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WO2012063498A2 - Novel exemestane solid dispersion - Google Patents

Novel exemestane solid dispersion Download PDF

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Publication number
WO2012063498A2
WO2012063498A2 PCT/JP2011/006331 JP2011006331W WO2012063498A2 WO 2012063498 A2 WO2012063498 A2 WO 2012063498A2 JP 2011006331 W JP2011006331 W JP 2011006331W WO 2012063498 A2 WO2012063498 A2 WO 2012063498A2
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WIPO (PCT)
Prior art keywords
exemestane
polymer
solubility
composition according
dissolution
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Ceased
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PCT/JP2011/006331
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French (fr)
Japanese (ja)
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WO2012063498A3 (en
Inventor
洋介 平井
直任 尾塩
仁 坂井
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Fuji Chemical Industries Co Ltd
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Fuji Chemical Industries Co Ltd
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Publication of WO2012063498A2 publication Critical patent/WO2012063498A2/en
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    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • 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
    • A61K31/568—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
    • A61K31/5685—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 substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A61K9/1694—Processes resulting in granules or microspheres of the matrix type containing more than 5% of excipient

Definitions

  • the present invention relates to a solid dispersion of exemestane having high solubility in water, a method for producing the solid dispersion of exemestane, and a pharmaceutical containing the exemestane solid dispersion.
  • a method of increasing the surface area by pulverizing drug crystals to nano size a method of adding a surfactant, a method of forming an inclusion compound of an inclusion molecule and a drug, a method of non-crystallizing a drug, examples thereof include a method of forming a crystal form having a high dissolution rate, and a method of forming a solid dispersion from a polymer and a drug.
  • a coprecipitation method, a spray drying method, a mixing and pulverizing method, a melting method, a mechanochemical method, and the like are known as methods for forming a solid dispersion.
  • a solubility is improved is a characteristic inherent to the drug, and many drugs do not have an improved solubility.
  • exemestane, astaxanthin, ⁇ -carotene and the like do not have high solubility even when a solid dispersion is formed.
  • the solubility when exemestane forms a solid dispersion, the solubility temporarily increases, but the solubility rapidly decreases. This is because in the case of a solid dispersion, the solubility is high, but after elution in an aqueous solution, the solubility in water is low and the rate of crystallization is high, so the drug crystals re-precipitate easily. is there.
  • Solid dispersions of exemestane include solid dispersions in which exemestane is included by cyclodextrin (Cited document 1), and solid dispersions composed of exemestane, vitamin E derivatives and polymers (cited document 2). Has been.
  • a solid dispersion containing two kinds of polymers, a concentration increasing polymer and a stabilizing polymer, and a drug having low solubility (cited reference 3)
  • a cellulose polymer composition A pharmaceutical composition (cited document 4) comprising a solid dispersion comprising a cellulose polymer and a low-solubility drug is disclosed.
  • the above-mentioned document is a combination of a polymer that improves the solubility of the drug in water and a polymer that improves the stability of the solid dispersion by humidity, and there is no description of the change in solubility of the drug over time.
  • the solid dispersion part is composed of a drug and one type of polymer, and the solid dispersion of the drug is included in another type of polymer, and the solid dispersion of the drug composed of two types of polymers Not the body.
  • a solid dispersion composition of exemestane with improved solubility of exemestane in water in order to improve the bioavailability of exemestane is provided.
  • solubility improving polymer By forming a solid dispersion of exemestane consisting of two types of polymers, a solubility improving polymer and an elution inhibiting polymer, the solubility of exemestane in water can be maintained for a long time.
  • the exemestane solid dispersion of the present invention makes it possible to maintain the solubility of exemestane in water for a long period of time, and to improve not only bioavailability by improving the dissolution property, but also to reduce the variation in solid difference, the influence of meals, etc. , Improve patient compliance.
  • the exemestane solid dispersion composition of the present invention is described below.
  • the exemestane solid dispersion of the present invention comprises exemestane, an elution enhancing polymer and an elution inhibiting polymer.
  • the structure of the solid dispersion of the present invention is a state in which exemestane and an elution-inhibiting polymer are in solid solution at the molecular level in the elution-enhancing polymer. Therefore, (1) the exemestane crystal is not substantially confirmed by the powder X-ray structural analysis described later, and (2) the endothermic peak peculiar to the exemestane crystal is not confirmed by the thermal analysis.
  • “two types of polymers” refers to an elution improving polymer and an elution suppressing polymer.
  • the exemestane of the present invention can be used in any form of anhydride, hydrate, solvate, and salt acceptable for pharmaceuticals.
  • Exemestane used as a raw material may be used in any form since it is dispersed in the size of a single molecule or nanoparticle in production. Either crystalline or amorphous or a mixture may be used, and any of known crystal polymorphs may be used as the crystal.
  • the elution improving polymer of the present invention is a polymer that dissolves in water among polymers generally used in binders and coating agents in the field of pharmaceuticals.
  • examples of the dissolution improving polymer include cellulose polymers, synthetic polymer monopolymers, synthetic polymer copolymers, and natural polymers.
  • Cellulose polymers include nonionic cellulose polymers and ionic cellulose polymers.
  • nonionic cellulose polymers include hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .: TC-5E, TC-5R, Metrose 60SH, etc.), hydroxypropyl cellulose (Nippon Soda Co., Ltd .: NISSO HPC-L, HPC-SSL, etc.), hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate, hydroxyethyl cellulose acetate and the like.
  • Examples of the ionic cellulose polymer include hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd .: Shin-Etsu AQOAT-AS-LF, AS-MF, AS-HG, etc.), hydroxypropyl methylcellulose succinate, hydroxypropyl Cellulose acetate succinate, hydroxyethylmethylcellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd .: HP-50, HP-55, etc.), hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose Acetate phthalate, carboxyethyl cellulose, ethyl carboxymethyl cellulose, carboxymethyl Cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose
  • Examples of the synthetic polymer monopolymer include polyvinyl pyrrolidone (manufactured by BASF: Kollidon K30, K90, K17, etc.), cross-linked polyvinyl pyrrolidone, polyethylene glycol (manufactured by Sanyo Chemical Industries, Ltd .: Macrogol 4000, 6000, 20000). Etc.), polyvinyl alcohol, polyvinyl acetate phthalate, polyvinyl acetal diethylaminoacetate, carboxyvinyl polymer, and the like.
  • Synthetic polymer copolymers include, for example, methacrylic acid copolymers (Rohm: Eudragit L100, L100-55, S100, L30D-55, etc.), aminoalkyl methacrylate copolymers (Rohm: Eudragit E100, RS100, etc.), polyvinyl Examples thereof include alcohol polyvinyl acetate copolymer, polyethylene glycol polypropylene glycol copolymer, polyethylene polyvinyl alcohol copolymer, polyvinyl pyrrolidone copolymer (manufactured by BASF: Kollidon VA64, SR, etc.).
  • hypromellose hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylpyrrolidone, polyvinylpyrrolidone copolymer, and methacrylic acid copolymer are preferable.
  • the dissolution inhibiting polymer of the present invention is a polymer that is generally used in the field of pharmaceuticals as a coating agent that imparts sustained release properties to drugs.
  • a polymer that is generally used in the field of pharmaceuticals as a coating agent that imparts sustained release properties to drugs.
  • the blending ratio of exemestane and the dissolution enhancing polymer is 1: 0.1 to 1:10, preferably 1: 0.2 to 1: 5, more preferably 1: 0.5 to 3. is there. From the same range, if the proportion of elution-improving polymer is small relative to exemestane, exemestane does not crystallize, so the elution is not improved. Dissolution does not improve.
  • the blending ratio of the elution improving polymer and the elution inhibiting polymer is 1: 0.01 to 1: 2, preferably 1: 0.05 to 1: 1, more preferably 1: 0.1 to 0.8. From the same range, if the proportion of the dissolution-inhibiting polymer is small relative to the dissolution-enhancing polymer, the solubility of exemestane will not be maintained for a long time, and the solubility will decrease in a short time. Increases and does not improve dissolution.
  • the solid dispersion composition of the present invention has a solubility of 2 times or more, preferably 4 times or more, more preferably 6 times or more of the exemestane crystal.
  • the solid dispersion composition of the present invention is 1.2 times or more, preferably 1.5 times or more, more preferably 2 times or more, and most preferably 3 times the solid dispersion composed of exemestane and an elution promoting polymer. It has the above-mentioned solubility of exemestane.
  • the solubility here is the solubility after 30 minutes or 60 minutes of the below-mentioned dissolution test.
  • the crystals of exemestane were not substantially confirmed by X-RD (X'Pert-MPD type, manufactured by Philips), and DSC (Thermoplus DSC8230, manufactured by Rigaku Corporation) The endothermic peak of the crystal transition of exemestane is not confirmed. From these, it is assumed that the solid dispersion of exemestane is dispersed in two types of polymers composed of a polymer phase with a particle size that does not exhibit physical properties as single molecules and / or crystals.
  • the solid dispersion of the present invention has higher solubility of exemestane in water and maintains a higher concentration than the solid dispersion of exemestane crystal or exemestane and an elution improving polymer.
  • the solubility of exemestane in the solid dispersion formed with the dissolution enhancing polymer reaches a maximum of exemestane in 0 to 10 minutes, and then the solubility decreases, and the solubility is reduced to 1/10 to 3/4 of the maximum solubility. descend.
  • the solid dispersion of the present invention does not cause such a decrease in solubility, and can maintain the maximum solubility in the dissolution test at least after 60 minutes. In order to improve the absorption of exemestane in the digestive tract, particularly in the upper small intestine, it is preferable to maintain the maximum solubility for about 30 to 60 minutes.
