JPWO2017130576A1 - Pharmaceutical composition - Google Patents

Abstract

  Fulvestrant, castor oil, aromatic carboxylic acid, and at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol, and the content of ethanol is the whole of the pharmaceutical composition The pharmaceutical composition which is less than 1 mass% with respect to mass.

Description

  The present disclosure relates to pharmaceutical compositions.

Fulvestrant (7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17β-diol) is an estrogen receptor It is a body antagonist and is sold by AstraZeneca Co., Ltd. as an intramuscular injection product under the trade name FASLODEX (registered trademark). Fesodex contains the indicated amount of fulvestrant 50 mg / mL, and contains ethanol, benzyl alcohol, benzyl benzoate, and castor oil as additives, and 5 mL is supplied in the form of a pre-filled syringe. Yes.
In recent years, various reports have been made on pharmaceutical preparations containing fulvestrant.

For example, Japanese Patent No. 3713237 discloses a pharmaceutical preparation suitable for intramuscular injection containing fulvestrant, pharmaceutically acceptable alcohols (ethanol, benzyl alcohol, etc.), benzyl benzoate, and castor oil. .
JP 2009-509942 A discloses a preparation containing fulvestrant, a pharmaceutically acceptable alcohol (ethanol, benzyl alcohol, etc.), propylene glycol or polyethylene glycol, and castor oil.
JP 2011-514349 discloses a fulvestrant formulation for intramuscular injection that contains fulvestrant, glycofurol, propylene glycol, polyethylene glycol, and the like and is substantially free of castor oil. Has been.
International Publication No. 2015/033302 discloses a formulation comprising fulvestrant, benzoic acid, alcohol (such as ethanol), and vegetable oil.

By the way, fulvestrant is a drug that is hardly soluble in water. Therefore, conventionally, ethanol is used as a solvent in pharmaceutical preparations containing fulvestrant.
However, the use of ethanol in pharmaceutical preparations is not preferable from the viewpoint of application to a wide range of patients because it limits the administration to patients who have an allergic reaction to ethanol such as alcohol hypersensitivity. .

Regarding the above-mentioned points, the pharmaceutical preparation described in Japanese Patent No. 3713237 contains a high concentration of ethanol in order to blend fulvestrant at a high concentration. In addition, the pharmaceutical preparations described in JP-T-2009-509942 and International Publication No. 2015/033302 can be prepared without using a non-aqueous ester solvent (such as benzyl benzoate) having good solubility of fulvestrant. However, the use of ethanol cannot be ruled out.
Therefore, it is difficult to administer the pharmaceutical preparations described in Japanese Patent No. 3713237, Japanese Translation of PCT International Publication No. 2009-509942 and International Publication No. 2015/033302 to a patient who causes an allergic reaction to ethanol.

  On the other hand, since the pharmaceutical preparation described in JP-T-2011-514349 is formulated without using ethanol, it can be administered to a patient who causes an allergic reaction to ethanol. However, since the pharmaceutical preparation described in JP-T-2011-514349 is substantially free of castor oil, for example, when administered intramuscularly, the therapeutically effective blood fulvestrant concentration is constant. It becomes difficult to hold for a period of time, and it cannot be said that it is a therapeutically appropriate pharmaceutical preparation.

  In addition to the solubility of fulvestrant in alternative solvents, alternative solvents and other components (for example, solvents such as castor oil) can be used to select a solvent to replace ethanol (hereinafter also referred to as “alternative solvent”). )) Must be taken into consideration. In particular, in the case of an injection solution formulation, if the compatibility of the contained components is not good, turbidity resulting from phase separation or precipitation may occur when stored at low temperatures, which is not preferable.

  The problem to be solved by one embodiment of the present invention is to provide a pharmaceutical composition that has good solubility of fulvestrant and is hardly turbid even when stored at a low temperature, and is substantially free of ethanol. That is.

  Specific means for solving the above problems include the following embodiments.

