JP2024545690A - Pharmaceutical composition of fulvestrant with improved solubility and its preparation method - Google Patents

Abstract

The present invention relates to a pharmaceutical composition containing fulvestrant and a manufacturing method thereof. More specifically, the present invention relates to a pharmaceutical composition and a manufacturing method thereof that contains a specific nonionic surfactant, lecithin, castor oil and a specific alcohol in combination with fulvestrant, a poorly soluble drug, thereby improving the solubility of the drug and increasing the concentration of the drug in the formulation, thereby reducing the number of times the drug is administered while exhibiting the same pharmacological therapeutic effect as conventional fulvestrant formulations, thereby reducing the inconvenience of conventional formulations and increasing convenience for patients and medicine providers.
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Description

The present invention relates to a pharmaceutical composition containing fulvestrant and a method for producing the same. More specifically, the present invention relates to a pharmaceutical composition and a method for producing the same, which contains a specific nonionic surfactant, lecithin, castor oil, and a specific alcohol in combination with fulvestrant, a poorly soluble drug, thereby improving the solubility of the drug and increasing the concentration of the drug in the formulation, thereby reducing the number of times the drug is administered while exhibiting the same pharmacological therapeutic effect as conventional fulvestrant formulations, thereby reducing the inconvenience of conventional formulations, and increasing convenience for patients and pharmaceutical providers.

The chemical name of Fulvestrant is 7-alpha-[9-(4,4,5,5,5-penta fluoropentylsulphinyl) nonyl]estra-1,3,5-(10)-triene-3,17beta-diol and has the following chemical structure:

Fulvestrant is the only drug in the SERD (selective estrogen receptor degrader) series approved for use in the treatment of hormone receptor positive (ER+), HER2 negative (HER2-) advanced breast cancer. Fulvestrant is sold under the brand name Faslocdex (registered trademark) intramuscular injection (manufactured by AstraZeneca), which is a formulation containing 250 mg of fulvestrant per 5 mL of injection solution. The basic dosage is 500 mg (2 prefilled syringes) administered intramuscularly once every two weeks for the first month, and then once a month thereafter.

When administering Faslodex® intramuscularly to a patient, the administration method is set to inject into each of the left and right gluteal muscles for 1-2 minutes, but this causes considerable pain to the person receiving the injection and considerable inconvenience to the healthcare provider administering the drug. The reason for this method of administration is believed to be that the total volume of the entire injection solution is 10 mL, which greatly exceeds the maximum volume that can be administered in one dose (approximately 5 mL) when administered intramuscularly.

Fulvestrant has extremely low solubility in aqueous solutions, and according to FDA documents, it is known to be "practically insoluble" in pure water (in the formulation of Faslodex (registered trademark) injection, the saturated solubility of fulvestrant has been investigated to be about 90 mg/mL at room temperature and about 65 mg/mL when stored in a refrigerator, and the concentration of the product is 50 mg/mL as fulvestrant). Therefore, a solubilizer is essential when formulating fulvestrant, and in the case of Faslodex (registered trademark) intramuscular injection, ethanol and benzyl alcohol are used as the main solubilizers, both of which are organic solvents. However, when an organic solvent is used in an excessive amount, it can increase the solubility of the drug in the formulation, but the amount of organic solvent used in the human body is limited, and it is released rapidly after administration, which rapidly increases the initial release of the drug, which not only increases the C _max excessively, but also increases the risk of drug precipitation in the formulation that remains after the rapid release, which is undesirable. Therefore, in order to improve the solubility of fulvestrant, it is urgently necessary to improve the solubility by utilizing other additives in addition to an appropriate amount of organic solvent.

Faslodex® Intramuscular Injection is an oil depot formulation, with castor oil being the largest component of the additives. Oil depots are a common formulation for sustained release injections, with the matrix mostly made up of oil. Unlike sustained release formulations that use polymers, such as in situ gel formation, in situ polymer precipitation, and polymer implant formulations, they are characterized by maintaining a liquid state inside the body. Oil depots are formulations that can be injected both subcutaneously and intramuscularly, while Faslodex® Intramuscular Injection is used only for intramuscular injection.