  • the reason why the exemestane solubility of the solid dispersion composed of exemestane and the dissolution enhancing polymer temporarily increases is considered to be due to reprecipitation of exemestane crystals because exemestane is in an over-dissolved state in an aqueous solution.
  • the reason why the solubility can be maintained by the addition of the elution-inhibiting polymer is not due to the increase in the dissolution equilibrium of exemestane but to the decrease in the crystal precipitation rate of exemestane. This is confirmed by a decrease in the elution degree after the elution inhibiting polymer is physically mixed in the solid dispersion composed of exemestane and the elution improving polymer.
  • the method for producing the solid dispersion of the present invention will be described below.
  • the solid dispersion of the present invention can be generally produced by a method for producing a solid dispersion of a drug. Examples thereof include a solvent method, a melting method, a mechanochemical method, and the like, and a solvent method and a melting method are preferable.
  • the solvent method is produced by suspending or dissolving exemestane, two types of polymers and, if necessary, other pharmaceutical additive components in an organic solvent, and then removing or precipitating the solvent.
  • Examples of the method for removing the solvent include an evaporation method, a spray method, a filtration method, and a freeze-drying method.
  • Spray methods include fluidized bed method, spray drying method, rolling bed method, agitation method, supercritical method, etc., and the solvent can be removed in a short time, so exemestane, dissolution enhancing polymer and dissolution inhibiting polymer are the same as in solvent
  • the spray method is preferable because a solid dispersion in a molecular dispersion state can be obtained uniformly.
  • the spray drying method is preferable because the solvent can be instantaneously removed to enable continuous production in large quantities and desired powder physical properties such as particle size and bulk density can be easily obtained.
  • the time required for removing the solvent is preferably shorter, preferably within 120 minutes, preferably within 60 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, and most preferably within 2 minutes.
  • the shorter the time required for removing the solvent the higher the degree of molecular dispersion between exemestane and the polymer, which is preferable.
  • the time required for removing the solvent is a time for obtaining a solid dispersion of the exemestane solid dispersion of the present invention, and a part of the solvent may remain. The remaining solvent can be removed by secondary drying described later.
  • the solvent used may be a pharmaceutically acceptable solvent, and a solvent in which exemestane is dissolved, for example, ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutyl ketone, tetrahydrofuran (THF), tetrahydropyran, 1,4-dioxane, diethyl ether, diisopropyl ether, t-butyl methyl ether, hexane, heptane, toluene, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), water, and the like, which may be used in combination with a single solvent or
  • the precipitation method is a coprecipitation method.
  • Exemestane and the two polymers of the present invention are dissolved or suspended in a solvent and precipitated by adding a solvent in which the dissolved exemestane and / or two polymers are insoluble, or by lowering the dissolution concentration by decreasing the temperature.
  • the manufacturing method by the evaporation method is described in detail.
  • Exemestane and two polymers are dissolved or suspended in a solvent.
  • the concentration at this time is 0.2 to 40% by weight of the solid content, and preferably 1 to 20% by weight.
  • the solvent is then removed under reduced pressure or normal pressure.
  • the temperature at this time is a temperature at which the solvent can be distilled off, and can be appropriately selected from the distillation time, and is ⁇ 10 to 120 ° C., preferably 0 to 100 ° C.
  • Exemestane and two polymers are dissolved or suspended in an organic solvent.
  • the concentration at this time may be any concentration that allows spray drying, and the solid content is 0.1 to 80% by weight, preferably 0.5 to 50% by weight.
  • the solvent is then removed and granulated simultaneously by spray drying.
  • a disc-type or nozzle-type for example, pressure nozzle, two-fluid nozzle, four-fluid nozzle
  • the inlet temperature is preferably about 20 to 150 ° C.
  • the outlet temperature is preferably about 0 to 85 ° C.
  • secondary drying can be performed.
  • the secondary drying can be performed by a drying method usually used in the manufacture of pharmaceuticals as long as the method can stably maintain the exemestane solid dispersion.
  • the melting method produces exemestane solid dispersion by heating exemestane and two kinds of polymers and, if necessary, other pharmaceutical additive components to a temperature at which any of the components melts or higher, and then cooling.
  • the method can be arbitrarily selected according to the machine used, the temperature, and the conventional method. Extruders are examples of machines.
  • a solvent may be added to lower the melting point, and the solvent is removed after melting.
  • the mechanochemical method is a method for producing an exemestane solid dispersion by simultaneously pulverizing and impacting exemestane, two types of polymers, and other pharmaceutical additive components as necessary.
  • the machine to be used, the temperature, and the pulverization conditions can be arbitrarily selected according to a conventional method.
  • the exemestane solid dispersion obtained in this way is subjected to dry granulation and wet granulation using additives that can be used in pharmaceuticals for tablet mixing, dissolution, sustained release, and bitterness masking. It can be carried out.
  • additives that can be used in pharmaceuticals for tablet mixing, dissolution, sustained release, and bitterness masking. It can be carried out.
  • the particle size and bulk density can be increased by thickening with a roller compactor or the like.
  • Exemestane solid dispersion and / or exemestane solid dispersion-containing particles are mixed with a pharmaceutical additive to obtain an oral pharmaceutical composition such as a tablet, capsule, powder, liquid, emulsion or suspension.
  • a pharmaceutical additive such as a tablet, capsule, powder, liquid, emulsion or suspension.
  • pharmaceutical compositions such as injections, suppositories, eye drops, inhalants, and external preparations for skin can also be obtained as parenteral agents. As these production methods, known methods can be used.
  • Pharmaceutical additives include binders (eg, carmellose, hydroxypropyl cellulose, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, dextrin, etc.), excipients (eg, starch, D-mannitol, lactose , Trehalose, crystalline cellulose, magnesium aluminate metasilicate, calcium hydrogen phosphate, hydrotalcite, anhydrous silicic acid, etc.), disintegrant (eg, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, etc.), interface Activators (eg polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, sodium lauryl sulfate), lubricant (sucrose Acid esters, magnesium stearate, talc, sodium stearyl fumarate
  • the pharmaceutical composition comprising the exemestane solid dispersion of the present invention can be expected to have an AUC equivalent to that of conventional crystalline exemestane even if the dosage is reduced due to an increase in the dissolution concentration of exemestane.
  • Example 1 Solvent evaporation method 50 mg of 10 mg of crystalline exemestane (manufactured by RPG Life Sciences), 10 mg of hydroxypropylmethylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd .: HPMCP HP-55) and 2 mg of ethylcellulose (manufactured by Dow Chemical Company) was added to 30 ml of an 8: 2 solution of dichloromethane and methanol and dissolved at room temperature. The solvent was distilled off at 37 ° C. under reduced pressure of an aspirator, and then dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain an exemestane solid dispersion.
  • Example 2 Solvent evaporation method 10 mg of crystalline exemestane, 10 mg of hydroxypropylmethylcellulose phthalate and 2 mg of methacrylic acid copolymer (Eudragit RS: manufactured by Rohm) were placed in a 50 ml eggplant-shaped flask, and 30 ml of an 8: 2 solution of dichloromethane and methanol was added. In addition, it was dissolved at room temperature. The solvent was distilled off at 37 ° C. under reduced pressure of an aspirator, and then dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain an exemestane solid dispersion.
  • Eudragit RS manufactured by Rohm
  • Example 3 Spray drying Crystal exemestane (100 mg), hydroxypropylmethylcellulose phthalate (300 mg) and ethylcellulose (50 mg) were dissolved at room temperature by adding 17.5 ml of an 8: 2 solution of dichloromethane and methanol. Next, spray drying was performed at a heat input temperature of 80 ° C., exhaust heat temperature of 50 ° C., and a spray rate of 6 ml / min, followed by drying overnight at 40 ° C. under reduced pressure (5 Torr or less), and a powder of a solid dispersion of exemestane Got.
  • Example 4 Spray drying Crystal exemestane 100 mg, hydroxypropylmethylcellulose phthalate 300 mg, and ethylcellulose 200 mg were dissolved in an 8: 2 solution of dichloromethane and methanol at room temperature. Next, spray drying was performed at a heat input temperature of 80 ° C., exhaust heat temperature of 50 ° C., and a spray rate of 6 ml / min, followed by drying overnight at 40 ° C. under reduced pressure (5 Torr or less), and a powder of a solid dispersion of exemestane Got.
  • Comparative Example 5 Physical Mixing Crystal Exemestane 20 mg, Hydroxypropyl Methylcellulose Phthalate 60 mg, and Ethylcellulose 10 mg were mixed in a plastic bag to obtain a mixed powder of exemestane.
  • Example 3 and Example 4 of the exemestane solid dispersion of the present invention maintain a solubility of 6 times or more with respect to the crystal exemestane of Comparative Example 1 during 2 to 30 minutes of the dissolution test.
  • the solid dispersion of exemestane and hydroxypropylmethylcellulose phthalate of Comparative Example 6 showed a temporary increase in solubility after 2 minutes, but the solubility decreased to about half after 5 minutes.
  • the solubility of Comparative Example 7 in which ethyl cellulose was added to the solid dispersion of Comparative Example 6 was less than half of Examples 3 and 4.
  • Examples 3 to 4 and Comparative Examples 6 to 7 were subjected to X-ray measurement (X-RD) using an X′Pert-MPD type (manufactured by Philips).
  • X-RD X-ray measurement
  • X′Pert-MPD manufactured by Philips
  • the crystal peak of exemestane did not appear and it was confirmed that a solid dispersion was formed.
  • the X-RD patterns of Example 3 and Comparative Example 1 are shown in FIG.
  • the crystal exemestane of Comparative Example 1 shows a significant peak, but the solid dispersion of Example 3 shows a halo pattern without a clear peak.
  • the effect of ethyl cellulose is not the effect of increasing the dissolution equilibrium of exemestane, but the three components of hydroxypropyl cellulose phthalate, which is an elution improving polymer, and ethyl cellulose and exemestane, which is an elution inhibiting polymer, form a solid dispersion. It can be seen that the decrease in solubility due to reprecipitation of exemestane is prevented and the solubility is maintained for a long time.