[1] Fulvestrant, castor oil, aromatic carboxylic acid, and at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol, and the content of ethanol is a pharmaceutical composition The pharmaceutical composition which is less than 1 mass% with respect to the total mass of a thing.
[2] The pharmaceutical composition according to [1], wherein the ethanol content is less than 0.5% by mass relative to the total mass of the pharmaceutical composition.
[3] The pharmaceutical composition according to [1] or [2], wherein the polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol is propylene glycol.
[4] The pharmaceutical composition according to [3], wherein the content of propylene glycol is 9% by mass or more and 18% by mass or less with respect to the total mass of the pharmaceutical composition.
[5] The pharmaceutical composition according to any one of [1] to [4], wherein the aromatic carboxylic acid is benzoic acid.

[6] The pharmaceutical composition according to any one of [1] to [5], wherein the content of the aromatic carboxylic acid is 2.5% by mass to 10% by mass with respect to the total mass of the pharmaceutical composition. object.
[7] The pharmaceutical composition according to any one of [1] to [6], further comprising benzyl benzoate.
[8] The pharmaceutical composition according to [7], wherein the content of benzyl benzoate is 1% by mass to 20% by mass with respect to the total mass of the pharmaceutical composition.
[9] The pharmaceutical composition according to any one of [1] to [8], further comprising an aromatic alcohol.
[10] The pharmaceutical composition according to any one of [1] to [9], which is for intramuscular injection.

  According to one embodiment of the present invention, there is provided a pharmaceutical composition substantially free of ethanol that has good solubility of fulvestrant and is less susceptible to turbidity even when stored at low temperatures.

  Hereinafter, specific embodiments of the present invention will be described in detail. However, the present invention is not limited to the following embodiments, and may be appropriately changed within the scope of the object of one embodiment of the present invention. Can be added.

In the present specification, a numerical range indicated using “to” means a range including the numerical values described before and after “to” as a minimum value and a maximum value, respectively.
In the numerical ranges described stepwise in the present specification, the upper limit value or lower limit value described in a numerical range may be replaced with the upper limit value or lower limit value of the numerical range described in other steps. . Further, in the numerical ranges described in this specification, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the values shown in the examples.
In the present specification, the amount of each component in the pharmaceutical composition is such that when there are a plurality of substances corresponding to each component in the pharmaceutical composition, the plurality of substances present in the pharmaceutical composition unless otherwise specified. Means the total amount.

  In this specification, the term “process” is not limited to an independent process, and is included in this term if the intended purpose of the process is achieved even when it cannot be clearly distinguished from other processes. It is.

In the present specification, “low temperature” generally refers to a temperature applied when refrigerated and stored for a pharmaceutical composition containing fulvestrant as an active ingredient, and specifically means a range of 2 ° C. to 8 ° C. To do.
In the present specification, “substantially free of ethanol” means that the content of ethanol is less than 1% by mass with respect to the total mass of the pharmaceutical composition.

[Pharmaceutical composition]
The pharmaceutical composition of the present disclosure includes at least one polyhydric alcohol selected from fulvestrant, castor oil, aromatic carboxylic acid, propylene glycol and 1,3-butylene glycol (hereinafter referred to as “specific polyhydric alcohol”). And the content of ethanol is less than 1% by mass with respect to the total mass of the pharmaceutical composition.

Fulvestrant, which is an active ingredient in the pharmaceutical composition of the present disclosure, is a drug that is sparingly soluble in water. Therefore, in a pharmaceutical preparation containing conventional fulvestrant, ethanol is selected as a solvent excellent in solubility of fulvestrant.
However, the use of ethanol in pharmaceutical preparations restricts administration to patients who have an allergic reaction to ethanol such as alcohol hypersensitivity and is not preferable from the viewpoint of application to a wide range of patients.

  The pharmaceutical composition of the present disclosure comprises ethanol by containing fulvestrant in combination with castor oil, an aromatic carboxylic acid, and at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol. Even if it does not contain substantially, the solubility of a fulvestrant becomes favorable. In addition, since the above-described components included in the pharmaceutical composition of the present disclosure have good compatibility, it is considered that the pharmaceutical composition of the present disclosure is less likely to become turbid even when stored at a low temperature.