When formulating fulvestrant, the type and amount of oil, the type and ratio of organic solvent, and the types and ratios of additives are very important, and these not only determine the solubility of fulvestrant in the matrix, but are also the main factors that determine the sustained release characteristics (release rate, initial release amount, etc.).

The present invention aims to solve the problem of conventional fulvestrant formulations in which the dosage is excessively large due to poor solubility of fulvestrant, and the object of the present invention is to provide a fulvestrant-containing composition and a method for producing the same that can improve the solubility of fulvestrant in the formulation and increase the drug concentration.

One aspect of the present invention provides a pharmaceutical composition for treating cancer, comprising as an active ingredient fulvestrant; a non-ionic surfactant which is a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester or a combination thereof; lecithin; castor oil; and a C2-C5 alcohol.

Another aspect of the present invention provides a method for producing a pharmaceutical composition for cancer treatment, comprising the steps of: (1) dissolving fulvestrant and lecithin in a C2-C5 alcohol; and (2) adding a nonionic surfactant, which is a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester, or a combination thereof, and castor oil to the product of step (1).

The pharmaceutical composition of fulvestrant provided by the present invention exhibits physicochemical equivalence to conventional fulvestrant formulations, and equivalence has been confirmed in non-clinical and bioequivalence studies, and it exhibits the same pharmacological therapeutic effect, while being able to increase the fulvestrant concentration in the formulation compared to conventional formulations and reduce the number of administrations (reducing the conventional two-time administration to one), thereby improving the inconvenience of conventional formulations and increasing convenience for patients and healthcare providers.

Throughout the specification of the present invention, unless otherwise specified, "comprise" or "contain" means, without any particular limitation, the inclusion of a specific component (or components) and is not to be construed as excluding the addition of other components (or components).

The present invention will now be described in more detail.
One aspect of the present invention relates to a pharmaceutical composition for treating cancer, comprising as an active ingredient fulvestrant; a non-ionic surfactant which is a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester or a combination thereof; lecithin; castor oil; and a C2-C5 alcohol.

In one embodiment, the content of the fulvestrant contained in the pharmaceutical composition may be, for example, 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, or 9% by weight or more, and may be 20% by weight or less, 18% by weight or less, 15% by weight or less, 13% by weight or less, or 11% by weight or less, based on 100% by weight of the total amount of the composition, but is not limited thereto.

In one embodiment, the C2 to C5 alcohol may be ethanol.
In one embodiment, the content of the C2-C5 alcohol in the pharmaceutical composition may be, for example, 1 wt % or more, 3 wt % or more, 5 wt % or more, 7 wt % or more, 10 wt % or more, or 15 wt % or more, and may be 40 wt % or less, 35 wt % or less, 30 wt % or less, 25 wt % or less, or 20 wt % or less, relative to 100 wt % of the total amount of the composition, but is not limited thereto.

In another embodiment, the content of the C2-C5 alcohol in the pharmaceutical composition may be, for example, 3 parts by weight or more, 5 parts by weight or more, 7 parts by weight or more, 10 parts by weight or more, or 15 parts by weight or more, and may be 45 parts by weight or less, 40 parts by weight or less, 35 parts by weight or less, 30 parts by weight or less, or 25 parts by weight or less, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, but is not limited thereto.

In one embodiment, the content of the nonionic surfactant contained in the pharmaceutical composition may be, for example, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, or 0.5% by weight or more, relative to the total weight of the composition (100% by weight), and may be 30% by weight or less, 25% by weight or less, 20% by weight or less, 15% by weight or less, 10% by weight or less, or 8% by weight or less, but is not limited thereto.

In another embodiment, the content of the nonionic surfactant contained in the pharmaceutical composition may be, for example, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.2 parts by weight or more, or 0.3 parts by weight or more, and may be 19 parts by weight or less, 18 parts by weight or less, 17 parts by weight or less, 16 parts by weight or less, or 15 parts by weight or less, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, but is not limited thereto.