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Abstract

[Problem] The absorption of sparingly soluble drugs is increased by improving the solubility thereof by using a polymer to make a sparingly soluble drug, such as exemestane, into a solid dispersion. However, while the exemestane temporarily exhibits high solubility, the exemestane precipitates due to supersaturation and the like, and a reduction in solubility occurs. An exemestane solid dispersion is required that is capable of maintaining solubility over a long period of time without the solubility decreasing over time. [Solution] A drug composition in which the exemestane has a high, non decreasing, level of solubility, is provided by using two types of polymer, an elution improving polymer and a dissolution inhibiting polymer, to make a sparingly soluble drug into a solid dispersion by a method such as a solvent method, a melting method, or a mechanochemical method.

Description

新規なエキセメスタン固体分散体A novel exemestane solid dispersion

　本発明は、水への溶解性の高いエキセメスタンの固体分散体、そのエキセメスタンの固体分散の製造法、及びそのエキセメスタン固体分散体を含有する医薬品に関する。 The present invention relates to a solid dispersion of exemestane having high solubility in water, a method for producing the solid dispersion of exemestane, and a pharmaceutical containing the exemestane solid dispersion.

　これまでも水に難溶性の薬物が開発されていたが、近年、新規に開発中の薬物のほとんどが難溶性の薬物である。難溶性薬物の医薬品を開発するにあたって、人への吸収性を高めるため水への溶解度を向上することが求められており、これまで種々の方法が提案されてきた。例えば、薬物結晶をナノサイズに粉砕することによって表面積を増加させる方法、界面活性剤を添加させる方法、包接分子と薬物の包接化合物を形成させる方法、薬物を非結晶化する方法、薬物を溶解速度の高い結晶形とする方法、高分子などと薬物から固体分散体を形成させる方法などが挙げられる。 Until now, poorly water-soluble drugs have been developed, but in recent years, most of the newly developed drugs are poorly soluble drugs. In developing drugs with poorly soluble drugs, it is required to improve the solubility in water in order to increase the absorbability to humans, and various methods have been proposed so far. For example, a method of increasing the surface area by pulverizing drug crystals to nano size, a method of adding a surfactant, a method of forming an inclusion compound of an inclusion molecule and a drug, a method of non-crystallizing a drug, Examples thereof include a method of forming a crystal form having a high dissolution rate, and a method of forming a solid dispersion from a polymer and a drug.

　これらの方法のうち、固体分散体を形成させる方法として、共沈法、噴霧乾燥法、混合粉砕法、溶融法、メカノケミカル法などが知られている。しかし、薬物は固体分散体を形成しても、溶解度が向上するか否かは、薬物固有の特性であり溶解度が向上しない薬物も多い。例えば、エキセメスタン、アスタキサンチン、β－カロテンなどは、固体分散体を形成しても溶解度は高くはならない。 Among these methods, a coprecipitation method, a spray drying method, a mixing and pulverizing method, a melting method, a mechanochemical method, and the like are known as methods for forming a solid dispersion. However, even if a drug forms a solid dispersion, whether or not the solubility is improved is a characteristic inherent to the drug, and many drugs do not have an improved solubility. For example, exemestane, astaxanthin, β-carotene and the like do not have high solubility even when a solid dispersion is formed.