<Ethanol>
In the pharmaceutical composition of the present disclosure, the ethanol content is less than 1% by mass with respect to the total mass of the pharmaceutical composition.
When the content of ethanol in the pharmaceutical composition of the present disclosure is less than 1% by mass with respect to the total mass of the pharmaceutical composition, the subject of the present disclosure also has an allergic reaction to ethanol such as alcohol hypersensitivity. The pharmaceutical composition can be applied and can be administered to a wide range of patients.
In addition, when the content of ethanol in the pharmaceutical composition of the present disclosure is less than 1% by mass with respect to the total mass of the pharmaceutical composition, since the amount of volatile ethanol is very small, the production of the pharmaceutical composition is easy. It becomes.

  The content of ethanol in the pharmaceutical composition of the present disclosure is preferably less than 0.5% by mass, more preferably less than 0.3% by mass, and still more preferably based on the total mass of the pharmaceutical composition. It is less than 0.1% by mass, and particularly preferably no ethanol is contained, that is, 0% by mass.

  Hereinafter, each component of the pharmaceutical composition of the present disclosure will be described.

<Fulvestrant>
The pharmaceutical composition of the present disclosure contains fulvestrant as an active ingredient.
Fulvestrant (7α- [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17β-diol) is an estrogen receptor It is a body antagonist and is known as a drug for treating breast cancer.

The content of fulvestrant in the pharmaceutical composition of the present disclosure is preferably 4.5% by mass or more, more preferably 5% by mass with respect to the total mass of the pharmaceutical composition, for example, from the viewpoint of dosage. % Or more.
The upper limit of the content of fulvestrant in the pharmaceutical composition is not particularly limited, and is, for example, 10% by mass or less from the viewpoint of solubility of fulvestrant.

<Castor oil>
The pharmaceutical composition of the present disclosure comprises castor oil.
By including castor oil, the pharmaceutical composition of the present disclosure can maintain a therapeutically effective blood fulvestrant concentration for a certain period of time.

The content of castor oil in the pharmaceutical composition of the present disclosure is not particularly limited, and for example, is preferably 40% by mass or more and 80% by mass or less, and more preferably 45% by mass with respect to the total mass of the pharmaceutical composition. % To 75% by mass, and more preferably 50% to 70% by mass.
When the content of castor oil in the pharmaceutical composition is within the above range, a therapeutically effective blood fulvestrant concentration can be maintained for a certain period of time, and the fulvestrant can be dissolved uniformly. The necessary amount of ingredients other than castor oil can be ensured.

<Aromatic carboxylic acid>
The pharmaceutical composition of the present disclosure includes an aromatic carboxylic acid.
In the pharmaceutical composition of the present disclosure, the aromatic carboxylic acid contributes to the solubility of fulvestrant.
The aromatic carboxylic acid has an aromatic group and a carboxy group and is considered to have high affinity with fulvestrant. The pharmaceutical composition of the present disclosure is considered to improve the solubility of fulvestrant by including an aromatic carboxylic acid having high affinity with fulvestrant.

The aromatic carboxylic acid is not particularly limited, and for example, at least one selected from benzoic acid and salicylic acid is preferable, and benzoic acid is more preferable.
The pharmaceutical composition of the present disclosure contains benzoic acid as an aromatic carboxylic acid, so that the solubility of fulvestrant becomes better. Further, even when stored at a low temperature, turbidity hardly occurs.

  The pharmaceutical composition of this indication may contain only 1 type of aromatic carboxylic acid, and may contain 2 or more types.

The content of the aromatic carboxylic acid in the pharmaceutical composition of the present disclosure is not particularly limited.
For example, the content of the aromatic carboxylic acid (preferably benzoic acid) in the pharmaceutical composition is preferably 2.5% by mass or more and 10% by mass or less, more preferably based on the total mass of the pharmaceutical composition. Is 5 mass% or more and 10 mass% or less.
One embodiment of the present invention that when the content of the aromatic carboxylic acid in the pharmaceutical composition is within the above range, the solubility of the fulvestrant is good and turbidity hardly occurs even when stored at a low temperature. The effect of is more effective.

