WO2017130576A1 - Composition médicinale - Google Patents

Composition médicinale 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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English (en)
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/ja
Publication of WO2017130576A1 publication Critical patent/WO2017130576A1/fr

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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

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Abstract

L'invention concerne une composition médicinale comprenant du fulvestrant, de l'huile de ricin, un acide carboxylique aromatique et au moins un type de polyalcool choisi parmi le propylène glycol et le 1,3-butylène glycol, la teneur en éthanol étant inférieure à 1 % en masse par rapport à la masse totale de la composition médicinale.
PCT/JP2016/086459 2016-01-28 2016-12-07 Composition médicinale WO2017130576A1 (fr)

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JP2024501166A (ja) * 2020-12-04 2024-01-11 サムヤン、ホールディングス、コーポレーション フルベストラントの徐放性医薬組成物及びその製造方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2009509942A (ja) * 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 フルベストラント製剤
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