　特にエキセメスタンは、固体分散体を形成した場合、溶解度は一時的には増加するものの、急激に溶解度が低下する。これは、固体分散体状の場合は溶解度が高いが、水溶液中に溶出したあと、水での溶解度が低いことと結晶化への速度が速いため、容易に薬物の結晶が再析出するからである。 In particular, when exemestane forms a solid dispersion, the solubility temporarily increases, but the solubility rapidly decreases. This is because in the case of a solid dispersion, the solubility is high, but after elution in an aqueous solution, the solubility in water is low and the rate of crystallization is high, so the drug crystals re-precipitate easily. is there.

　これまでエキセメンスタンの固体分散体としては、エキセメスタンをシクロデキストリンによって包接した固体分散体（引用文献１）、エキセメンスタン、ビタミンＥ誘導体及びポリマーからなる固体分散体（引用文献２）が開示されている。 Conventional solid dispersions of exemestane include solid dispersions in which exemestane is included by cyclodextrin (Cited document 1), and solid dispersions composed of exemestane, vitamin E derivatives and polymers (cited document 2). Has been.

　また、２種類のポリマーを用いる固体分散体の方法としては、濃度増大ポリマーと安定化ポリマーの２種類のポリマーと低溶解度の薬物を含む固体分散体（引用文献３）、セルロースポリマー組成物中にセルロースポリマーと低溶解度の薬物を含む固体分散体を含む医薬組成物（引用文献４）が開示されている。前述の文献は、薬物の水への溶解度を向上させるポリマーと固体分散体の湿度による安定化を向上させるポリマーの組み合わせであり、薬物の溶解度の経時変化についての記載はない。後述の文献は、固体分散体部分は薬物と１種類のポリマーからなり、その薬物の固体分散体を別の１種のポリマーの中に包含しており、２種類のポリマーからなる薬物の固体分散体ではない。 In addition, as a method of a solid dispersion using two kinds of polymers, a solid dispersion containing two kinds of polymers, a concentration increasing polymer and a stabilizing polymer, and a drug having low solubility (cited reference 3), a cellulose polymer composition A pharmaceutical composition (cited document 4) comprising a solid dispersion comprising a cellulose polymer and a low-solubility drug is disclosed. The above-mentioned document is a combination of a polymer that improves the solubility of the drug in water and a polymer that improves the stability of the solid dispersion by humidity, and there is no description of the change in solubility of the drug over time. According to the following literature, the solid dispersion part is composed of a drug and one type of polymer, and the solid dispersion of the drug is included in another type of polymer, and the solid dispersion of the drug composed of two types of polymers Not the body.

国際公開２００３／０４３６０２号パンフレットInternational Publication No. 2003/043602 Pamphlet 国際公開２００３／０４３６０２号パンフレットInternational Publication No. 2003/043602 Pamphlet 特開２０００－２２９８８７号公報JP 2000-229887 A 特開２０００－２２９８８８号公報JP 2000-229888 A

　エキセメスタンのバイオアベイラビリティーを向上するため、エキセメスタンの水への溶解性を向上させたエキセメスタンの固体分散体組成物を提供する。 Provided is a solid dispersion composition of exemestane with improved solubility of exemestane in water in order to improve the bioavailability of exemestane.

　エキセメスタンを溶解度向上ポリマーと溶出抑制ポリマーの２種類のポリマーからなる固体分散を形成させることによって、水へのエキセメスタンの溶解度を長時間持続することができる。 By forming a solid dispersion of exemestane consisting of two types of polymers, a solubility improving polymer and an elution inhibiting polymer, the solubility of exemestane in water can be maintained for a long time.

　本発明のエセメスタン固体分散体により、エキセメスタンの水への溶解度を長時間維持可能とし、溶出性を改善する事によってバイオアベイラビリティーの向上のみならず、固体差変動・食事の影響などを減少させるため、患者への服薬コンプライアンス向上を行うことができる。 The exemestane solid dispersion of the present invention makes it possible to maintain the solubility of exemestane in water for a long period of time, and to improve not only bioavailability by improving the dissolution property, but also to reduce the variation in solid difference, the influence of meals, etc. , Improve patient compliance.

実施例１～２、比較例１～４の溶出試験の結果を示す。The result of the elution test of Examples 1-2 and Comparative Examples 1-4 is shown. 実施例３～４、比較例１、５～７の溶出試験の結果を示す。The results of dissolution tests of Examples 3 to 4 and Comparative Examples 1 and 5 to 7 are shown. 実施例３、比較例１のＸ－ＲＤチャートを示す。The X-RD charts of Example 3 and Comparative Example 1 are shown.

　本発明のエキセメスタン固体分散体組成物について以下に述べる。
　本発明のエキセメスタン固体分散体は、エキセメスタン、溶出向上ポリマー及び溶出抑制ポリマーからなる。本発明の固体分散体の構造は、溶出向上ポリマー中にエキセメスタンと溶出抑制ポリマーが、分子レベルで固溶した状態である。そのため、（１）後述の粉末Ｘ線構造解析によってエキセメスタン結晶が実質的に確認されないこと、（２）熱分析によってエキセメスタン結晶特有の吸熱ピークが確認されないことから同定することができる。なお、本発明において特に記載がない場合、「２種のポリマー」は溶出向上ポリマーと溶出抑制ポリマーをさす。 The exemestane solid dispersion composition of the present invention is described below.
The exemestane solid dispersion of the present invention comprises exemestane, an elution enhancing polymer and an elution inhibiting polymer. The structure of the solid dispersion of the present invention is a state in which exemestane and an elution-inhibiting polymer are in solid solution at the molecular level in the elution-enhancing polymer. Therefore, (1) the exemestane crystal is not substantially confirmed by the powder X-ray structural analysis described later, and (2) the endothermic peak peculiar to the exemestane crystal is not confirmed by the thermal analysis. In the present invention, unless otherwise specified, “two types of polymers” refers to an elution improving polymer and an elution suppressing polymer.

　本発明のエキセメスタンは、無水物、水和物、溶媒和物、医薬品に許容される塩の形態のいずれでも用いることができる。原料として用いるエキセメスタンは、製造上で単分子またはナノ粒子サイズに分散させるため、いずれの形態のものを用いてもよい。結晶、非晶質のいずれでも混合物でもよく、結晶としては公知の結晶多形のうち、いずれを用いてもよい。 The exemestane of the present invention can be used in any form of anhydride, hydrate, solvate, and salt acceptable for pharmaceuticals. Exemestane used as a raw material may be used in any form since it is dispersed in the size of a single molecule or nanoparticle in production. Either crystalline or amorphous or a mixture may be used, and any of known crystal polymorphs may be used as the crystal.

　本発明の溶出向上ポリマーは、医薬品の分野で一般に結合剤やコーティング剤に用いられているポリマーのうち、水に溶解するポリマーである。溶出向上ポリマーとしては、セルロース系ポリマー、合成高分子モノポリマー、合成高分子コポリマー、天然高分子があげられる。 The elution improving polymer of the present invention is a polymer that dissolves in water among polymers generally used in binders and coating agents in the field of pharmaceuticals. Examples of the dissolution improving polymer include cellulose polymers, synthetic polymer monopolymers, synthetic polymer copolymers, and natural polymers.