In one embodiment, the polyoxyethylene castor oil derivative may be a polyoxyl castor oil (e.g., Cremophor EL, Cremophor ELP, polyoxyl-35 castor oil, polyoxyl-40 castor oil, or a combination thereof), more specifically, Cremophor EL, Cremophor ELP, polyoxyl-35 castor oil, or a combination thereof, and even more specifically, Cremophor EL, Cremophor ELP, or a combination thereof, but is not limited thereto.

In one embodiment, when the pharmaceutical composition contains a polyoxyethylene castor oil derivative, the content of the polyoxyethylene castor oil derivative in the composition may be, for example, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, or 0.5% by weight or more, relative to the total weight of the composition (100% by weight), and may be, but is not limited to, 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, 10% by weight or less, or 8% by weight or less.

In another embodiment, when the pharmaceutical composition contains a polyoxyethylene castor oil derivative, the content of the polyoxyethylene castor oil derivative in the composition may be, for example, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.2 parts by weight or more, or 0.3 parts by weight or more, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, and may be, but is not limited to, 19 parts by weight or less, 17 parts by weight or less, 15 parts by weight or less, 13 parts by weight or less, 11 parts by weight or less, or 10 parts by weight or less.

In one embodiment, the polyoxyethylene sorbitan fatty acid ester may be a polysorbate (e.g., Tween 80, Tween 60, Tween 20, etc.), more specifically, Tween 80 may be used, but is not limited thereto.

In one embodiment, when the pharmaceutical composition contains a polyoxyethylene sorbitan fatty acid ester, the content of the polyoxyethylene sorbitan fatty acid ester in the composition may be, for example, 0.01% by weight or more, 0.05% by weight or more, 0.1% by weight or more, 0.2% by weight or more, 0.3% by weight or more, 0.4% by weight or more, or 0.5% by weight or more, relative to the total weight of the composition (100% by weight), and may be, but is not limited to, 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, 10% by weight or less, or 6% by weight or less.

In another embodiment, when the pharmaceutical composition contains a polyoxyethylene sorbitan fatty acid ester, the content of the polyoxyethylene sorbitan fatty acid ester in the composition may be, for example, 0.05 parts by weight or more, 0.1 parts by weight or more, 0.2 parts by weight or more, 0.3 parts by weight or more, 0.4 parts by weight or more, or 0.5 parts by weight or more, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, but is not limited thereto.

In one embodiment, the content of the lecithin contained in the pharmaceutical composition may be, for example, 0.1% by weight or more, 0.3% by weight or more, 0.5% by weight or more, 1% by weight or more, or 1.5% by weight or more, relative to the total weight of the composition (100% by weight), and may be 30% by weight or less, 25% by weight or less, 20% by weight or less, 15% by weight or less, or 10% by weight or less, but is not limited thereto.

In another embodiment, the content of the lecithin contained in the pharmaceutical composition may be, for example, 0.1 parts by weight or more, 0.2 parts by weight or more, or 0.3 parts by weight or more, and may be 20 parts by weight or less, 19 parts by weight or less, 18 parts by weight or less, 17 parts by weight or less, 16 parts by weight or less, or 15 parts by weight or less, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, but is not limited thereto.

In one embodiment, the weight ratio of the lecithin to 1 part by weight of the nonionic surfactant contained in the pharmaceutical composition may be, for example, 1 or more, 1.1 or more, 1.2 or more, or 1.3 or more, and may be 5 or less, 4.9 or less, 4.8 or less, or 4.7 or less, but is not limited thereto.

In one embodiment, the content of the castor oil contained in the pharmaceutical composition may be, for example, 1% by weight or more, 10% by weight or more, 20% by weight or more, 30% by weight or more, 40% by weight or more, or 50% by weight or more, and may be 95% by weight or less, 90% by weight or less, 85% by weight or less, 80% by weight or less, or 75% by weight or less, relative to 100% by weight of the total amount of the composition, but is not limited thereto.

