WO2017130576A1 - Medicinal composition - Google Patents

Medicinal composition Download PDF

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Publication number
WO2017130576A1
WO2017130576A1 PCT/JP2016/086459 JP2016086459W WO2017130576A1 WO 2017130576 A1 WO2017130576 A1 WO 2017130576A1 JP 2016086459 W JP2016086459 W JP 2016086459W WO 2017130576 A1 WO2017130576 A1 WO 2017130576A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
mass
fulvestrant
present disclosure
content
Prior art date
Application number
PCT/JP2016/086459
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French (fr)
Japanese (ja)
Inventor
浩輝 谷坂
京子 千賀
Original Assignee
富士フイルム株式会社
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Application filed by 富士フイルム株式会社 filed Critical 富士フイルム株式会社
Priority to JP2017563728A priority Critical patent/JPWO2017130576A1/en
Publication of WO2017130576A1 publication Critical patent/WO2017130576A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin

Definitions

  • the present disclosure relates to a pharmaceutical composition.
  • Fulvestrant (7 ⁇ - [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17 ⁇ -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.
  • 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 containing fulvestrant, glycofurol, propylene glycol, polyethylene glycol and the like and substantially free of castor oil.
  • International Publication No. 2015/033302 discloses a formulation comprising fulvestrant, benzoic acid, alcohol (such as ethanol), and vegetable oil.
  • 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. .
  • the pharmaceutical preparation described in Japanese Patent No. 3713237 contains a high concentration of ethanol in order to blend fulvestrant at a high concentration.
  • 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.
  • a non-aqueous ester solvent such as benzyl benzoate
  • 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 patients who have an allergic reaction to ethanol.
  • the pharmaceutical formulation described in JP-T-2011-514349 is formulated without using ethanol, it can be administered to patients who have an allergic reaction to ethanol.
  • the pharmaceutical preparation described in JP-T-2011-514349 is substantially free of castor oil, the therapeutically effective blood fulvestrant concentration is constant when administered intramuscularly, for example. It becomes difficult to hold for a period of time, and it cannot be said that it is a therapeutically appropriate pharmaceutical preparation.
  • alternative solvents and other components can be used to select a solvent to replace ethanol (hereinafter also referred to as “alternative solvent”). ))
  • alternative solvents and other components for example, solvents such as castor oil
  • solvents such as castor oil
  • 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.
  • a pharmaceutical composition comprising fulvestrant, castor oil, aromatic carboxylic acid, and at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol, wherein the ethanol content is The pharmaceutical composition which is less than 1 mass% with respect to the total mass of a thing.
  • a pharmaceutical composition which has good solubility of fulvestrant and hardly causes turbidity even when stored at a low temperature and substantially does not contain ethanol.
  • a numerical range indicated by using “to” means a range including the numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • 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.
  • 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.
  • 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.
  • 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.
  • low temperature generally refers to a temperature applied when refrigerated storage of a pharmaceutical composition containing fulvestrant as an active ingredient, and specifically means a range of 2 ° C. to 8 ° C. To do.
  • 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.
  • 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.
  • ethanol is selected as a solvent excellent in solubility of fulvestrant.
  • 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, 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.
  • the ethanol content is less than 1% by mass with respect to the total mass of the pharmaceutical composition.
  • 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.
  • 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.
  • Fulvestrant 7 ⁇ - [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17 ⁇ -diol
  • Fulvestrant 7 ⁇ - [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17 ⁇ -diol
  • Fulvestrant 7 ⁇ - [9- (4,4,5,5,5-pentafluoropentylsulfinyl) nonyl] estra-1,3,5 (10) -triene-3,17 ⁇ -diol
  • 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.
  • the pharmaceutical composition of the present disclosure comprises castor oil.
  • 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.
  • 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.
  • the pharmaceutical composition of the present disclosure includes an aromatic carboxylic acid.
  • 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. Moreover, even if it preserve
  • the pharmaceutical composition of the present disclosure may contain only one type of aromatic carboxylic acid, or may contain two or more types.
  • the content of the aromatic carboxylic acid in the pharmaceutical composition of the present disclosure is not particularly limited.
  • 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.
  • 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).
  • the specific polyhydric alcohol contributes to the solubility of fulvestrant.
  • propylene glycol is particularly preferable.
  • 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.
  • 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.
  • the solubility of fulvestrant becomes better.
  • 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.
  • 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.
  • the pharmaceutical composition of the present disclosure may further comprise benzyl benzoate.
  • the content of benzyl benzoate in the pharmaceutical composition is not particularly limited.
  • 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.
  • the pharmaceutical composition of the present disclosure preferably further contains an aromatic alcohol.
  • 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.
  • 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.
  • the content of the aromatic alcohol in the pharmaceutical composition is not particularly limited.
  • 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.
  • the ratio of the content of the aromatic alcohol to the content of the specific polyhydric alcohol in the pharmaceutical composition (the content of the aromatic alcohol / the content of the specific polyhydric alcohol)
  • the amount is preferably from 0.1 to 2.0, more preferably from 0.15 to 1.5, and even more preferably from 0.2 to 1.2 on a mass basis.
  • the pharmaceutical composition of the present disclosure may further contain polyethylene glycol (PEG) as a polyhydric alcohol other than the specific polyhydric alcohol.
  • PEG polyethylene glycol
  • 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.
  • Polyethylene glycol is preferably suitable as a pharmaceutical additive as defined by the Japanese Pharmacopoeia, Pharmaceutical Additive Standards, or the pharmacopoeia of each country.
  • the pharmaceutical composition of the present disclosure contains polyethylene glycol, it may contain only one type of polyethylene glycol or two or more types.
  • the content of polyethylene glycol in the pharmaceutical composition is not particularly limited.
  • 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.
  • 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.
  • a pharmaceutically acceptable additive as necessary, as long as the effect of the embodiment of the present invention is not impaired.
  • an additive suitable for intramuscular injection it is preferable to further include an additive suitable for intramuscular injection.