　セルロース系ポリマーには、非イオン性セルロース系ポリマーとイオン性セルロース系ポリマーがあり、非イオン性セルロース系ポリマーとしては、例えば、ヒプロメロース（信越化学工業（株）製：ＴＣ－５Ｅ、ＴＣ－５Ｒ、メトローズ６０ＳＨなど）、ヒドロキシプロピルセルロース（日本曹達社製：ＮＩＳＳＯ　ＨＰＣ－Ｌ、ＨＰＣ－ＳＳＬなど）、ヒドロキシエチルメチルセルロース、ヒドロキシプロピルメチルセルロースアセテート、ヒドロキシエチルセルロースアセテートなどがあげられる。 Cellulose polymers include nonionic cellulose polymers and ionic cellulose polymers. Examples of nonionic cellulose polymers include hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .: TC-5E, TC-5R, Metrose 60SH, etc.), hydroxypropyl cellulose (Nippon Soda Co., Ltd .: NISSO HPC-L, HPC-SSL, etc.), hydroxyethyl methylcellulose, hydroxypropyl methylcellulose acetate, hydroxyethyl cellulose acetate and the like.

　イオン性セルロース系ポリマーとしては、例えば、ヒドロキシプロピルメチルセルロースアセテートサクシネート（信越化学工業（株）製：信越ＡＱＯＡＴ－ＡＳ－ＬＦ，ＡＳ－ＭＦ，ＡＳ－ＨＧなど）、ヒドロキシプロピルメチルセルロースサクシネート、ヒドロキシプロピルセルロースアセテートサクシネート、ヒドロキシエチルメチルセルロースサクシネート、ヒドロキシエチルセルロースアセテートサクシネート、ヒドロキシプロピルメチルセルロースフタレート（信越化学工業（株）製：ＨＰ－５０，ＨＰ－５５など）、ヒドロキシエチルメチルセルロースアセテートサクシネート、ヒドロキシエチルメチルセルロースアセテートフタレート、カルボキシエチルセルロース、エチルカルボキシメチルセルロース、カルボキシメチルセルロース、カルボキシメチルエチルセルロース、セルロースアセテートフタレート、メチルセルロースアセテートフタレート、エチルセルロースアセテートフタレート、ヒドロキシプロピルセルロースアセテートフタレート、ヒドロキシプロピルメチルセルロースアセテートフタレート、ヒドロキシプロピルセルロースアセテートフタレートサクシネート、ヒドロキシプロピルメチルセルロースアセテートサクシネートフタレート、ヒドロキシプロピルメチルセルロースサクシネートフタレート、セルロースプロピオネートフタレート、ヒドロキシプロピルセルロースブチレートフタレート、セルロースアセテートトリメリテート、メチルセルロースアセテートトリメリテート、エチルセルロースアセテートトリメリテート、ヒドロキシプロピルセルロースアセテートトリメリテート、ヒドロキシプロピルメチルセルロースアセテートトリメリテート、ヒドロキシプロピルセルロースアセテートトリメリテートサクシネート、セルロースプロピオネートトリメリテート、セルロースブチレートトリメリテート、セルロースアセテートテレフタレート、セルロースアセテートイソフタレート、セルロースアセテートピリジンカルボキシレート、サリチル酸セルロースアセテート、ヒドロキシプロピルサリチル酸セルロースアセテート、エチル安息香酸セルロースアセテート、ヒドロキシプロピルエチル安息香酸セルロースアセテート、エチルフタル酸セルロースアセテート、エチルニコチン酸セルロースアセテート、エチルピコリン酸セルロースアセテートなどである。 Examples of the ionic cellulose polymer include hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd .: Shin-Etsu AQOAT-AS-LF, AS-MF, AS-HG, etc.), hydroxypropyl methylcellulose succinate, hydroxypropyl Cellulose acetate succinate, hydroxyethylmethylcellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd .: HP-50, HP-55, etc.), hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose Acetate phthalate, carboxyethyl cellulose, ethyl carboxymethyl cellulose, carboxymethyl Cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate succinate, hydroxypropyl methylcellulose acetate succinate phthalate, hydroxypropyl methylcellulose succinate Nate phthalate, cellulose propionate phthalate, hydroxypropyl cellulose butyrate phthalate, cellulose acetate trimellitate, methyl cellulose acetate trimellitate, ethyl cellulose acetate trimellitate, hydroxy Propyl cellulose acetate trimellitate, hydroxypropyl methylcellulose acetate trimellitate, hydroxypropyl cellulose acetate trimellitate succinate, cellulose propionate trimellitate, cellulose butyrate trimellitate, cellulose acetate terephthalate, cellulose acetate isophthalate, Cellulose acetate pyridinecarboxylate, salicylic acid cellulose acetate, hydroxypropyl salicylic acid cellulose acetate, ethyl benzoic acid cellulose acetate, hydroxypropylethyl benzoic acid cellulose acetate, ethyl phthalic acid cellulose acetate, ethyl nicotinic acid cellulose acetate, ethyl picolinic acid cellulose acetate and the like.

　合成高分子モノポリマーとしては、例えば、ポリビニルピロリドン（ＢＡＳＦ社製：Ｋｏｌｌｏｄｏｎ　Ｋ３０、Ｋ９０、Ｋ１７など）、架橋型ポリビニルピロリドン、ポリエチレングルコール（三洋化成工業（株）製：マクロゴール４０００，６０００，２００００など）、ポリビニルアルコール、ポリビニルアセテートフタレート、ポリビニルアセタールジエチルアミノアセテート、カルボキシビニルポリマーなどである。 Examples of the synthetic polymer monopolymer include polyvinyl pyrrolidone (manufactured by BASF: Kollidon K30, K90, K17, etc.), cross-linked polyvinyl pyrrolidone, polyethylene glycol (manufactured by Sanyo Chemical Industries, Ltd .: Macrogol 4000, 6000, 20000). Etc.), polyvinyl alcohol, polyvinyl acetate phthalate, polyvinyl acetal diethylaminoacetate, carboxyvinyl polymer, and the like.

　合成高分子コポリマーとしては、例えば、メタクリル酸コポリマー（Ｒｏｈｍ社製：オイドラギットＬ１００、Ｌ１００－５５、Ｓ１００、Ｌ３０Ｄ－５５など）、アミノアルキルメタアクリレートコポリマー（Ｒｏｈｍ社製：オイドラギットＥ１００、ＲＳ１００など）、ポリビニルアルコールポリビニルアセタートコポリマー、ポリエチレングリコールポリプロピレングリコールコポリマー、ポリエチレンポリビニルアルコールコポリマー、ポリビニルピロリドンコポリマー（ＢＡＳＦ社製：Ｋｏｌｌｏｄｏｎ　ＶＡ６４、ＳＲなど）などである。 Synthetic polymer copolymers include, for example, methacrylic acid copolymers (Rohm: Eudragit L100, L100-55, S100, L30D-55, etc.), aminoalkyl methacrylate copolymers (Rohm: Eudragit E100, RS100, etc.), polyvinyl Examples thereof include alcohol polyvinyl acetate copolymer, polyethylene glycol polypropylene glycol copolymer, polyethylene polyvinyl alcohol copolymer, polyvinyl pyrrolidone copolymer (manufactured by BASF: Kollidon VA64, SR, etc.).

　上述、溶出向上ポリマーのうち、好ましくはヒプロメロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ポリビニルピロリドン、ポリビニルピロリドンコポリマー、メタクリル酸コポリマーである。 Among the above-mentioned elution improving polymers, hypromellose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, polyvinylpyrrolidone, polyvinylpyrrolidone copolymer, and methacrylic acid copolymer are preferable.