(Specific polyhydric alcohol)
The pharmaceutical composition of the present disclosure contains at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol (that is, a specific polyhydric alcohol).
In the pharmaceutical composition of the present disclosure, the specific polyhydric alcohol contributes to the solubility of fulvestrant.

As the specific polyhydric alcohol, propylene glycol is particularly preferable.
By including propylene glycol, the pharmaceutical composition of the present disclosure is more effective in the effect of the embodiment of the present invention, in which the solubility of fulvestrant is good and turbidity hardly occurs even when stored at low temperatures. Can be played.

The content of the specific polyhydric alcohol in the pharmaceutical composition of the present disclosure is not particularly limited.
For example, the content of the specific polyhydric alcohol (preferably propylene glycol) in the pharmaceutical composition is preferably 9% by mass or more and 18% by mass or less, more preferably 12% with respect to the total mass of the pharmaceutical composition. It is 0.5 mass% or more and 18 mass% or less, More preferably, it is 15 mass% or more and 18 mass% or less.
When the content of the specific polyhydric alcohol in the pharmaceutical composition is 9% by mass or more with respect to the total mass of the pharmaceutical composition, the solubility of fulvestrant becomes better. In addition, when the content of the specific polyhydric alcohol in the pharmaceutical composition is 18% by mass or less with respect to the total mass of the pharmaceutical composition, the compatibility with castor oil is sufficient, and thus the composition was stored at a low temperature. In some cases, turbidity is less likely to occur.

<Other ingredients>
In addition to fulvestrant, castor oil, aromatic carboxylic acid, and a specific polyhydric alcohol, the pharmaceutical composition of the present disclosure may include other components as necessary within a range that does not impair the effect of the embodiment of the present invention. May be included.
Examples of other components include, but are not limited to, benzyl benzoate, aromatic alcohol, polyethylene glycol, and other additives.

(Benzyl benzoate)
The pharmaceutical composition of the present disclosure may further comprise benzyl benzoate.
When the pharmaceutical composition of the present disclosure contains benzyl benzoate, the content of benzyl benzoate in the pharmaceutical composition is not particularly limited.
For example, the content of benzyl benzoate in the pharmaceutical composition is preferably 1% by mass to 20% by mass, and more preferably 5% by mass to 20% by mass with respect to the total mass of the pharmaceutical composition. More preferably, it is 10 mass% or more and 20 mass% or less.

(Aromatic alcohol)
The pharmaceutical composition of the present disclosure preferably further contains an aromatic alcohol.
In the pharmaceutical composition of the present disclosure, the aromatic alcohol can function as an auxiliary for the specific polyhydric alcohol (preferably propylene glycol) described above with respect to the dissolution of fulvestrant.
The pharmaceutical composition of the present disclosure includes a combination of the specific polyhydric alcohol (preferably propylene glycol) described above and an aromatic alcohol (eg, benzyl alcohol), so that the solubility of fulvestrant is better. Become.

The aromatic alcohol is not particularly limited, and examples thereof include benzyl alcohol and phenethyl alcohol.
Among these, benzyl alcohol is preferable as the aromatic alcohol from the viewpoint of the solubility of fulvestrant.

  When the pharmaceutical composition of the present disclosure contains an aromatic alcohol, it may contain only one kind of aromatic alcohol or two or more kinds.

When the pharmaceutical composition of the present disclosure contains an aromatic alcohol, the content of the aromatic alcohol in the pharmaceutical composition is not particularly limited.
For example, the content of the aromatic alcohol (preferably benzyl alcohol) in the pharmaceutical composition is preferably 0.01% by mass or more and 30% by mass or less, more preferably based on the total mass of the pharmaceutical composition. It is 1 mass% or more and 25 mass% or less, More preferably, it is 1 mass% or more and 15 mass% or less.

  When the pharmaceutical composition of the present disclosure contains an aromatic alcohol, the ratio of the content of the aromatic alcohol to the content of the specific polyhydric alcohol in the pharmaceutical composition (content of the aromatic alcohol / content of the specific polyhydric alcohol) Amount) is preferably 0.1 to 2.0, more preferably 0.15 to 1.5, and still more preferably 0.2 to 1.2 on a mass basis.