  • 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, ⁇ - 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
  • the pharmaceutical composition of the present disclosure may include only one other additive or two or more 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.
  • 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.
  • 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.
  • 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.
  • 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 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.
  • 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.
  • 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”).
  • 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.
  • the first step is a step of mixing a fulvestrant, an aromatic carboxylic acid, and a specific polyhydric alcohol to obtain a fulvestrant solution.
  • a fulvestrant solution 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.
  • 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.
  • 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.
  • 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.
  • the fulvestrant solution and castor oil may be mixed at one time.
  • 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.
  • 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.
  • the manufacturing method of this embodiment may have other processes other than a 1st process and a 2nd process as needed.
  • 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.
  • a 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.
  • 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.
  • PG propylene glycol
  • Examples 2 to 22 Except that the composition of the pharmaceutical composition was changed to the composition shown in Table 1 below, the same operations as in Example 1 were performed to obtain the pharmaceutical compositions of Examples 2 to 22.
  • Reference Examples 1 and 2 were obtained in the same manner as in Example 1 except that the composition of the pharmaceutical composition was changed to the composition shown in Table 1 below.
  • 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.
  • the state in which no turbidity is confirmed in the pharmaceutical composition contained in the glass bottle 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.
  • the state where turbidity is confirmed in the pharmaceutical composition contained in the glass bottle indicates that 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.
  • 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 Comparative Examples 1 to 5 that do not contain at least one of an aromatic carboxylic acid and a specific polyhydric alcohol have good results in evaluating 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.
  • a pharmaceutical composition further containing benzyl alcohol eg, Example 19
  • a pharmaceutical composition not containing benzyl alcohol eg, Example 1

Abstract

A medicinal composition comprising fulvestrant, castor oil, an aromatic carboxylic acid and at least one kind of polyhydric alcohol selected from between propylene glycol and 1,3-butylene glycol, wherein the content of ethanol is less than 1 mass% relative to the total mass of the medicinal composition.

Description

医薬組成物Pharmaceutical composition
　本開示は、医薬組成物に関する。 The present disclosure relates to a pharmaceutical composition.
　フルベストラント（７α－［９－（４，４，５，５，５－ペンタフルオロペンチルスルフィニル）ノニル］エストラ－１，３，５（１０）－トリエン－３，１７β－ジオール）は、エストロゲン受容体アンタゴニストであり、アストラゼネカ（株）により、筋肉内注射製剤として、フェソロデックス（ＦＡＳＬＯＤＥＸ）（登録商標）の商品名で販売されている。フェソロデックスは、フルベストラントを表示量５０ｍｇ／ｍＬ含み、かつ、添加剤として、エタノール、ベンジルアルコール、安息香酸ベンジル、及びヒマシ油を含み、５ｍＬが予め充填されたシリンジの形態で供給されている。
　近年、フルベストラントを含む医薬製剤に関して、種々の報告がなされている。 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.
　例えば、特許第３７１３２３７号公報には、フルベストラント、医薬的に許容できるアルコール類（エタノール、ベンジルアルコール等）、安息香酸ベンジル、及びヒマシ油を含む筋肉内注射に適する医薬製剤が開示されている。
　特表２００９－５０９９４２号公報には、フルベストラント、製薬上許容されるアルコール（エタノール、ベンジルアルコール等）、プロピレングリコール又はポリエチレングリコール、及びヒマシ油を含む製剤が開示されている。
　特表２０１１－５１４３４９号公報には、フルベストラント、グリコフロール、プロピレングリコール、ポリエチレングリコール等を含み、かつ、実質的にヒマシ油を含まない、筋肉内注射のためのフルベストラント配合物が開示されている。
　国際公開第２０１５／０３３３０２号には、フルベストラント、安息香酸、アルコール（エタノール等）、及び植物油を含む製剤が開示されている。 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 containing fulvestrant, glycofurol, propylene glycol, polyethylene glycol and the like and 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.
　ところで、フルベストラントは、水に対して難溶性を示す薬物である。そのため、従来、フルベストラントを含む医薬製剤では、溶剤としてエタノールを使用している。
　しかし、医薬製剤におけるエタノールの使用は、アルコール過敏症等のエタノールに対してアレルギー反応を起こす患者への投与を制限することになるため、幅広い患者への適用の観点からは、好ましいとはいえない。 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. .
　上述の点に関し、特許第３７１３２３７号公報に記載された医薬製剤は、フルベストラントを高濃度で配合するために、高濃度のエタノールを含んでいる。また、特表２００９－５０９９４２号公報及び国際公開第２０１５／０３３３０２号に記載された医薬製剤では、フルベストラントの溶解性が良好な非水性エステル溶媒（安息香酸ベンジル等）を使用せずに製剤化しているものの、エタノールの使用を排除することはできていない。
　したがって、特許第３７１３２３７号公報、特表２００９－５０９９４２号公報、及び国際公開第２０１５／０３３３０２号に記載された医薬製剤を、エタノールに対してアレルギー反応を起こす患者に投与することは困難である。 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 patients who have an allergic reaction to ethanol.
　一方、特表２０１１－５１４３４９号公報に記載された医薬製剤では、エタノールを使用せずに製剤化しているため、エタノールに対してアレルギー反応を起こす患者に対しても投与が可能である。しかし、特表２０１１－５１４３４９号公報に記載された医薬製剤は、ヒマシ油を実質的に含まないため、例えば、筋肉内投与を行った場合に、治療上有効な血中フルベストラント濃度を一定期間保持させることが困難となり、治療上適切な医薬製剤とはいえない。 On the other hand, since the pharmaceutical formulation described in JP-T-2011-514349 is formulated without using ethanol, it can be administered to patients who have an allergic reaction to ethanol. However, since the pharmaceutical preparation described in JP-T-2011-514349 is substantially free of castor oil, the therapeutically effective blood fulvestrant concentration is constant when administered intramuscularly, for example. It becomes difficult to hold for a period of time, and it cannot be said that it is a therapeutically appropriate pharmaceutical preparation.
