base amounts of vinorelbine present in amounts ranging from about 5 mg to about 100 mg, preferably in the range between about 20 mg and about 80 mg per soft capsule. With respect to the percentage, the composition of this invention may preferably include vinorelbine tartrate in a pharmaceutically effective amount ranging from about 14 wt.% To about 18 wt.% Of the total weight of the filler composition.

Ethanol is present as a co-solvent with polyethylene glycol in the filler composition of the present invention and is important to ensure the stability and solubility of vinorelbine and the stability of the capsule shell. The amount and ratio of ethanol and polyethylene glycol in the excipient composition of the invention may be critical to obtaining an acceptable soft capsule. During storage of capsules containing compositions with ethanol, ethanol usually tends to vaporize the liquid filler composition, causing a “dent” effect on the capsule. Preferably, the amount of ethanol for use in the filler composition of the present invention is relatively low. Thus, ethanol is present in majesty in the range of from about 0.3 wt.% To about 7.5 wt.% Of the total weight of the filler composition. Preferably, ethanol is present in an amount of from about 1.6 wt.% To about 5 wt.% Of the total weight of the composition.

The mass ratio of water to ethanol in the composition of this invention may be from about 2: 1 to about 3: 1. Preferably, the mass ratio of water to ethanol is from about 2.3: 1 to about 2.7: 1, more preferably 2.5: 1. The aqueous content of the composition, preferably in the form of purified water, comprises an amount of from about 1 wt.% To about 15 wt.% Of the total weight of the filler composition.

The composition in accordance with this invention may also include glycerin, sorbitol and propylene glycol and mixtures thereof. The total amount of glycerol, sorbitol and / or propylene glycol used in the composition may range from about 0.1 wt.% To about 20 wt.% Of the total weight of the composition, preferably from about 0.2 wt.% To about 12 wt. .%. In an even more preferred embodiment, the total glycerol, sorbitol and / or propylene glycol is present in an amount in the range between about 0.8 wt.% And 1.4 wt.% Of the total filler mass.

A form of polyethylene glycol that can be used in the invention is a liquid form of polyethylene glycol having an average molecular weight in the range of from about 200 to about 600 daltons. In a preferred embodiment, polyethylene glycol having an average molecular weight of from about 300 to about 400, most preferably 400, is used. Polyethylene glycol may be present in the composition of the present invention in an amount ranging from about 66 wt.% To about 78 wt.% Of the total mass of the composition.

In an even more preferred embodiment, the soft capsule material comprises a mixture of porcine and bovine gelatin in a weight ratio of from about 2: 1 to 1: 2. In the following examples, all percentages are mass percentages unless otherwise specified.

EXAMPLES

The finished form of vinorelbine in the form of a soft capsule

Example 1. The finished form of vinorelbine for soft capsules

Vinorelbine tartrate is dissolved in a mixture of excipients: purified water, ethanol, glycerol and polyethylene glycol 400 using a Becomix mixer or an equivalent mixer. An alternative method consists, firstly, in dissolving vinorelbine tartrate in purified water and ethanol and, secondly, in the slow addition of glycerol and polyethylene glycol 400.

The following finished form of soft capsule filler is prepared in accordance with the invention. It also constitutes the best practice of the present invention.

Formula 1

Ingredient: Amount, %: Vinorelbine Tartrate 15.8 Ethanol 2.9 Purified water 7.1 Glycerol 1,1 Polyethylene glycol 400 73.1 General content 100.0

The shell of the soft capsule can be made of any polymer or polymer mixture that are suitable for use in pharmaceutical dosage forms in the form of soft capsules. A variety of such soft capsule materials may be used that are well known to those skilled in the art. See, for example, US Pat. No. 6,340,473. Soft capsule shell materials that may be used include, but are not limited to, those disclosed in US Pat. No. 6,340,473. Capsule shell materials may also include plasticizers, such as glycerin , sorbitol and propylene glycol. In yet another embodiment, the capsule shell material may further include an embrittlement inhibitor. One such inhibitor composition is described in European Patent No. 121321, the entire text of which is incorporated herein by reference. When brittleness inhibitor is used in the shell material, other polyalcohols can also be combined with sorbitol and sorbitan mixtures. One example of a polyalcohol, which can thus be combined, includes hydrogenated polysaccharides. In one embodiment, the capsule material comprises from about 4 wt.% To about 25 wt.% Sorbitol / sorbitan mixture, preferably from about 9 wt.% To about 15 wt.%, Relative to the total weight of the capsule shell.