　本発明の溶出抑制ポリマーは、医薬品の分野で一般に薬剤に徐放性を付与するコーティング剤などとして用いられているポリマーである。例えば、アラビアゴム、寒天、グアーガム、穀物ゴム、デキストラン、カゼイン、ペクチン、カラゲーニン、ワックス、セラック、水素添加植物性油、ヒドロキシプロピルセルロース（日本曹達製：ＨＰＣ－ＳＳＬ，－ＳＬＬなど）、ヒドロキシエチルセルロース（ＨＥＣ）、ヒドロキシプロピルメチルセルロース（信越化学製：ＴＣ－５シリーズなど）、カルボキシメチルセルロースナトリウム、ポリ（エチレン）オキシド、アルキルセルロース、エチルセルロース（ダウケミカル製：エトセルなど）、メチルセルロース（信越化学製：メトローズ　ＳＭ－２５，－１００など）、カルボキシメチルセルロース（ＣＭＣ）、カルボキシメチルエチルセルロース（フロイント産業製：ＣＭＥＣ）、ポリエチレングリコール、ポリビニルピロリドン、酢酸セルロース、酢酸酪酸セルロース、酢酸フタル酸セルロース、酢酸トリメリト酸セルロース、ポリ酢酸フタル酸ビニル、フタル酸ヒドロキシプロピルメチルセルロース、酢酸コハク酸ヒドロキシプロピルメチルセルロース、ポリアセタールジエチルアミノ酢酸ビニル、ポリ（メタクリル酸アルキル）、ポリ（酢酸ビニル）、アクリル酸またはメタクリル酸とこれらそれぞれのエステルから誘導されたポリマー、およびアクリル酸またはメタクリル酸とこれらそれぞれのエステルから誘導されたコポリマー（例えば、Ｒｏｈｍ社製：オイドラギットＲＬ１００、ＲＬＰ０、ＲＬ３０Ｄ、ＲＳ１００、ＲＳＰ０、ＲＳ３０Ｄ、ＮＥ３０Ｄ、Ｅ１００，ＥＰＯ，Ｌ１００，Ｌ１００－５５，Ｌ３０Ｄ－５５，Ｓ１００など）、ポリビニルアルコールポリエチレングリコールグラフトコポリマー（ＢＡＳＦ製：コリコートＩＲ）、ポリビニルアセタールジエチルアミノアセテート（三菱化学フーズ製：ＡＥＡ）などがあげられる。好ましくは、エチルセルロース、オイドラギット、カルボキシメチルエチルセルロース、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコールポリエチレングリコールグラフトコポリマーである。 The dissolution inhibiting polymer of the present invention is a polymer that is generally used in the field of pharmaceuticals as a coating agent that imparts sustained release properties to drugs. For example, gum arabic, agar, guar gum, cereal rubber, dextran, casein, pectin, carrageenan, wax, shellac, hydrogenated vegetable oil, hydroxypropylcellulose (manufactured by Nippon Soda: HPC-SSL, -SLL, etc.), hydroxyethylcellulose ( HEC), hydroxypropyl methylcellulose (manufactured by Shin-Etsu Chemical: TC-5 series, etc.), sodium carboxymethylcellulose, poly (ethylene) oxide, alkylcellulose, ethylcellulose (manufactured by Dow Chemical: etosel, etc.), methylcellulose (manufactured by Shin-Etsu Chemical: Metroles SM- 25, -100, etc.), carboxymethylcellulose (CMC), carboxymethylethylcellulose (manufactured by Freund Industries: CMEC), polyethylene glycol, polyvinyl pyrrole , Cellulose acetate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitic acid, poly vinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose succinate, polyacetal diethylaminovinyl acetate, poly (alkyl methacrylate), Polymers derived from poly (vinyl acetate), acrylic acid or methacrylic acid and their respective esters, and copolymers derived from acrylic acid or methacrylic acid and their respective esters (eg, manufactured by Rohm: Eudragit RL100, RLP0, RL30D, RS100, RSP0, RS30D, NE30D, E100, EPO, L100, L100-55, L30D-55, S100, etc.), polyvinyl Le Call polyethylene glycol graft copolymer (BASF Corporation: Kollicoat IR), polyvinyl acetal diethylamino acetate (manufactured by Mitsubishi-Kagaku Foods Corporation: AEA) and the like, such as. Preferred are ethyl cellulose, Eudragit, carboxymethyl ethyl cellulose, polyvinyl acetal diethylaminoacetate, polyvinyl alcohol polyethylene glycol graft copolymer.

　本発明において、エキセメスタンと溶出向上ポリマーの配合比は１：０．１～１：１０であり、好ましくは１：０．２～１：５であり、より好ましくは１：０．５～３である。同範囲よりエキセメスタンに対して、溶出向上ポリマーの割合が少ないとエキセメスタンの非結晶化が起こらないため溶出性が向上せず、溶出向上ポリマーの割合が多いとエキセメスタンの水への接触面が少なくなり溶出性が向上しない。 In the present invention, the blending ratio of exemestane and the dissolution enhancing polymer is 1: 0.1 to 1:10, preferably 1: 0.2 to 1: 5, more preferably 1: 0.5 to 3. is there. From the same range, if the proportion of elution-improving polymer is small relative to exemestane, exemestane does not crystallize, so the elution is not improved. Dissolution does not improve.

　本発明において、溶出向上ポリマーと溶出抑制ポリマーの配合比は１：０．０１～１：２であり、好ましくは１：０．０５～１：１であり、より好ましくは１：０．１～０．８である。同範囲より溶出向上ポリマーに対して、溶出抑制ポリマーの割合が少ないとエキセメスタンの溶解度の長時間の維持が生じず短時間に溶解度が減少し、溶出抑制ポリマーの割合が多いとエキセメスタンの被膜効果が高くなり溶出性が向上しない。 In the present invention, the blending ratio of the elution improving polymer and the elution inhibiting polymer is 1: 0.01 to 1: 2, preferably 1: 0.05 to 1: 1, more preferably 1: 0.1 to 0.8. From the same range, if the proportion of the dissolution-inhibiting polymer is small relative to the dissolution-enhancing polymer, the solubility of exemestane will not be maintained for a long time, and the solubility will decrease in a short time. Increases and does not improve dissolution.

　本発明の固体分散体組成物は、エキセメスタンの結晶体に対して、２倍以上、好ましくは４倍以上、より好ましくは６倍以上の溶解度を有する。本発明の固体分散体組成物は、エキセメスタンと溶出促進ポリマーからなる固体分散体に対して、１．２倍以上、好ましくは１．５倍以上、より好ましくは２倍以上、最も好ましくは３倍以上のエキセメスタンの溶解度を有する。なお、ここでの溶解度は後述の溶出試験の３０分又６０分後の溶解度である。 The solid dispersion composition of the present invention has a solubility of 2 times or more, preferably 4 times or more, more preferably 6 times or more of the exemestane crystal. The solid dispersion composition of the present invention is 1.2 times or more, preferably 1.5 times or more, more preferably 2 times or more, and most preferably 3 times the solid dispersion composed of exemestane and an elution promoting polymer. It has the above-mentioned solubility of exemestane. In addition, the solubility here is the solubility after 30 minutes or 60 minutes of the below-mentioned dissolution test.

　本発明の固体分散体は、Ｘ－ＲＤ（Ｘ'Ｐｅｒｔ－ＭＰＤ型、フィリップス社製）によりエキセメスタンの結晶が実質的に確認されず、また、ＤＳＣ（Thermo plus DSC8230、（株）リガク製）により、エキセメスタンの結晶転移の吸熱ピークが確認されない。これらよりエキセメスタンの固体分散体は、単分子及び／又は結晶として物性が発現しない程度の粒子サイズでポリマー相からなる２種類のポリマー中に分散していると想定される。 In the solid dispersion of the present invention, the crystals of exemestane were not substantially confirmed by X-RD (X'Pert-MPD type, manufactured by Philips), and DSC (Thermoplus DSC8230, manufactured by Rigaku Corporation) The endothermic peak of the crystal transition of exemestane is not confirmed. From these, it is assumed that the solid dispersion of exemestane is dispersed in two types of polymers composed of a polymer phase with a particle size that does not exhibit physical properties as single molecules and / or crystals.