　また、エタノールに代わる溶剤（以下、「代替溶剤」ともいう。）の選択には、代替溶剤に対するフルベストラントの溶解性だけでなく、代替溶剤とその他の含有成分（例えば、ヒマシ油等の溶剤）との相溶性を考慮する必要がある。特に、注射液製剤では、含まれる成分の相溶性が良好でないと、低温で保存した場合に相分離又は析出に起因する濁りが生じ得るため、好ましいとはいえない。 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.
　本発明の一実施形態が解決しようとする課題は、フルベストラントの溶解性が良好で、かつ、低温で保存しても濁りが生じ難い、エタノールを実質的に含まない医薬組成物を提供することである。 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.
　上記課題を解決するための具体的な手段には、以下の実施態様が含まれる。 Specific means for solving the above-described problems include the following embodiments.
　［１］　フルベストラントと、ヒマシ油と、芳香族カルボン酸と、プロピレングリコール及び１，３－ブチレングリコールから選ばれる少なくとも１種の多価アルコールと、を含み、エタノールの含有量が、医薬組成物の全質量に対して１質量％未満である医薬組成物。
　［２］　エタノールの含有量が、医薬組成物の全質量に対して０．５質量％未満である［１］に記載の医薬組成物。
　［３］　プロピレングリコール及び１，３－ブチレングリコールから選ばれる多価アルコールが、プロピレングリコールである［１］又は［２］に記載の医薬組成物。
　［４］　プロピレングリコールの含有量が、医薬組成物の全質量に対して９質量％以上１８質量％以下である［３］に記載の医薬組成物。
　［５］　芳香族カルボン酸が、安息香酸である［１］～［４］のいずれか１つに記載の医薬組成物。 [1] A pharmaceutical composition comprising fulvestrant, castor oil, aromatic carboxylic acid, and at least one polyhydric alcohol selected from propylene glycol and 1,3-butylene glycol, wherein the ethanol content is 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］　芳香族カルボン酸の含有量が、医薬組成物の全質量に対して２．５質量％以上１０質量％以下である［１］～［５］のいずれか１つに記載の医薬組成物。
　［７］　安息香酸ベンジルを更に含む［１］～［６］のいずれか１つに記載の医薬組成物。
　［８］　安息香酸ベンジルの含有量が、医薬組成物の全質量に対して１質量％以上２０質量％以下である［７］に記載の医薬組成物。
　［９］　芳香族アルコールを更に含む［１］～［８］のいずれか１つに記載の医薬組成物。
　［１０］　筋肉内注射用である［１］～［９］のいずれか１つに記載の医薬組成物。 [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 or more and 10% by mass or less 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.
　本発明の一実施形態によれば、フルベストラントの溶解性が良好で、かつ、低温で保存しても濁りが生じ難い、エタノールを実質的に含まない医薬組成物が提供される。 According to one embodiment of the present invention, there is provided a pharmaceutical composition which has good solubility of fulvestrant and hardly causes turbidity even when stored at a low temperature and substantially does not contain ethanol.
　以下、本発明の具体的な実施形態について詳細に説明するが、本発明は、以下の実施形態に何ら限定されるものではなく、本発明の一実施形態の目的の範囲内において、適宜、変更を加えて実施することができる。 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.
　本明細書において「～」を用いて示された数値範囲は、「～」の前後に記載される数値をそれぞれ最小値及び最大値として含む範囲を意味する。
　本明細書中に段階的に記載されている数値範囲において、ある数値範囲で記載された上限値又は下限値は、他の段階的な記載の数値範囲の上限値又は下限値に置き換えてもよい。また、本明細書中に記載されている数値範囲において、ある数値範囲で記載された上限値又は下限値は、実施例に示されている値に置き換えてもよい。
　本明細書において、医薬組成物中の各成分の量は、各成分に該当する物質が医薬組成物中に複数存在する場合には、特に断らない限り、医薬組成物中に存在する複数の物質の合計量を意味する。 In the present specification, a numerical range indicated by using “to” means a range including the numerical values described before and after “to” as the minimum value and the 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.
　本明細書において、「工程」との語は、独立した工程だけではなく、他の工程と明確に区別できない場合であってもその工程の所期の目的が達成されれば、本用語に含まれる。 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.
　本明細書において、「低温」とは、一般にフルベストラントを有効成分として含む医薬組成物を冷蔵保存する際に適用される温度を指し、具体的には、２℃～８℃の範囲を意味する。
　本明細書において、「エタノールを実質的に含まない」とは、エタノールの含有量が、医薬組成物の全質量に対して１質量％未満であることを意味する。 In the present specification, “low temperature” generally refers to a temperature applied when refrigerated storage of 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.
［医薬組成物］
　本開示の医薬組成物は、フルベストラントと、ヒマシ油と、芳香族カルボン酸と、プロピレングリコール及び１，３－ブチレングリコールから選ばれる少なくとも１種の多価アルコール（以下、「特定多価アルコール」ともいう。）と、を含み、エタノールの含有量が、医薬組成物の全質量に対して１質量％未満の医薬組成物である。 [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.
　本開示の医薬組成物中の有効成分であるフルベストラントは、水に対して難溶性を示す薬物である。そのため、従来のフルベストラントを含む医薬製剤では、フルベストラントの溶解性に優れる溶剤として、エタノールを選択している。
　しかし、医薬製剤におけるエタノールの使用は、アルコール過敏症等のエタノールに対してアレルギー反応を起こす患者への投与を制限することになり、幅広い患者への適用の観点からは、好ましいとはいえない。 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.