In another embodiment, the content of the castor oil contained in the pharmaceutical composition may be, for example, 10 parts by weight or more, 20 parts by weight or more, 30 parts by weight or more, 40 parts by weight or more, or 50 parts by weight or more, or may be 95 parts by weight or less, 90 parts by weight or less, 85 parts by weight or less, or 80 parts by weight or less, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, but is not limited thereto.

In one embodiment, the weight ratio of castor oil to C2-C5 alcohol in the pharmaceutical composition may be, for example, but is not limited to, 1-10:1, or 1-5:1, or 2-4:1, or 2.5-3:1.

In one embodiment, the pharmaceutical composition may further comprise polyethylene glycol.
The polyethylene glycol may have a weight average molecular weight of, for example, but not limited to, 200 to 1,000 g/mol.

In one embodiment, when the pharmaceutical composition further comprises polyethylene glycol, the content of polyethylene glycol in the composition may be, for example, 0.1% by weight or more, 0.3% by weight or more, or 0.5% by weight or more, relative to the total weight of the composition (100% by weight), and may be, but is not limited to, 10% by weight or less, 9% by weight or less, 8% by weight or less, 7% by weight or less, 6% by weight or less, or 5% by weight or less.

In another embodiment, when the pharmaceutical composition further comprises polyethylene glycol, the content of polyethylene glycol in the composition may be, for example, 0.1 parts by weight or more, 0.3 parts by weight or more, or 0.5 parts by weight or more, and may be 5 parts by weight or less, 4 parts by weight or less, 3 parts by weight or less, or 2 parts by weight or less, relative to 100 parts by weight of the total of the remaining components excluding fulvestrant, but is not limited thereto.

In one embodiment, the pharmaceutical composition may further comprise an additional non-ionic surfactant in addition to the polyoxyethylene castor oil derivative and the polyoxyethylene sorbitan fatty acid ester.

In one embodiment, the additional nonionic surfactant may be a polyoxyethylene alkyl or aryl ether, a sorbitan ester, or a combination thereof.

In one embodiment, the polyoxyethylene alkyl or aryl ether may be, but is not limited to, a polyoxyethylene alkyl phenyl ether (e.g., Triton X-100, etc.).

In one embodiment, the sorbitan ester may be, but is not limited to, a sorbitan fatty acid ester (e.g., Span 20, Span 80, etc.).

In one embodiment, when the pharmaceutical composition includes the additional nonionic surfactant, the content of the additional nonionic surfactant in the composition may be, for example, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, or 3% by weight or more, relative to the total weight of the composition (100% by weight), and may be, but is not limited to, 30% by weight or less, 25% by weight or less, 20% by weight or less, or 15% by weight or less.

In one embodiment, the pharmaceutical composition may further comprise an additional vegetable oil in addition to the castor oil.
In one embodiment, the additional vegetable oil may be sesame oil.
In one embodiment, when the pharmaceutical composition comprises the additional vegetable oil, the content of the additional vegetable oil in the composition may be, for example, but is not limited to, 0.1% by weight or more, 0.5% by weight or more, 1% by weight or more, 2% by weight or more, or 3% by weight or more, and 15% by weight or less, 14% by weight or less, 13% by weight or less, 12% by weight or less, 11% by weight or less, or 10% by weight or less, relative to the total weight of the composition (100% by weight).

In one embodiment, the pharmaceutical composition may further comprise benzyl benzoate (BB) to prevent the phenomenon of the C _max value of the composition increasing significantly and to help reduce unexpected side effects of the drug.
In one embodiment, when the pharmaceutical composition contains benzyl benzoate, the content thereof may be, for example, 0.01% by weight or more or 0.05% by weight or more, and may be 1% by weight or less or 0.5% by weight or less, relative to 100% by weight of the total amount of the composition, but is not limited thereto.

In one embodiment, the pharmaceutical composition is an injection, more specifically an intramuscular injection.
In one embodiment, the injection force of the injection solution may be 0.5 to 10 kgf.
In one embodiment, the concentration of fulvestrant in the injection may be 90-300 mg/mL.
In one embodiment, the in vitro release time of the injection using a dialysis bag may be 14 to 60 days.