When gelatin is used as the capsule material, a mixture of porcine and bovine gelatins is preferred. In an even more preferred embodiment, the capsule shell comprises 2 parts of porcine gelatin for each part of bovine gelatin. Other additives, such as colorants and lubricants, may also be used in the capsule material.

The pharmaceutical composition of the present invention can be obtained using conventional methods and equipment for the production of pharmaceutical compositions. Soft capsules that contain the pharmaceutical composition of the invention can also be prepared using conventional manufacturing methods and equipment for encapsulating soft capsules. Encapsulation techniques are well known to those skilled in the art.

Example 2. Comparative data on the ethanol content and the relationship between the water content and the ethanol content

Two filler compositions are prepared using different amounts of ethanol in the filler composition. Formula 1 and Formula 2 are obtained in the same way. Firstly, vinorelbine tartrate is dissolved in a mixture of purified water and ethanol, and secondly, glycerol and polyethylene glycol 400 are slowly added and mixed until a homogeneous mixture is obtained.

Evaluated filler compositions are as follows:

Table 1
Finished forms of vinorelbine (for the theoretical ratio of vinorelbine tartrate / vinorelbine base equal to 1.385) Formula 1 Formula 2 Ingredient: (mg) (%) (mg) (%) Vinorelbine Tartrate 55.40 15.8 55.40 26.6 (vinorelbine base) (40.00) (40.00) Ethanol 10.0 2.9 20.60 9.9 Purified water 25.00 7.1 12.40 6.0 Glycerol 4.00 1,1 8.80 4.2 PEG 400 255.60 73.1 110.80 53.3 Total 350,0 100.0 208.00 100.0

The formulations are prepared so that, for comparison, a 7% weight difference in ethanol concentrations in the formulations is presented. Formula 1 has a ratio of water to ethanol of approximately 2.5: 1, while the ratio of water to ethanol in Formula 2 is approximately 0.6: 1. The finished filler forms are then encapsulated in a capsule material made from a mixture comprising 2 parts of pork and 1 part of bovine gelatins.

The appearance of dents in 100 percent of the 20 capsules containing Formula 2, packed in a container of amber glass with a volume of 50 cm ³ , is observed after 18 months of storage. This "denting" phenomenon occurs due to the evaporation of ethanol from the filler composition. The results demonstrate that both the ethanol content and the ratio of water to ethanol presented in the excipient composition of the invention are important for maintaining the desired properties of both the pharmaceutical composition and the capsule material.

Example 3. Comparative data of the finished forms of vinorelbine in the form of soft capsules

Five different liquid filler compositions containing vinorelbine are obtained and their solubility characteristics are evaluated. Each of the compared formulations is prepared with the same amount of active vinorelbine tartrate, while at the same time changing the amount of other ingredients. From 50 g to 100 g of excipient are obtained for each formulation by using a laboratory disk mixer and introducing the drug into various ingredients. Solubility is evaluated by visual inspection of the transparency of each excipient preparation. The ingredients of the composition and relative amounts are summarized in the following table 2:

table 2
Finished forms of vinorelbine (for the theoretical ratio of vinorelbine tartrate / vinorelbine base equal to 1.385) Ingredient Formula 3 % Formula 4 % Formula 5 % Formula 6 % Formula 7 (2) % Vinorelbine Tartrate 27.70 mg 73.5 27.70 mg 19.1 27.70 mg 73.5 27.70 mg 62.7 27.70 mg 26.6 (Vinorelbine base) (20.00 mg) (20.00 mg) (20.00 mg) (20.00 mg) (20.00 mg) Ethanol 0 0 10.00 mg 26.5 10.30 mg 23.3 10.30 mg 9.9 Purified water 10.00 mg 26.5 11.20 mg 7.7 0 6.20 mg 14.0 6.20 mg 6.0 Polyethylene Glycol 400 0 104.60 mg 72.1 0 0 55.40 mg 53.3 Total amount 37.70 mg 100.0 145.10 mg 100.0 37.70 mg 100.0 44.20 mg 100.0 104.00 one hundred