　本開示の医薬組成物は、フルベストラントを、ヒマシ油と、芳香族カルボン酸と、プロピレングリコール及び１，３－ブチレングリコールから選ばれる少なくとも１種の多価アルコールと組み合わせて含むことにより、エタノールを実質的に含まなくても、フルベストラントの溶解性が良好となる。また、本開示の医薬組成物に含まれる上述の各成分は相溶性が良好であるため、本開示の医薬組成物は、低温で保存しても濁りが生じ難いと考えられる。 The pharmaceutical composition of the present disclosure comprises ethanol by containing fulvestrant in combination with castor oil, 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.
＜エタノール＞
　本開示の医薬組成物は、エタノールの含有量が医薬組成物の全質量に対して１質量％未満である。
　本開示の医薬組成物中のエタノールの含有量が、医薬組成物の全質量に対して１質量％未満であると、アルコール過敏症等のエタノールに対してアレルギー反応を起こす患者にも本開示の医薬組成物を適用することが可能になり、幅広い患者への投与が可能となる。
　また、本開示の医薬組成物中のエタノールの含有量が、医薬組成物の全質量に対して１質量％未満であると、揮発性のエタノールが微量であるため、医薬組成物の製造が容易となる。 <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.
　本開示の医薬組成物中のエタノールの含有量は、医薬組成物の全質量に対して、好ましくは０．５質量％未満であり、より好ましくは０．３質量％未満であり、更に好ましくは０．１質量％未満であり、特に好ましくはエタノールを含まないこと、即ち、０質量％である。 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.
　以下、本開示の医薬組成物の各成分について、説明する。 Hereinafter, each component of the pharmaceutical composition of the present disclosure will be described.
＜フルベストラント＞
　本開示の医薬組成物は、有効成分として、フルベストラントを含む。
　フルベストラント（７α－［９－（４，４，５，５，５－ペンタフルオロペンチルスルフィニル）ノニル］エストラ－１，３，５（１０）－トリエン－３，１７β－ジオール）は、エストロゲン受容体アンタゴニストであり、乳癌を治療するための薬物として知られている。 <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.
　本開示の医薬組成物中のフルベストラントの含有量は、例えば、投与量の観点から、医薬組成物の全質量に対して４．５質量％以上であることが好ましく、より好ましくは５質量％以上である。
　医薬組成物中のフルベストラントの含有量の上限は、特に限定されず、例えば、フルベストラントの溶解性の観点から、１０質量％以下である。 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.
＜ヒマシ油＞
　本開示の医薬組成物は、ヒマシ油を含む。
　本開示の医薬組成物は、ヒマシ油を含むことで、治療上有効な血中フルベストラント濃度を一定期間保持させることができる。 <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.
　本開示の医薬組成物中のヒマシ油の含有量は、特に限定されず、例えば、医薬組成物の全質量に対して、好ましくは４０質量％以上８０質量％以下であり、より好ましくは４５質量％以上７５質量％以下であり、更に好ましくは５０質量％以上７０質量％以下である。
　医薬組成物中のヒマシ油の含有量が上記の範囲内であると、治療上有効な血中フルベストラント濃度を一定期間保持させることができ、かつ、フルベストラントを均一に溶解させるために必要なヒマシ油以外の含有成分の配合量を確保できる。 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.
＜芳香族カルボン酸＞
　本開示の医薬組成物は、芳香族カルボン酸を含む。
　本開示の医薬組成物において、芳香族カルボン酸は、フルベストラントの溶解性に寄与する。
　芳香族カルボン酸は、芳香族基及びカルボキシ基を有しており、フルベストラントとの親和性が高いと考えられる。本開示の医薬組成物は、フルベストラントとの親和性が高い芳香族カルボン酸を含むことで、フルベストラントの溶解性が良好になると考えられる。 <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.
　芳香族カルボン酸としては、特に限定されず、例えば、安息香酸及びサリチル酸から選ばれる少なくとも１種が好ましく、安息香酸がより好ましい。
　本開示の医薬組成物は、芳香族カルボン酸として安息香酸を含むことで、フルベストラントの溶解性がより良好となる。また、低温で保存しても濁りが生じ難い。 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. Moreover, even if it preserve | saves at low temperature, it is hard to produce turbidity.
　本開示の医薬組成物は、芳香族カルボン酸を１種のみ含んでいてもよく、２種以上含んでいてもよい。 The pharmaceutical composition of the present disclosure may contain only one type of aromatic carboxylic acid, or may contain two or more types.
　本開示の医薬組成物中の芳香族カルボン酸の含有量は、特に限定されない。
　例えば、医薬組成物中の芳香族カルボン酸（好ましくは、安息香酸）の含有量は、医薬組成物の全質量に対して、好ましくは２．５質量％以上１０質量％以下であり、より好ましくは５質量％以上１０質量％以下である。
　医薬組成物中の芳香族カルボン酸の含有量が上記の範囲内であると、フルベストラントの溶解性が良好で、かつ、低温で保存しても濁りを生じ難いという本発明の一実施形態の効果がより効果的に奏される。 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.
（特定多価アルコール）
　本開示の医薬組成物は、プロピレングリコール及び１，３－ブチレングリコールから選ばれる少なくとも１種の多価アルコール（即ち、特定多価アルコール）を含む。
　本開示の医薬組成物において、特定多価アルコールは、フルベストラントの溶解性に寄与する。 (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.
　特定多価アルコールとしては、プロピレングリコールが特に好ましい。
　本開示の医薬組成物は、プロピレングリコールを含むことで、フルベストラントの溶解性が良好で、かつ、低温で保存しても濁りを生じ難いという本発明の一実施形態の効果をより効果的に奏することができる。 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.
　本開示の医薬組成物中の特定多価アルコールの含有量は、特に限定されない。
　例えば、医薬組成物中の特定多価アルコール（好ましくは、プロピレングリコール）の含有量は、医薬組成物の全質量に対して、好ましくは９質量％以上１８質量％以下であり、より好ましくは１２．５質量％以上１８質量％以下であり、更に好ましくは１５質量％以上１８質量％以下である。
　医薬組成物中の特定多価アルコールの含有量が、医薬組成物の全質量に対して、９質量％以上であると、フルベストラントの溶解性がより良好となる。また、医薬組成物中の特定多価アルコールの含有量が、医薬組成物の全質量に対して、１８質量％以下であると、ヒマシ油との相溶性が十分となるため、低温で保存した場合に濁りをより生じ難い。 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.