(Polyethylene glycol)
The pharmaceutical composition of the present disclosure may further contain polyethylene glycol (PEG) as a polyhydric alcohol other than the specific polyhydric alcohol.

The average molecular weight of polyethylene glycol is not particularly limited.
The average molecular weight of polyethylene glycol is preferably 200 or more and 5000 or less, more preferably 200 or more and 4000 or less, and further preferably 200 or more and 1000 or less, from the viewpoint of using, for example, those suitable for intramuscular injection. Particularly preferably, it is 200 or more and 600 or less.
The average molecular weight of polyethylene glycol is measured by the method described in the 16th revised Japanese Pharmacopoeia.

  Examples of the polyethylene glycol having an average molecular weight of 200 or more and 600 or less include polyethylene glycol 200, polyethylene glycol 300, polyethylene glycol 400, and polyethylene glycol 600.

  The polyethylene glycol is preferably one suitable as a pharmaceutical additive as defined by the Japanese Pharmacopoeia, Pharmaceutical Additive Standards, or the Pharmacopeia of each country.

  When the pharmaceutical composition of this indication contains polyethyleneglycol, it may contain only 1 type of polyethyleneglycol and may contain 2 or more types.

When the pharmaceutical composition of the present disclosure contains polyethylene glycol, the content of polyethylene glycol in the pharmaceutical composition is not particularly limited.
For example, the content of polyethylene glycol in the pharmaceutical composition is preferably 0.01% by mass or more and 10% by mass or less, more preferably 1% by mass or more and 8% by mass or less, with respect to the total mass of the pharmaceutical composition. More preferably, it is 1 mass% or more and 6 mass% or less.

(Other additives)
The pharmaceutical composition of the present disclosure may further include a pharmaceutically acceptable additive as necessary, as long as the effect of the embodiment of the present invention is not impaired. When the pharmaceutical composition of the present disclosure is applied for intramuscular injection, it is preferable to further include an additive suitable for intramuscular injection.
Other additives include glycerin, ascorbic acid or its salt, hydrochloric acid, gluconic acid or its salt, acetic acid or its salt, lactic acid or its salt, boric acid or its salt, phosphoric acid or its salt, sulfuric acid or its salt, Tartaric acid or a salt thereof, citric acid or a salt thereof, potassium hydroxide, calcium hydroxide, sodium hydroxide, magnesium hydroxide, monoethanolamine, diethanolamine, triethanolamine, trometamol, meglumine, glycine, histidine or a salt thereof, ε- Amino caproic acid, arginine or salt thereof, cysteine or salt thereof, methionine, alanine, leucine, aspartic acid or salt thereof, glutamic acid or salt thereof, arginine or salt thereof, thioglycerin, thioglycolic acid or salt thereof, taurine, sodium edetate Lidocaine or Salt, nicotinamide, chlorobutanol, creatinine, sesame oil, peanut oil, camellia oil, butylhydroxytoluene, butylhydroxyanisole, sorbitan sesquioleate, ethyl oleate, ethyl lactate, tiromesal, polyoxyethylene hydrogenated castor oil, polysorbate 20, polysorbate 80 and the like.
However, other additives are not limited to these.

When the pharmaceutical composition of the present disclosure includes other additives, it may include only one other additive or two or more other additives.
When the pharmaceutical composition of the present disclosure includes other additives, the content of the other additives in the pharmaceutical composition is preferably 10% by mass or less with respect to the total mass of the pharmaceutical composition.

(water)
It is preferable that the pharmaceutical composition of the present disclosure does not substantially contain water from the viewpoint that the effect of one embodiment of the present invention that is less likely to cause turbidity even when stored at a low temperature is more effectively exhibited.
Here, “substantially free of water” means that it does not contain an amount of water that exceeds the amount of water that would be contained by moisture absorption from the atmosphere. “The amount of water to be contained by moisture absorption from the atmosphere” includes the amount of water retained in the pharmaceutical composition during storage of the pharmaceutical composition.
Specifically, the content of water in the pharmaceutical composition of the present disclosure is preferably 5% by mass or less, more preferably 3% by mass or less, and still more preferably with respect to the total mass of the pharmaceutical composition. Is 2% by mass or less, particularly preferably 1% by mass or less.