The pharmaceutical composition is for treating cancer, more specifically for treating breast cancer, more specifically for treating advanced breast cancer.

Another aspect of the present invention relates to a method for preparing a pharmaceutical composition for cancer treatment, comprising the steps of: (1) dissolving fulvestrant and lecithin in a C2-C5 alcohol; and (2) adding a nonionic surfactant, which is a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester or a combination thereof, and castor oil to the product of the step (1).
In one embodiment, the method for producing the pharmaceutical composition may further comprise the step of adding polyethylene glycol to the product of step (1).

In the method for producing the pharmaceutical composition, the fulvestrant, lecithin, castor oil, C2-C5 alcohol, polyoxyethylene castor oil derivative, polyoxyethylene sorbitan fatty acid ester, and polyethylene glycol are as described above.

In one embodiment, the step (1) may further comprise partially removing the C2 to C5 alcohol from a mixture of fulvestrant, lecithin and the C2 to C5 alcohol.
The removal of the C2-C5 alcohols can be carried out, for example, but not limited to, using a rotary evaporator at 30-80°C.

In one embodiment, the product of step (1) may be a lecithin film containing fulvestrant.

In one embodiment, when the step (1) further comprises partially removing alcohol from the mixture of fulvestrant, lecithin and a C2-C5 alcohol, the method for producing the pharmaceutical composition may further comprise, after the step (2), a step of adding a C2-C5 alcohol to the product of the step (2).

In one embodiment, the method for producing the pharmaceutical composition may further include one or more steps of simultaneously or sequentially adding an additional vegetable oil to the product of step (2) in addition to the C2-C5 alcohol and castor oil.

The following are preferred examples to aid in understanding the present invention. However, the following examples are intended to illustrate the present invention and are not intended to limit the present invention.

A. Solubility of Drug 1. Preparation Production Preparations for solubility measurement in each Example and Comparative Example were produced using the types and contents of components and excess fulvestrant shown in Table 1 below. The specific production method is as follows.
Fulvestrant, lecithin and ethanol were mixed, and then the mixture was heated, stirred and dissolved at a medium temperature of 50°C for 30 minutes. Polyethylene glycol (PEG) was optionally added to the resulting solution, followed by Cremophor EL (C-EL) or Tween 80 (T-80). Benzyl alcohol (BA) was optionally added to the resulting solution, followed by benzyl benzoate (BB) and then castor oil.

2. Measurement of solubility The saturated solubility of fulvestrant was measured for each of the preparations of the examples and comparative examples by a solubility test method that was independently established. The saturated solubility was measured at room temperature (25°C), and after filtering with a 0.45 μm PVDF syringe filter, the concentration was measured by HPLC. The measurement results are shown in Table 1.

Comparative Example A1 was manufactured in the same manner as the formulation of the control drug Faslodex (registered trademark) intramuscular injection. From the results in Table 1 above, it can be seen that the room temperature saturated solubility of fulvestrant is improved in the formulations of Examples A1 to A5 (135.8 mg/mL or more) compared to the formulations of Comparative Examples A1 to A6 (112.2 mg/mL or less).

B. Bioequivalence of Preparations 1. Preparation Production Preparations for pharmacokinetic studies of each Example and Comparative Example (excluding Comparative Example B1) were produced using the types and amounts of ingredients shown in Table 2 below. The specific preparation production method was the same as in A. Comparative Example B1 used Faslodex (registered trademark), a commercially available control drug, intramuscular injection.

2. Pharmacokinetics Test Rabbits were used as experimental animals for Example B1 and Comparative Example B1 (Faslodex (registered trademark) intramuscular injection), rats for Example B2 and Comparative Example B1, and beagles for Comparative Examples B1 to B4. After administration of each formulation to each animal, the blood concentration was measured for 28 days and the profile was observed. The results are shown in Table 3 below.