＜他の成分＞
　本開示の医薬組成物は、フルベストラント、ヒマシ油、芳香族カルボン酸、及び特定多価アルコール以外に、本発明の一実施形態の効果を損なわない範囲において、必要に応じて、他の成分を含んでいてもよい。
　他の成分としては、例えば、安息香酸ベンジル、芳香族アルコール、ポリエチレングリコール、及びその他の添加剤が挙げられるが、これらに限定されるものではない。 <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.
（安息香酸ベンジル）
　本開示の医薬組成物は、安息香酸ベンジルを更に含んでいてもよい。
　本開示の医薬組成物が安息香酸ベンジルを含む場合、医薬組成物中の安息香酸ベンジルの含有量は、特に限定されない。
　例えば、医薬組成物中の安息香酸ベンジルの含有量は、医薬組成物の全質量に対して、好ましくは１質量％以上２０質量％以下であり、より好ましくは５質量％以上２０質量％以下であり、更に好ましくは１０質量％以上２０質量％以下である。 (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.
（芳香族アルコール）
　本開示の医薬組成物は、芳香族アルコールを更に含むことが好ましい。
　本開示の医薬組成物において、芳香族アルコールは、フルベストラントの溶解に関し、既述の特定多価アルコール（好ましくは、プロピレングリコール）の助剤として機能し得る。
　本開示の医薬組成物は、既述の特定多価アルコール（好ましくは、プロピレングリコール）と芳香族アルコール（例えば、ベンジルアルコール）との組み合わせを含むことで、フルベストラントの溶解性がより良好となる。 (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.
　芳香族アルコールとしては、特に限定されず、例えば、ベンジルアルコール及びフェネチルアルコールが挙げられる。
　これらの中でも、芳香族アルコールとしては、フルベストラントの溶解性の観点から、ベンジルアルコールが好ましい。 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.
　本開示の医薬組成物が芳香族アルコールを含む場合、芳香族アルコールを１種のみ含んでいてもよく、２種以上含んでいてもよい。 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.
　本開示の医薬組成物が芳香族アルコールを含む場合、医薬組成物中の芳香族アルコールの含有量は、特に限定されない。
　例えば、医薬組成物中の芳香族アルコール（好ましくは、ベンジルアルコール）の含有量は、医薬組成物の全質量に対して、好ましくは０．０１質量％以上３０質量％以下であり、より好ましくは１質量％以上２５質量％以下であり、更に好ましくは１質量％以上１５質量％以下である。 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.
　本開示の医薬組成物が芳香族アルコールを含む場合、医薬組成物中における、特定多価アルコールの含有量に対する芳香族アルコールの含有量の比率（芳香族アルコールの含有量／特定多価アルコールの含有量）は、質量基準で、好ましくは０．１～２．０であり、より好ましくは０．１５～１．５であり、更に好ましくは０．２～１．２である。 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 (the content of the aromatic alcohol / the content of the specific polyhydric alcohol) The amount is preferably from 0.1 to 2.0, more preferably from 0.15 to 1.5, and even more preferably from 0.2 to 1.2 on a mass basis.
（ポリエチレングリコール）
　本開示の医薬組成物は、特定多価アルコール以外の多価アルコールとして、ポリエチレングリコール（ＰＥＧ）を更に含んでいてもよい。 (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.
　ポリエチレングリコールの平均分子量は、特に限定されない。
　ポリエチレングリコールの平均分子量は、例えば、筋肉注射用途に適するものを使用するという観点から、好ましくは２００以上５０００以下であり、より好ましくは２００以上４０００以下であり、更に好ましくは２００以上１０００以下であり、特に好ましくは２００以上６００以下である。
　なお、ポリエチレングリコールの平均分子量は、第１６改正日本薬局方に記載の方法によって測定される。 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.
　平均分子量が２００以上６００以下のポリエチレングリコールとしては、ポリエチレングリコール２００、ポリエチレングリコール３００、ポリエチレングリコール４００、及びポリエチレングリコール６００が挙げられる。 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.
　ポリエチレングリコールとしては、日本薬局方、医薬品添加物規格、又は各国の薬局方にて規定された、医薬品添加物として適するものが好ましい。 Polyethylene glycol is preferably suitable as a pharmaceutical additive as defined by the Japanese Pharmacopoeia, Pharmaceutical Additive Standards, or the pharmacopoeia of each country.
　本開示の医薬組成物がポリエチレングリコールを含む場合、ポリエチレングリコールを１種のみ含んでいてもよく、２種以上含んでいてもよい。 When the pharmaceutical composition of the present disclosure contains polyethylene glycol, it may contain only one type of polyethylene glycol or two or more types.
　本開示の医薬組成物がポリエチレングリコールを含む場合、医薬組成物中のポリエチレングリコールの含有量は、特に限定されない。
　例えば、医薬組成物中のポリエチレングリコールの含有量は、医薬組成物の全質量に対して、好ましくは０．０１質量％以上１０質量％以下であり、より好ましくは１質量％以上８質量％以下であり、更に好ましくは１質量％以上６質量％以下である。 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.