The results of this experiment are summarized in table 3 as follows:

Table 3
Solubility data Formula 3 Formula 4 Formula 5 Formula 6 Formula 2 Observation Vinorelbine is not completely dissolved Vinorelbine is not completely dissolved High viscosity Vinorelbine dissolved Vinorelbine dissolved

Since vinorelbine does not completely dissolve in Formulas 3 and 4, they are not retained for further evaluation. Formula 5 is excluded due to its high viscosity and the inability to feed the pump into the encapsulation machine. Formula 2 is preferable to Formula 6, since the liquid filler composition must include polyethylene glycol 400 to maintain good compatibility with the capsule material. In addition, the high percentage of ethanol in Formula 6 may lead to an unacceptable phenomenon of dents. The results demonstrate the need for the presence of water and ethanol together with polyethylene glycol, as well as the presence of certain amounts / ratios to ensure the desired solubility of vinorelbine in the finished form.

The finished form of this invention increases the concentration of dissolved vinorelbine, while minimizing the presence of both water and ethanol. As can be seen from the data, 20 mg of vinorelbine does not completely dissolve in 10 mg of water and an attempt to dissolve an amount of vinorelbine equal to 20 mg in 10 mg of ethanol results in a viscous product. Surprisingly, it was found that 20 mg of vinorelbine can be dissolved in a mixture of only 6.20 mg of water and 10.30 mg of ethanol, before the addition of polyethylene glycol, without the observed precipitation of vinorelbine. Thus, the finished form of the invention is particularly suitable for dosage forms in the form of soft capsules.

Example 4. Data on the stability of vinorelbine

Vinorelbine stability: 1) in the form of a powder (active pharmaceutical ingredient) in a container consisting of an aluminum bottle coated with an epoxy varnish from the inside, and 2) a filler for a soft capsule dissolved in a blister pack, dissolved in the composition, evaluated by measuring the impurity content and color after storage.

The impurity content is measured in accordance with the method of HPLC to quantify the presence of active vinorelbine, and the measurements are carried out at intervals of 3, 6, 9, 12, 18 and 24 months. The applied HPLC chromatographic method includes an assembly equipped with an automatic injector and a UV detector with a variable wavelength tuned to 267 nm. A stainless steel column 150 mm long and 3.9 mm in diameter is filled with octadecyl silica gel - 300 Å - spherical, 5 μm. The mobile phase is sodium decansulfonate (1.2217 g), 0.05 M phosphate buffer (pH = 4.2) 380 ml and methanol (620 ml) with a thermostatically controlled column temperature of + 40 ° C and a mobile flow rate phase 1 ml / min.

Each load is stored for an analysis time at 5 ± 3 ° C.

The average deviation is calculated as the difference between the average value of the results for a given analysis time and the average value of the results at the initial value of time (t ₀ ) for several downloads (3 downloads for vinorelbine powder, 3 downloads for 20 mg soft capsules, 4 downloads for 30 mg soft capsules , 3 downloads for 40 mg soft capsules, 3 downloads for 80 mg soft capsules).

The results are summarized in table 4.