Taking the results of the commercially available control drug, Faslodex (registered trademark) intramuscular injection (Comparative Example B1), as 100%, AUC _28d is the relative area under the curve (%) of the 28-day drug blood concentration profile, and C _max is the relative maximum drug blood concentration (%). In non-clinical studies, if the tested formulation shows an AUC _28d and C _max of 80-125% compared to the control drug, it is evaluated as being bioequivalent to the control drug.
Thus, the formulations of Examples B1 and B2 exhibited AUC _28d of 89.7% and 82.7%, and C _max of 84.1% and 119.9%, respectively, relative to the control drug, and were evaluated as being bioequivalent, whereas the formulations of Comparative Examples B2 to B4 exhibited AUC _28d of 36.2%, 42.9%, and 38.9%, and C _max of 56.7%, 75.2%, and 60.4%, respectively, relative to the control drug, and were evaluated as not being bioequivalent.

C. Bioavailability of the Preparation 1. Preparation Preparation The preparation for the pharmacokinetic test of Example C1 was prepared using the types and contents of components shown in Table 4 below. The specific preparation method was the same as that described in A. As Comparative Example C1, Faslodex (registered trademark), a commercially available control drug, was used for intramuscular injection.

2. Pharmacokinetics Test For Example C1 and Comparative Example C1 (Faslodex (registered trademark) intramuscular injection), rats and rabbits were used as experimental animals. After administration of each formulation to each animal, the blood concentration was measured for 28 days and the profile was observed. The results are shown in Table 5 below.

The formulation of Example C1 demonstrated increased bioavailability compared to the control drug with an AUC _28d of 135.8% and a C _max of 135.4% in rats and an AUC _28d of 135.2% and a C _max of 156.6% in rabbits.
Therefore, compared to control drugs, the formulations of the present invention not only reduce the number of administrations and improve drug usage (e.g., reduce the conventional two-time administration to one), but also reduce the administered dose, thereby improving the inconvenience of conventional formulations and increasing convenience for patients and providers.

Claims (15)

Fulvestrant as the active ingredient;
nonionic surfactants which are polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, or combinations thereof;
lecithin;
Castor oil; and C2-C5 alcohol;
A pharmaceutical composition for treating cancer comprising: The pharmaceutical composition according to claim 1, wherein the polyoxyethylene castor oil derivative is polyoxyl castor oil. The pharmaceutical composition according to claim 1, wherein the polyoxyethylene sorbitan fatty acid ester is a polysorbate. The pharmaceutical composition according to claim 1, further comprising an additional non-ionic surfactant in addition to the polyoxyethylene castor oil derivative and the polyoxyethylene sorbitan fatty acid ester. The pharmaceutical composition according to claim 4, wherein the additional nonionic surfactant is a polyoxyethylene alkyl or aryl ether, a sorbitan ester, or a combination thereof. The pharmaceutical composition of claim 1 further comprising polyethylene glycol. The pharmaceutical composition of claim 1 further comprising an additional vegetable oil in addition to castor oil. The pharmaceutical composition according to claim 7, wherein the additional vegetable oil is sesame oil. The pharmaceutical composition according to claim 1, wherein the C2-C5 alcohol is ethanol. The pharmaceutical composition according to claim 7, wherein the weight ratio of the vegetable oil to the C2-C5 alcohol in the composition is 1-10:1. The pharmaceutical composition according to claim 1, further comprising benzyl benzoate. The pharmaceutical composition according to any one of claims 1 to 11, wherein the composition is an intramuscular injection. (1) dissolving fulvestrant and lecithin in a C2-C5 alcohol; and (2) adding a non-ionic surfactant, which is a polyoxyethylene castor oil derivative, a polyoxyethylene sorbitan fatty acid ester or a combination thereof, and castor oil to the product of step (1);
A method for producing a pharmaceutical composition for treating cancer comprising the steps of: The method for producing a pharmaceutical composition for cancer treatment according to claim 13, further comprising the step of adding polyethylene glycol to the product of step (1). The method for producing the pharmaceutical composition according to claim 13 further comprises one or more steps of simultaneously or sequentially adding an additional vegetable oil to the product of step (2) in addition to the C2-C5 alcohol and castor oil.