（その他の添加剤）
　本開示の医薬組成物は、本発明の一実施形態の効果を損なわない範囲において、必要に応じて、医薬的に許容される添加剤を更に含んでいてもよい。本開示の医薬組成物を筋肉内注射用として適用する場合には、筋肉内注射に適した添加剤を更に含むことが好ましい。
　その他の添加剤としては、グリセリン、アスコルビン酸又はその塩、塩酸、グルコン酸又はその塩、酢酸又はその塩、乳酸又はその塩、ホウ酸又はその塩、リン酸又はその塩、硫酸又はその塩、酒石酸又はその塩、クエン酸又はその塩、水酸化カリウム、水酸化カルシウム、水酸化ナトリウム、水酸化マグネシウム、モノエタノールアミン、ジエタノールアミン、トリエタノールアミン、トロメタモール、メグルミン、グリシン、ヒスチジン又はその塩、ε-アミノカプロン酸、アルギニン又はその塩、システイン又はその塩、メチオニン、アラニン、ロイシン、アスパラギン酸又はその塩、グルタミン酸又はその塩、アルギニン又はその塩、チオグリセリン、チオグリコール酸又はその塩、タウリン、エデト酸ナトリウム、リドカイン又はその塩、ニコチン酸アミド、クロロブタノール、クレアチニン、ゴマ油、ラッカセイ油、ツバキ油、ブチルヒドロキシトルエン、ブチルヒドロキシアニソール、ソルビタンセスキオレイン酸エステル、オレイン酸エチル、乳酸エチル、チロメサール、ポリオキシエチレン硬化ヒマシ油、ポリソルベート２０、ポリソルベート８０等が挙げられる。
　但し、その他の添加剤は、これらに限定されない。 (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.
　本開示の医薬組成物がその他の添加剤を含む場合、その他の添加剤を１種のみ含んでいてもよいし、２種以上含んでいてもよい。
　本開示の医薬組成物がその他の添加剤を含む場合、医薬組成物中のその他の添加剤の含有量は、医薬組成物の全質量に対して１０質量％以下であることが好ましい。 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.
（水）
　本開示の医薬組成物は、低温で保存しても濁りを生じ難いという本発明の一実施形態の効果がより効果的に奏されるという観点から、水を実質的に含まないことが好ましい。
　ここでいう「水を実質的に含まない」とは、大気からの吸湿によって含まれることになる水分量を超える量の水分を含まないことを意味する。「大気からの吸湿によって含まれることになる水分量」には、医薬組成物の保管中に、医薬組成物中に保持される水分の量が含まれる。
　具体的には、本開示の医薬組成物中の水の含有量は、医薬組成物の全質量に対して、好ましくは５質量％以下であり、より好ましくは３質量％以下であり、更に好ましくは２質量％以下であり、特に好ましくは１質量％以下である。 (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.
［医薬組成物の用途］
　本開示の医薬組成物は、筋肉内注射用として好適に用いることができる。
　本開示の医薬組成物は、フルベストラントの溶解性が良好で、かつ、低温（２℃～８℃）で保存しても、医薬組成物に含まれる成分に相分離又は析出が生じ難く、フルベストラント等の成分が良好に混合されている状態が安定に保持されているため、筋肉内注射に適した製剤である。 [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 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.
［医薬組成物の製造方法］
　本開示の医薬組成物の製造方法は、既述の医薬組成物を製造できればよく、特に限定されるものではない。
　本開示の医薬組成物を製造する方法としては、含まれる成分が均一に混合された医薬組成物を得やすいという観点から、以下で説明する、本実施形態の医薬組成物の製造方法が好ましい。 [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.
　本実施形態の医薬組成物の製造方法（以下、「本実施形態の製造方法」ともいう。）は、フルベストラントと、芳香族カルボン酸と、プロピレングリコール及び１，３－ブチレングリコールから選ばれる少なくとも１種の多価アルコール（特定多価アルコール）と、を混合し、フルベストラントの溶解液を得る工程（以下、「第１の工程」ともいう。）、並びに、得られたフルベストラントの溶解液と、ヒマシ油と、を混合し、医薬組成物を得る工程（以下、「第２の工程」ともいう。）を有する。
　本実施形態の製造方法は、フルベストラントと、芳香族カルボン酸と、特定多価アルコールと、ヒマシ油と、を一括して混合する場合と比較して、含まれる成分が均一に混合された医薬組成物を得やすいという利点を有する。
　以下、本実施形態の製造方法について説明するが、既述の医薬組成物と共通する事項、例えば、医薬組成物に含まれる成分及びその量については、説明を省略する。 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.
＜第１の工程＞
　第１の工程は、フルベストラントと、芳香族カルボン酸と、特定多価アルコールと、を混合し、フルベストラントの溶解液を得る工程である。
　既述の医薬組成物が、安息香酸ベンジル、芳香族アルコール等のその他の成分を含む場合には、フルベストラントと、芳香族カルボン酸と、特定多価アルコールと、その他の成分と、を混合し、フルベストラントの溶解液を得ることが好ましい。 <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.
　第１の工程において、混合する各成分は、単に混合すればよく、全ての成分を一度に混合してもよいし、各成分をいくつかに分けて混合してもよい。
　混合の方法としては、特に限定されず、例えば、撹拌による混合が挙げられる。 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.
　混合の際の温度条件としては、特に限定されず、例えば、混合する成分の組成（種類及び量）等に応じて、適宜設定することができる。
　第１の工程では、通常、雰囲気温度１５℃～６０℃の条件下で、フルベストラントと、芳香族カルボン酸と、特定多価アルコールと、を混合し、フルベストラントの溶解液を得る。 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.
＜第２の工程＞
　第２の工程は、第１の工程で得られたフルベストラントの溶解液と、ヒマシ油と、を混合し、医薬組成物を得る工程である。
　混合の方法としては、特に限定されず、例えば、撹拌による混合が挙げられる。 <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.
　第２の工程では、フルベストラントの溶解液とヒマシ油とを一度に混合してもよいし、例えば、フルベストラントの溶解液を撹拌しながら、ヒマシ油を徐々に添加して、フルベストラントの溶解液とヒマシ油とを混合してもよい。 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.
　混合の際の温度条件は、特に限定されない。
　第２の工程では、通常、雰囲気温度１５℃～６０℃の条件下で、フルベストラントの溶解液とヒマシ油とを混合し、医薬組成物を得る。 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.