Table 4
The relative spatial percentage of impurities Analysis time (months) 3 6 9 12 eighteen 24 Vinorelbine (powder): Mean deviation (t ₀ → analysis time) N.p. 0.12 N.p. 0.39 0.78 1.13 Maximum deviation (t ₀ → analysis time) N.p. 0.21 N.p. 0.44 0.85 1.32 Vinorelbine (liquid): Mean deviation (t ₀ → analysis time) 0.08 0.15 0.12 0.15 0.16 0.10 Maximum deviation (t ₀ → analysis time) 0.25 0.36 0.32 0.42 0.42 0.32 N.p. = do not spend

As can be seen from the results, a liquid filler composition containing dissolved vinorelbine in a soft capsule has a significantly lower percentage of impurities for time periods of 12, 18 and 24 months. The results demonstrate that the liquid formulation of vinorelbine of the invention has a longer shelf life than the powder form of the drug.

Example 5. Comparative evolution of color

Comparative color evolution is also evaluated for each sample and the corresponding time interval, as shown in Example 4. In this experiment, the pure powdered form of vinorelbine is compared with the liquid composition of the encapsulated vinorelbine filler of the invention for a soft capsule (Formula 1). Color is measured at 5 ± 3 ° C by absorption in the ultraviolet range at 420 nm of an aqueous solution of vinorelbine at 10 mg / ml in the form of a base of vinorelbine. Color data is an indicator of degradation of vinorelbine by non-chromatographically oxidized impurities. The average deviation is calculated as the difference between the average value of the results for a given analysis time and the average value of the results at the initial value of time (t ₀ ) for several downloads (3 downloads for vinorelbine powder, 3 downloads for 20 mg soft capsules, 4 downloads for 30 mg soft capsules , 3 downloads for 40 mg soft capsules, 3 downloads for 80 mg soft capsules).

The results are summarized in table 5

Table 5
Color Evolution Data Analysis time (months) 3 6 9 12 eighteen 24 Vinorelbine (powder): Mean deviation (t ₀ → analysis time) N.p. 0.006 N.p. 0.013 0.017 0,029 Maximum deviation (t ₀ → analysis time) N.p. 0.012 N.p. 0.015 0,025 0, wt.% Vinorelbine (liquid): Mean deviation (t ₀ → analysis time) 0,000 0.002 0.005 0.005 0.005 0.006 Maximum deviation (t ₀ → analysis time) 0.015 0.006 0.011 0.006 0,021 0.017 N.p. = do not spend

As can be seen from the above data, the liquid composition of vinorelbine exhibits a higher purity at the analysis time after 6, 12, 18 and 24 months compared to the powder form of the drug when using color as an indicator of storage stability.

Example 6. Comparative data for the capsule material

Many samples are obtained for two types of capsules containing identical excipient compositions, and capsule fragility is tested.

The composition of two different capsules are shown in the table

Soft capsules are stored for a period of two (2) years at a temperature of 5 ± 3 ° C. 10 capsules from each group are subjected to fracture tests using forceps and average values are calculated in each test. The average force for capsule 1 is 160 N, while the average force for capsule 2 is 98 N. Capsule 2 therefore exhibits greater fragility compared to capsule 1.

As can be seen from the above data, the capsule material itself can affect the structural integrity of the dosage form even in the case of identical excipient encapsulated excipient compositions. A capsule 1 containing a mixture of pork and bovine gelatins as a source of gelatin exhibits increased resistance to breaking forces compared to a capsule 2 containing only bovine gelatin as a source of gelatin.

A method of treatment using soft capsules containing vinorelbine.

Oral administration of soft capsules comprising vinorelbine obtained in accordance with this invention can be used to treat cancers that respond to vinorelbine by inhibiting the growth of cancer cells. The antineoplastic and antimitotic effects of vinorelbine by inhibiting tubulin polymerization are realized in connection with the systemic bioavailability of a drug substance by oral administration provided by the invention.

Industrial applicability

This invention can be used in chemotherapy for patients with cancer for whom the administration of vinorelbine and the associated antineoplastic and antimitotic effects may be beneficial. The invention is particularly applicable in situations where oral administration is a desirable or preferred intravenous route of administration.