　本発明の固体分散体は、エキセメスタンの結晶体又はエキセメスタンと溶出向上ポリマーからなる固体分散体よりも、エキセメスタンの水への溶解度が高く、高濃度を維持する。溶出向上ポリマーと形成してなる固体分散体のエキセメスタンの溶解度は、０～１０分でエキセメスタンの溶解度が最大となり、以降溶解度が低下し、溶解度が最大溶解度に対して１／１０～３／４に低下する。本発明の固体分散体は、このような溶解度の低下を起こさず、溶出試験で最大溶解度を少なくとも６０分後まで維持することができる。消化器官、特に小腸上部においてエキセメスタンの吸収性を向上させるためには、最大溶解度の維持を３０～６０分程度まで維持するのが好ましい。 The solid dispersion of the present invention has higher solubility of exemestane in water and maintains a higher concentration than the solid dispersion of exemestane crystal or exemestane and an elution improving polymer. The solubility of exemestane in the solid dispersion formed with the dissolution enhancing polymer reaches a maximum of exemestane in 0 to 10 minutes, and then the solubility decreases, and the solubility is reduced to 1/10 to 3/4 of the maximum solubility. descend. The solid dispersion of the present invention does not cause such a decrease in solubility, and can maintain the maximum solubility in the dissolution test at least after 60 minutes. In order to improve the absorption of exemestane in the digestive tract, particularly in the upper small intestine, it is preferable to maintain the maximum solubility for about 30 to 60 minutes.

　エキセメスタンと溶出向上ポリマーからなる固体分散体のエキセメスタン溶解度が、一時的に増加するのは、水溶液中でエキセメスタンが過溶解状態にあるため、エキセメスタン結晶の再析出を起こすものと考えられる。本発明において、溶出抑制ポリマーの添加によって溶解度を維持することができるのは、エキセメスタンの溶解平衡の増加ではなく、エキセメスタンの結晶析出速度の低下が原因と考えられる。エキセメスタンと溶出向上ポリマーからなる固体分散体に溶出抑制ポリマーを物理混合したあとでは、溶出度の低下を生じることから確認される。 The reason why the exemestane solubility of the solid dispersion composed of exemestane and the dissolution enhancing polymer temporarily increases is considered to be due to reprecipitation of exemestane crystals because exemestane is in an over-dissolved state in an aqueous solution. In the present invention, the reason why the solubility can be maintained by the addition of the elution-inhibiting polymer is not due to the increase in the dissolution equilibrium of exemestane but to the decrease in the crystal precipitation rate of exemestane. This is confirmed by a decrease in the elution degree after the elution inhibiting polymer is physically mixed in the solid dispersion composed of exemestane and the elution improving polymer.

　本発明の固体分散体の製造方法を以下に述べる。
　本発明の固体分散体は、一般的に薬物の固体分散体を製造する方法によって製造することができる。例えば、溶媒法、溶融法、メカノケミカル法などがあげられ、好ましくは溶媒法や溶融法である。 The method for producing the solid dispersion of the present invention will be described below.
The solid dispersion of the present invention can be generally produced by a method for producing a solid dispersion of a drug. Examples thereof include a solvent method, a melting method, a mechanochemical method, and the like, and a solvent method and a melting method are preferable.

　溶媒法は、エキセメスタン、２種類のポリマー、必要に応じてその他の医薬添加成分とを有機溶媒に懸濁又は溶解させた後、溶媒の除去または析出させることによって製造する。
　溶媒を除去する方法としては、エバポレーション法、噴霧法、ろ過法、凍結乾燥法などがあげられる。噴霧法には流動層法、噴霧乾燥法、転動層法、攪拌法、超臨界法などがあり、溶媒を短時間で除去できることから、エキセメスタンと溶出向上ポリマー及び溶出抑制ポリマーが溶媒中と同様に分子分散状態での固体分散体を均一に得ることができるため、噴霧法が好ましい。噴霧法のうち、溶媒を瞬時に除去し、大量に連続生産可能であること、粒径や嵩密度など所望の粉体物性を得られやすいことから噴霧乾燥法が好ましい。 The solvent method is produced by suspending or dissolving exemestane, two types of polymers and, if necessary, other pharmaceutical additive components in an organic solvent, and then removing or precipitating the solvent.
Examples of the method for removing the solvent include an evaporation method, a spray method, a filtration method, and a freeze-drying method. Spray methods include fluidized bed method, spray drying method, rolling bed method, agitation method, supercritical method, etc., and the solvent can be removed in a short time, so exemestane, dissolution enhancing polymer and dissolution inhibiting polymer are the same as in solvent The spray method is preferable because a solid dispersion in a molecular dispersion state can be obtained uniformly. Among the spraying methods, the spray drying method is preferable because the solvent can be instantaneously removed to enable continuous production in large quantities and desired powder physical properties such as particle size and bulk density can be easily obtained.

　溶媒の除去にかかる時間は、短いほうが好ましく１２０分以内、好ましくは６０分以内、より好ましくは１０分以内、さらに好ましくは５分以内、最も好ましくは２分以内である。溶媒の除去に要する時間が短いほど、エキセメスタンとポリマーの分子分散度合いが高いので好ましい。本発明の固体分散体の形成に要する時間が長いと、エキセメスタンの微細結晶やポリマーの巣などが形成されやすくなる。ここでの溶媒の除去にかかる時間とは本発明のエキセメスタンの固体分散体の固形物が得られる時間であって、溶媒は一部残留していてもよい。残留している溶媒は後述の２次乾燥で除去することができる。 The time required for removing the solvent is preferably shorter, preferably within 120 minutes, preferably within 60 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, and most preferably within 2 minutes. The shorter the time required for removing the solvent, the higher the degree of molecular dispersion between exemestane and the polymer, which is preferable. When the time required for forming the solid dispersion of the present invention is long, fine crystals of exemestane, polymer nests and the like are likely to be formed. Here, the time required for removing the solvent is a time for obtaining a solid dispersion of the exemestane solid dispersion of the present invention, and a part of the solvent may remain. The remaining solvent can be removed by secondary drying described later.

　用いる溶媒は、医薬的に許容される溶媒であればよく、エキセメスタンが溶解する溶媒、例えば、エタノール、メタノール、２－プロパノール、アセトン、２－ブタノン、メチルイソブチルケトン、テトラヒドロフラン（ＴＨＦ）、テトラヒドロピラン、１，４－ジオキサン、ジエチルエーテル、ジイソプロピルエーテル、ｔ－ブチルメチルエーテル、ヘキサン、ヘプタン、トルエン、アセトニトリル、塩化メチレン、クロロホルム、四塩化炭素、酢酸メチル、酢酸エチル、酢酸ブチル、酢酸、蟻酸、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡｃ）、ジメチルスルホキシド（ＤＭＳＯ）、水などがあげられ、これらを所望のエキセメスタンの固体分散体の性質にあわせて、１種の溶媒又は２種以上の混合溶媒として用いる事ができる。 The solvent used may be a pharmaceutically acceptable solvent, and a solvent in which exemestane is dissolved, for example, ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutyl ketone, tetrahydrofuran (THF), tetrahydropyran, 1,4-dioxane, diethyl ether, diisopropyl ether, t-butyl methyl ether, hexane, heptane, toluene, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO), water, and the like, which may be used in combination with a single solvent or a combination of the desired exemestane solid dispersion. 2 or more types It can be used as a mixed solvent.