＜その他の工程＞
　本実施形態の製造方法は、必要に応じて、第１の工程及び第２の工程以外のその他の工程を有していてもよい。また、第１の工程及び第２の工程は、複数の工程を含んで構成されていてもよい。
　その他の工程としては、医薬組成物を滅菌する工程、医薬組成物を容器に充填する工程等が挙げられる。
　滅菌する工程としては、滅菌フィルターを用いたろ過滅菌法が好ましい。 <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.
　医薬組成物を充填する容器としては、バイアル、アンプル、シリンジ等が挙げられる。
　これらの中でも、医薬組成物を充填する容器としては、医療現場における取り扱い性の観点から、シリンジが好ましく、ガラス製のシリンジがより好ましい。 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.
　本開示は、有効成分としてフルベストラント含む既述の医薬組成物を、乳癌の治療の対象となる患者へ投与することを含む乳癌の治療方法も包含する。 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.
　以下、本発明を実施例により更に具体的に説明するが、本発明はその主旨を越えない限り、以下の実施例に限定されるものではない。 Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples as long as the gist thereof is not exceeded.
［医薬組成物の製造］
＜実施例１＞
　撹拌子を入れた清潔なガラス容器に、フルベストラント５質量部、芳香族カルボン酸として安息香酸５質量部、特定多価アルコールとしてプロピレングリコール（ＰＧ）１５質量部、及び安息香酸ベンジル１５質量部を秤量した後、撹拌し、フルベストラントを溶解させた。次いで、得られたフルベストラントの溶解液にヒマシ油を加え、全量を１００質量部に調整した後、更に撹拌して均一化し、実施例１の医薬組成物を得た。 [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.
＜実施例２～２２＞
　医薬組成物の組成を、下記の表１に示す組成に変更したこと以外は、実施例１と同様の操作を行って、実施例２～２２の医薬組成物を得た。 <Examples 2 to 22>
Except that the composition of the pharmaceutical composition was changed to the composition shown in Table 1 below, the same operations as in Example 1 were performed to obtain the pharmaceutical compositions of Examples 2 to 22.
＜比較例１～５＞
　医薬組成物の組成を、下記の表１に示す組成に変更したこと以外は、実施例１と同様の操作を行って、比較例１～５の医薬組成物を得た。 <Comparative Examples 1 to 5>
Except that the composition of the pharmaceutical composition was changed to the composition shown in Table 1 below, the same operations as in Example 1 were performed to obtain the pharmaceutical compositions of Comparative Examples 1 to 5.
＜参考例１～２＞
　医薬組成物の組成を、下記の表１に示す組成に変更したこと以外は、実施例１と同様の操作を行って、参考例１～２の医薬組成物を得た。 <Reference Examples 1-2>
The pharmaceutical compositions of Reference Examples 1 and 2 were obtained in the same manner as in Example 1 except that the composition of the pharmaceutical composition was changed to the composition shown in Table 1 below.
［評価］
１．フルベストラントの溶解性
　上記にて得られた実施例１～２２、比較例１～５、及び参考例１～２の各医薬組成物に、更に少なくとも飽和量のフルベストラントを加え、少なくとも１日以上撹拌した後、１００００ｒｐｍ（round per minute）以上、１０分以上の条件にて遠心分離を行い、過剰のフルベストラントを除き、上清を得た。
　得られた上清に溶解しているフルベストラントの量を、下記の条件の高速液体クロマトグラフィー（ＨＰＬＣ）にて測定した。得られた測定値をフルベストラントの溶解許容量（単位：ｍｇ／ｇ）とした。フルベストラントの溶解許容量が４５ｍｇ／ｇ以上である場合を、フルベストラントの溶解性が良好であると判断した。結果を表１に示す。
　なお、表１では、溶解許容量が４５ｍｇ／ｇ以上である場合を「良好」と表記し、溶解許容量が４５ｍｇ／ｇ未満である場合を「不良」と表記した。 [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 was 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”.
　上記の評価において、医薬組成物におけるフルベストラントの溶解許容量の値が十分に高いことは、医薬組成物が、治療上必要なフルベストラントを十分に、かつ、均一に含む能力が高いことを示す。 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条件－
　カラム：ＸＢｒｉｄｇｅ　Ｃ８（製品名、粒子径：３．５μｍ、カラムサイズ：４．６ｍｍ×１５０ｍｍ、Ｗａｔｅｒｓ社）
　移動相Ａ：メタノール／水＝７０／３０
　移動相Ｂ：メタノール
　グラジェント条件（移動相Ｂの比率）：０％（開始）→０％（１２ｍｉｎ）→１００％（１２．１ｍｉｎ）→１００％（２０ｍｉｎ）→０％（２０．１ｍｉｎ）→０％（３０ｍｉｎ、停止）
　検出波長：２２５ｎｍ
　流量：１．０ｍＬ／ｍｉｎ
　カラム温度：４０℃ -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．濁りの有無
　上記にて得られた実施例１～２２、比較例１～５、及び参考例１～２の各医薬組成物の少なくとも１ｍＬを、それぞれ無色透明のガラス瓶（５ｍＬ容量）に量り取り、冷蔵庫（雰囲気温度：２℃～８℃）に保存した。保存開始から１時間以上経過後、冷蔵庫からガラス瓶を取り出した。取り出し直後に、ガラス瓶の表面に生じた曇りをキムワイプ（登録商標）で拭き取ってから、ガラス瓶に入った医薬組成物を目視にて観察し、濁りの有無を確認した。結果を表１に示す。
　なお、表１では、ガラス瓶に入った医薬組成物に、濁りが確認されなかった場合を「なし」と表記し、濁りが確認された場合を「あり」と表記した。 2. Existence of turbidity At least 1 mL of each of the pharmaceutical compositions 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 was stored in a refrigerator (atmosphere temperature: 2 ° C. to 8 ° C.). 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”.