Each patent and publication cited in this application is incorporated into this description by reference, as if the full text of each document was individually incorporated by reference. The invention is described above in this document with reference to various specific and preferred embodiments and methods. It should be understood, however, that reasonable modifications and variations of such embodiments and methods can be made without substantial departure, both from the spirit and scope of the invention as defined by the claims below.

Claims (13)

1. A liquid oral pharmaceutical composition for the treatment of cancer, suitable as a liquid excipient composition for a dosage form in the form of a soft capsule, said composition comprising: a) a pharmaceutically effective amount of vinorelbine or a pharmaceutically acceptable salt thereof; b) ethanol, present in an amount of from about 0.3 wt.% to about 7.5 wt.% of the total weight of the filler composition; c) water; d) glycerin and e) polyethylene glycol present in an amount of from about 66 wt.% to about 78 wt.% of the total weight of the filler composition. 2. The pharmaceutical composition according to claim 1, where the specified dosage form in the form of a soft capsule is a soft gelatin capsule. 3. The pharmaceutical composition according to claim 2, where the specified gelatin is a mixture of pork and bovine gelatin. 4. The pharmaceutical composition according to claim 1, where the specified pharmaceutically acceptable salt of vinorelbine is vinorelbine tartrate. 5. The pharmaceutical composition according to claim 1, where the specified polyethylene glycol has an average molecular weight in the range from about 200 to about 600. 6. The pharmaceutical composition according to claim 5, where the polyethylene glycol is a polyethylene glycol 400. 7. The pharmaceutical composition according to claim 1, where the specified composition includes: a) vinorelbine tartrate, present in an amount of from about 5 mg to about 100 mg per capsule; b) ethanol, present in an amount of from about 0.3 wt.% to about 7.5 wt.% of the total weight of the filler composition; c) water present in an amount of from about 1 wt.% to about 15 wt.% of the total weight of the filler composition; d) glycerin present in an amount of from about 0.1 wt.% to about 20 wt.% of the total weight of the filler composition; e) polyethylene glycol 400, present in an amount of from about 66 wt.% to about 78 wt.% of the total weight of the filler composition. 8. The pharmaceutical composition according to claim 7, where the specified composition includes: a) vinorelbine tartrate, present in an amount of from about 5 mg to about 100 mg per capsule; b) ethanol, present in an amount of from about 1.6 wt.% to about 5 wt.% of the total weight of the filler composition; c) water present in an amount of from about 1 wt.% to about 15 wt.% of the total weight of the filler composition; d) glycerin present in an amount of from about 0.2 wt.% to about 12 wt.% of the total weight of the filler composition; e) polyethylene glycol 400, present in an amount of from about 66 wt.% to about 78 wt.% of the total weight of the filler composition. 9. The pharmaceutical composition of claim 8, where the mass ratio of water to ethanol in the composition is in the range from about 2: 1 to about 3: 1. 10. The pharmaceutical composition according to claim 1, where the mass ratio of water to ethanol in the composition is in the range from about 2: 1 to about 3: 1. 11. The pharmaceutical composition according to claim 1, where the mass ratio of water to ethanol in the composition is in the range from about 2.3: 1 to about 2.7: 1. 12. A method of treating cancer, including oral administration to a patient in need of such treatment, a pharmaceutical composition comprising: a) a pharmaceutically effective amount of vinorelbine or a pharmaceutically acceptable salt thereof; b) ethanol, present in an amount of from about 0.3 wt.% to about 7.5 wt.% of the total weight of the filler composition; c) water; d) glycerin and e) polyethylene glycol present in an amount of from about 66 wt.% to about 78 wt.% of the total weight of the filler composition; where the specified composition is encapsulated in a soft capsule and where the mass ratio of water to ethanol in the composition is from about 2: 1 to about 3: 1. 13. The method according to item 12, where the specified composition includes: a) approximately 15.8 wt.% vinorelbine tartrate; b) approximately 2.9 wt.% ethanol; c) approximately 7.1 wt.% water; d) approximately 1.1 wt.% glycerol and e) approximately 73.1 wt.% polyethylene glycol 400.