[Use of pharmaceutical composition]
The pharmaceutical composition of the present disclosure can be suitably used for intramuscular injection.
The pharmaceutical composition of the present disclosure has good solubility of fulvestrant, and even when stored at a low temperature (2 ° C. to 8 ° C.), phase separation or precipitation hardly occurs in the components contained in the pharmaceutical composition, Since a state in which components such as fulvestrant are well mixed is stably maintained, the preparation is suitable for intramuscular injection.

[Method for producing pharmaceutical composition]
The method for producing the pharmaceutical composition of the present disclosure is not particularly limited as long as the above-described pharmaceutical composition can be produced.
As a method for producing the pharmaceutical composition of the present disclosure, the method for producing the pharmaceutical composition of the present embodiment described below is preferable from the viewpoint that it is easy to obtain a pharmaceutical composition in which contained components are uniformly mixed.

The method for producing the pharmaceutical composition of the present embodiment (hereinafter also referred to as “production method of the present embodiment”) is selected from fulvestrant, aromatic carboxylic acid, propylene glycol, and 1,3-butylene glycol. A step of mixing at least one polyhydric alcohol (specific polyhydric alcohol) to obtain a fulvestrant solution (hereinafter also referred to as “first step”), and the obtained fulvestrant And a castor oil are mixed to obtain a pharmaceutical composition (hereinafter also referred to as “second step”).
In the production method of the present embodiment, the contained components are uniformly mixed as compared with the case where fulvestrant, aromatic carboxylic acid, specific polyhydric alcohol, and castor oil are mixed together. It has the advantage that it is easy to obtain a pharmaceutical composition.
Hereinafter, although the manufacturing method of this embodiment is demonstrated, description is abbreviate | omitted about the matter which is common in the above-mentioned pharmaceutical composition, for example, the component contained in a pharmaceutical composition, and its quantity.

<First step>
The first step is a step of mixing a fulvestrant, an aromatic carboxylic acid, and a specific polyhydric alcohol to obtain a fulvestrant solution.
When the above-mentioned pharmaceutical composition contains other components such as benzyl benzoate and aromatic alcohol, fulvestrant, aromatic carboxylic acid, specific polyhydric alcohol, and other components are mixed. It is preferable to obtain a fulvestrant solution.

In the first step, the components to be mixed may be simply mixed, and all the components may be mixed at once, or each component may be divided into several parts and mixed.
The mixing method is not particularly limited, and examples thereof include mixing by stirring.

It does not specifically limit as temperature conditions in the case of mixing, For example, according to a composition (kind and quantity) of the component to mix, it can set suitably.
In the first step, fulvestrant, an aromatic carboxylic acid, and a specific polyhydric alcohol are usually mixed under conditions of an atmospheric temperature of 15 ° C. to 60 ° C. to obtain a fulvestrant solution.

<Second step>
The second step is a step of mixing the fulvestrant solution obtained in the first step and castor oil to obtain a pharmaceutical composition.
The mixing method is not particularly limited, and examples thereof include mixing by stirring.

  In the second step, the fulvestrant solution and castor oil may be mixed at one time. For example, the fulvestrant solution may be gradually added while stirring the fulvestrant solution, A solution of runt and castor oil may be mixed.

The temperature condition at the time of mixing is not specifically limited.
In the second step, a fulvestrant solution and castor oil are usually mixed under conditions of an atmospheric temperature of 15 ° C to 60 ° C to obtain a pharmaceutical composition.

<Other processes>
The manufacturing method of this embodiment may have other processes other than a 1st process and a 2nd process as needed. Further, the first step and the second step may include a plurality of steps.
Examples of the other steps include a step of sterilizing the pharmaceutical composition, a step of filling the container with the pharmaceutical composition, and the like.
As the sterilization step, a filtration sterilization method using a sterilization filter is preferable.