　上記の評価において、ガラス瓶に入った医薬組成物に濁りが確認されない（即ち、医薬組成物が澄明である）状態は、含まれる成分が均一に混合されている状態を示し、低温（２℃～８℃）での保存中に、医薬組成物に含まれる成分に相分離又は析出が生じず、フルベストラント等の成分が良好に混合されている状態が安定に保持されていることを意味する。
　一方、ガラス瓶に入った医薬組成物に濁りが確認される状態は、含まれる成分が均一に混合されていない状態を示し、低温（２℃～８℃）での保存中に医薬組成物に含まれる成分のいずれかが相分離又は析出しており、筋肉内注射に適した製剤とはいえないことを意味する。 In the above evaluation, the state in which no turbidity is 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 that 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.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表１中、「－」は、該当するものがないことを意味する。
　表１中、「プロピレングリコール」を「ＰＧ」、１，３－ブチレングリコールを「ＢＧ」と表記した。
　表１において、「ＰＥＧ４００」は、日局マクロゴール４００である。 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.
　表１に示すように、フルベストラント、ヒマシ油、芳香族カルボン酸、及び特定多価アルコールの１つであるプロピレングリコール（ＰＧ）を含み、エタノールの含有量が医薬組成物の全質量に対して１質量％未満である、実施例１～２２の医薬組成物は、フルベストラントの溶解性が良好で、かつ、低温で保存しても濁りが生じなかった。
　一方、芳香族カルボン酸及び特定多価アルコールの少なくとも一方を含まない、比較例１～５の医薬組成物は、フルベストラントの溶解性及び濁りの有無の少なくとも一方の評価において、結果が良好ではなく、フルベストラントの溶解性が良好であることと、低温で保存しても濁りが生じないこととを、両立しなかった。 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 have good results in evaluating 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.
　特定多価アルコールの１つであるプロピレングリコールに加えて、ベンジルアルコールを更に含む医薬組成物（例えば、実施例１９）では、ベンジルアルコールを含まない医薬組成物（例えば、実施例１）と比較して、フルベストラントの溶解許容量が顕著に増加した。 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.
　２０１６年１月２８日に出願された日本国特許出願２０１６－０１４４５３号の開示は、その全体が参照により本明細書に取り込まれる。
　本明細書に記載された全ての文献、特許出願、及び技術規格は、個々の文献、特許出願、及び技術規格が参照により取り込まれることが具体的に、かつ、個々に記された場合と同程度に、本明細書中に参照により取り込まれる。 The disclosure of Japanese Patent Application No. 2016-014453 filed on Jan. 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)

  1. 　フルベストラントと、
    　ヒマシ油と、
    　芳香族カルボン酸と、
    　プロピレングリコール及び１，３－ブチレングリコールから選ばれる少なくとも１種の多価アルコールと、を含み、
    　エタノールの含有量が、医薬組成物の全質量に対して１質量％未満である医薬組成物。     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.
  2. 　エタノールの含有量が、医薬組成物の全質量に対して０．５質量％未満である請求項１に記載の医薬組成物。 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.
  3. 　プロピレングリコール及び１，３－ブチレングリコールから選ばれる多価アルコールが、プロピレングリコールである請求項１又は請求項２に記載の医薬組成物。 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.
  4. 　プロピレングリコールの含有量が、医薬組成物の全質量に対して９質量％以上１８質量％以下である請求項３に記載の医薬組成物。 The pharmaceutical composition according to claim 3, wherein the content of propylene glycol is 9% by mass or more and 18% by mass or less based on the total mass of the pharmaceutical composition.
  5. 　芳香族カルボン酸が、安息香酸である請求項１～請求項４のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, wherein the aromatic carboxylic acid is benzoic acid.
  6. 　芳香族カルボン酸の含有量が、医薬組成物の全質量に対して２．５質量％以上１０質量％以下である請求項１～請求項５のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 5, wherein the aromatic carboxylic acid content is 2.5% by mass or more and 10% by mass or less based on the total mass of the pharmaceutical composition.
  7. 　安息香酸ベンジルを更に含む請求項１～請求項６のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, further comprising benzyl benzoate.
  8. 　安息香酸ベンジルの含有量が、医薬組成物の全質量に対して１質量％以上２０質量％以下である請求項７に記載の医薬組成物。 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.
  9. 　芳香族アルコールを更に含む請求項１～請求項８のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 8, further comprising an aromatic alcohol.
  10. 　筋肉内注射用である請求項１～請求項９のいずれか１項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 9, which is for intramuscular injection.
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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009509942A (en) * 2005-09-26 2009-03-12 ホスピラ・オーストラリア・ピーティーワイ・リミテッド Fulvestrant formulation
JP2011523620A (en) * 2007-11-22 2011-08-18 エスケー ケミカルズ カンパニー リミテッド Freeze-dried pharmaceutical composition having improved stability, containing taxane derivative, and method for producing the same
WO2015033302A2 (en) * 2013-09-06 2015-03-12 Salah Uddin Ahmed Fulvestrant compositions
JP2015511606A (en) * 2012-03-31 2015-04-20 リポント ファーマシューティカルズ インコーポレイテッド Oil-based preparation of fulvestrant or derivative thereof based on lactate and method for producing the same

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009509942A (en) * 2005-09-26 2009-03-12 ホスピラ・オーストラリア・ピーティーワイ・リミテッド Fulvestrant formulation
JP2011523620A (en) * 2007-11-22 2011-08-18 エスケー ケミカルズ カンパニー リミテッド Freeze-dried pharmaceutical composition having improved stability, containing taxane derivative, and method for producing the same
JP2015511606A (en) * 2012-03-31 2015-04-20 リポント ファーマシューティカルズ インコーポレイテッド Oil-based preparation of fulvestrant or derivative thereof based on lactate and method for producing the same
WO2015033302A2 (en) * 2013-09-06 2015-03-12 Salah Uddin Ahmed Fulvestrant compositions

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
IYAKUHIN TENKABUTSU JITEN 2007, 25 July 2007 (2007-07-25), pages 236, 242, 243 *

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