Examples of the container filled with the pharmaceutical composition include vials, ampoules, and syringes.
Among these, as a container filled with the pharmaceutical composition, a syringe is preferable and a glass syringe is more preferable from the viewpoint of handleability in a medical field.

  The present disclosure also includes a method for treating breast cancer, comprising administering the above-described pharmaceutical composition containing fulvestrant as an active ingredient to a patient to be treated for breast cancer.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples unless it exceeds the gist thereof.

[Manufacture of pharmaceutical composition]
<Example 1>
In a clean glass container containing a stirrer, 5 parts by mass of fulvestrant, 5 parts by mass of benzoic acid as an aromatic carboxylic acid, 15 parts by mass of propylene glycol (PG) as a specific polyhydric alcohol, and 15 parts by mass of benzyl benzoate Were weighed and stirred to dissolve the fulvestrant. Next, castor oil was added to the obtained fulvestrant solution to adjust the total amount to 100 parts by mass, and the mixture was further stirred and homogenized to obtain the pharmaceutical composition of Example 1.

<Examples 2 to 22>
Except having changed the composition of a pharmaceutical composition into the composition shown in following Table 1, operation similar to Example 1 was performed and the pharmaceutical composition of Examples 2-22 was obtained.

<Comparative Examples 1-5>
Except having changed the composition of a pharmaceutical composition into the composition shown in following Table 1, operation similar to Example 1 was performed and the pharmaceutical composition of Comparative Examples 1-5 was obtained.

<Reference Examples 1-2>
Except having changed the composition of a pharmaceutical composition into the composition shown in following Table 1, operation similar to Example 1 was performed and the pharmaceutical composition of the reference examples 1-2 was obtained.

[Evaluation]
1. Solubility of fulvestrant To each of the pharmaceutical compositions of Examples 1-22, Comparative Examples 1-5, and Reference Examples 1-2 obtained above, at least a saturating amount of fulvestrant is further added, and at least 1 After stirring for more than a day, centrifugation was performed under conditions of 10,000 rpm (round per minute) or more and 10 minutes or more to remove excess fulvestrant, and a supernatant was obtained.
The amount of fulvestrant dissolved in the obtained supernatant was measured by high performance liquid chromatography (HPLC) under the following conditions. The obtained measured value was taken as the dissolution tolerance (unit: mg / g) of fulvestrant. It was judged that the solubility of fulvestrant was good when the dissolution tolerance of fulvestrant was 45 mg / g or more. The results are shown in Table 1.
In Table 1, a case where the dissolution allowance was 45 mg / g or more was expressed as “good”, and a case where the dissolution allowance was less than 45 mg / g was described as “bad”.

  In the above evaluation, the sufficiently high value of the fulvestrant dissolution tolerance in the pharmaceutical composition means that the pharmaceutical composition has a sufficient ability to uniformly and uniformly contain the fulvestrant necessary for treatment. Indicates.

-HPLC conditions-
Column: XBridge C8 (product name, particle size: 3.5 μm, column size: 4.6 mm × 150 mm, Waters)
Mobile phase A: methanol / water = 70/30
Mobile phase B: methanol Gradient condition (ratio of mobile phase B): 0% (start) → 0% (12 min) → 100% (12.1 min) → 100% (20 min) → 0% (20.1 min) → 0% (30 min, stopped)
Detection wavelength: 225 nm
Flow rate: 1.0 mL / min
Column temperature: 40 ° C

2. Existence of turbidity At least 1 mL of each pharmaceutical composition of Examples 1-22, Comparative Examples 1-5, and Reference Examples 1-2 obtained above was weighed into a colorless and transparent glass bottle (5 mL capacity). It preserve | saved in the refrigerator (atmosphere temperature: 2 to 8 degreeC). The glass bottle was taken out from the refrigerator after 1 hour or more elapsed from the start of storage. Immediately after taking out, the cloudiness generated on the surface of the glass bottle was wiped off with Kimwipe (registered trademark), and then the pharmaceutical composition contained in the glass bottle was visually observed to confirm the presence or absence of cloudiness. The results are shown in Table 1.
In Table 1, the case where no turbidity was confirmed in the pharmaceutical composition contained in the glass bottle was described as “None”, and the case where turbidity was confirmed was described as “Yes”.

In the above evaluation, the state where turbidity is not confirmed in the pharmaceutical composition contained in the glass bottle (that is, the pharmaceutical composition is clear) indicates a state in which the contained components are uniformly mixed, and the low temperature (from 2 ° C. to 2 ° C.) During storage at 8 ° C), it means that phase separation or precipitation does not occur in the components contained in the pharmaceutical composition, and the state in which components such as fulvestrant are well mixed is stably maintained. .
On the other hand, the state where turbidity is confirmed in the pharmaceutical composition contained in the glass bottle indicates a state where the contained components are not uniformly mixed, and is contained in the pharmaceutical composition during storage at a low temperature (2 ° C to 8 ° C). This means that any of the components to be separated is phase-separated or precipitated, and cannot be said to be a preparation suitable for intramuscular injection.

In Table 1, “-” means that there is no corresponding item.
In Table 1, “propylene glycol” is represented as “PG”, and 1,3-butylene glycol is represented as “BG”.
In Table 1, “PEG 400” is the JP Macrogol 400.

As shown in Table 1, it contains fulvestrant, castor oil, aromatic carboxylic acid, and propylene glycol (PG), which is one of the specific polyhydric alcohols, and the ethanol content is based on the total mass of the pharmaceutical composition. The pharmaceutical compositions of Examples 1 to 22, which were less than 1% by mass, had good solubility of fulvestrant and did not become turbid even when stored at low temperatures.
On the other hand, the pharmaceutical compositions of Comparative Examples 1 to 5 that do not contain at least one of an aromatic carboxylic acid and a specific polyhydric alcohol are not satisfactory in the evaluation of at least one of the solubility of fulvestrant and the presence or absence of turbidity. In other words, the solubility of fulvestrant was not good and the turbidity did not occur even when stored at a low temperature.

  In addition to propylene glycol, which is one of the specific polyhydric alcohols, a pharmaceutical composition further containing benzyl alcohol (eg, Example 19) is compared with a pharmaceutical composition not containing benzyl alcohol (eg, Example 1). Thus, the dissolution tolerance of fulvestrant was significantly increased.

The disclosure of Japanese Patent Application No. 2016-014453 filed on January 28, 2016 is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards described in this specification are specifically and individually incorporated by reference as if individual documents, patent applications, and technical standards were incorporated by reference. To the extent it is incorporated herein by reference.

Claims (10)

Fulvestrant,
Castor oil,
An aromatic carboxylic acid;
And at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol,
A pharmaceutical composition, wherein the content of ethanol is less than 1% by mass relative to the total mass of the pharmaceutical composition.   The pharmaceutical composition according to claim 1, wherein the ethanol content is less than 0.5% by mass relative to the total mass of the pharmaceutical composition.   The pharmaceutical composition according to claim 1 or 2, wherein the polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol is propylene glycol.   The content of propylene glycol is 9 mass% or more and 18 mass% or less with respect to the total mass of a pharmaceutical composition, The pharmaceutical composition of Claim 3.   The pharmaceutical composition according to any one of claims 1 to 4, wherein the aromatic carboxylic acid is benzoic acid.   The content of aromatic carboxylic acid is 2.5 mass% or more and 10 mass% or less with respect to the total mass of a pharmaceutical composition, The pharmaceutical composition of any one of Claims 1-5.   The pharmaceutical composition according to any one of claims 1 to 6, further comprising benzyl benzoate.   The pharmaceutical composition according to claim 7, wherein the content of benzyl benzoate is 1% by mass or more and 20% by mass or less based on the total mass of the pharmaceutical composition.   The pharmaceutical composition according to any one of claims 1 to 8, further comprising an aromatic alcohol.   The pharmaceutical composition according to any one of claims 1 to 9, which is for intramuscular injection.