　溶媒法のうち析出させる方法は共沈法である。エキセメスタンと本発明の２種のポリマーを溶媒に溶解又は懸濁させ、溶解したエキセメスタン及び／又は２種のポリマーが不溶な溶媒の添加や、温度の低下などで溶解濃度を下げることによって析出させる。 Of the solvent methods, the precipitation method is a coprecipitation method. Exemestane and the two polymers of the present invention are dissolved or suspended in a solvent and precipitated by adding a solvent in which the dissolved exemestane and / or two polymers are insoluble, or by lowering the dissolution concentration by decreasing the temperature.

　エバポレーション法による製造方法について詳細に記載する。エキセメスタンと２種類のポリマーを溶媒に溶解又は懸濁させる。この時の濃度は、固形分０．２～４０重量％であり、好ましくは１～２０重量％である。次いで減圧下又は常圧下で溶媒を除去する。このときの温度は、溶媒が留去できる温度であって蒸留時間から適度に選ぶことができ、－１０～１２０℃、好ましくは０～１００℃である。 The manufacturing method by the evaporation method is described in detail. Exemestane and two polymers are dissolved or suspended in a solvent. The concentration at this time is 0.2 to 40% by weight of the solid content, and preferably 1 to 20% by weight. The solvent is then removed under reduced pressure or normal pressure. The temperature at this time is a temperature at which the solvent can be distilled off, and can be appropriately selected from the distillation time, and is −10 to 120 ° C., preferably 0 to 100 ° C.

　噴霧乾燥法による製造方法について詳細に記載する。エキセメスタンと２種類のポリマーを有機溶媒に溶解又は懸濁させる。この時の濃度は、噴霧乾燥できる濃度であればよく、固形分は０．１～８０重量％であり、好ましくは０．５～５０重量％である。ついで噴霧乾燥により溶媒の除去と造粒を同時に行う。噴霧乾燥機としては、円盤式またはノズル式（例えば、加圧ノズル、２流体ノズル、４流体ノズル）の噴霧乾燥機を用いる。噴霧乾燥の際の温度としては、入口温度が約２０～１５０℃であり、出口温度が約０～８５℃が好ましい。 Describe in detail the production method by spray drying. Exemestane and two polymers are dissolved or suspended in an organic solvent. The concentration at this time may be any concentration that allows spray drying, and the solid content is 0.1 to 80% by weight, preferably 0.5 to 50% by weight. The solvent is then removed and granulated simultaneously by spray drying. As the spray dryer, a disc-type or nozzle-type (for example, pressure nozzle, two-fluid nozzle, four-fluid nozzle) spray dryer is used. As the temperature during spray drying, the inlet temperature is preferably about 20 to 150 ° C., and the outlet temperature is preferably about 0 to 85 ° C.

　なお、エバポレーション法や噴霧乾燥法などの溶媒法によって、エキセメスタンの固体分散体を得、残留溶媒のさらなる除去が必要であった場合、２次乾燥を行うことができる。２次乾燥は、エキセメスタン固体分散体を安定に維持できる方法であれば、通常医薬品の製造で用いられている乾燥方法で行うことができる。 In addition, when a solid dispersion of exemestane is obtained by a solvent method such as an evaporation method or a spray drying method and further removal of the residual solvent is necessary, secondary drying can be performed. The secondary drying can be performed by a drying method usually used in the manufacture of pharmaceuticals as long as the method can stably maintain the exemestane solid dispersion.

　溶融法は、エキセメスタンと２種類のポリマー、必要に応じてその他の医薬添加成分とを、いずれかの成分が溶融する温度以上に加熱し、融解したのち冷却することによってエキセメスタン固体分散体を製造する方法である。使用する機械や温度、常法に従って任意に選択することができる。機械としてはエクストルーダーなどがあげられる。このとき融点を下げるため溶媒を添加してもよく、溶融後に溶媒を除去する。 The melting method produces exemestane solid dispersion by heating exemestane and two kinds of polymers and, if necessary, other pharmaceutical additive components to a temperature at which any of the components melts or higher, and then cooling. Is the method. It can be arbitrarily selected according to the machine used, the temperature, and the conventional method. Extruders are examples of machines. At this time, a solvent may be added to lower the melting point, and the solvent is removed after melting.

　メカノケミカル法は、エキセメスタンと２種類のポリマー、必要に応じてその他の医薬添加成分とを同時に粉砕・衝撃を与えることによってエキセメスタン固体分散体を製造する方法である。使用する機械や温度、粉砕条件は常法に従って任意に選択することができる。 The mechanochemical method is a method for producing an exemestane solid dispersion by simultaneously pulverizing and impacting exemestane, two types of polymers, and other pharmaceutical additive components as necessary. The machine to be used, the temperature, and the pulverization conditions can be arbitrarily selected according to a conventional method.

　このようにして得られたエキセメスタン固体分散体は、錠剤への混合性や溶出性、徐放性、苦味マスキングのために医薬品に使用可能な添加剤を用いて、乾式造粒や湿式造粒を行うことができる。エキセメスタン固体分散体の粒子径や嵩密度の違いで医薬添加物との混合性が劣る場合は、ローラーコンパクターなどで厚密化を行い、粒子径や嵩密度を大きくすることができる。 The exemestane solid dispersion obtained in this way is subjected to dry granulation and wet granulation using additives that can be used in pharmaceuticals for tablet mixing, dissolution, sustained release, and bitterness masking. It can be carried out. When mixing with a pharmaceutical additive is inferior due to the difference in particle size and bulk density of the exemestane solid dispersion, the particle size and bulk density can be increased by thickening with a roller compactor or the like.

　エキセメスタン固体分散体及び／又はエキセメスタン固体分散体含有粒子に医薬添加物を混合し、錠剤、カプセル、散剤、液剤、乳剤もしくは懸濁剤などの経口型の医薬組成物を得る。また、非経口剤として、注射剤、坐剤、点眼剤、吸入剤、皮膚外用剤などの医薬組成物も得ることができる。これらの製造方法は公知の方法を用いることができる。 医 薬 Exemestane solid dispersion and / or exemestane solid dispersion-containing particles are mixed with a pharmaceutical additive to obtain an oral pharmaceutical composition such as a tablet, capsule, powder, liquid, emulsion or suspension. In addition, pharmaceutical compositions such as injections, suppositories, eye drops, inhalants, and external preparations for skin can also be obtained as parenteral agents. As these production methods, known methods can be used.

　医薬添加物としては、結合剤（例えば、カルメロース、ヒドロキシプロピルセルロース、アルギン酸、ゼラチン、部分α化澱粉、ポピドン、アラビアガム、プルラン、デキストリンなど）、賦形剤（例えば、スターチ、Ｄ－マンニトール、乳糖、トレハロース、結晶セルロース、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、ハイドロタルサイト、無水ケイ酸など）、崩壊剤（例えば、クロスポビドン、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースなど）、界面活性剤（例えばポリオキシエチレン硬化ひまし油、ポリオキシエチレンポリオキシプロピレングリコール、ソルビタン脂肪酸エステル、ポリソルベート、脂肪酸グリセリンエステル、ラウリル硫酸ナトリウムなど）、滑沢剤（ショ糖脂肪酸エステル、ステアリン酸マグネシウム、タルク、フマル酸ステアリルナトリウムなど）、酸味料（例えば、クエン酸、酒石酸、リンゴ酸、アスコルビン酸など）、発泡剤（例えば炭酸水素ナトリウム、炭酸ナトリウムなど）、甘味剤（例えば、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなど）、香料（例えば、レモン油、オレンジ油、メントールなど）、着色剤（例えば、食用赤色２号、食用青色２号、食用黄色５号、食用レーキ色素、三二酸化鉄、アスタキサンチンなど）、安定化剤（例えば、エデト酸ナトリウム、トコフェロール、トコトリエノール、シクロデキストリンなど）、矯味剤、着香剤などがあげられる。これらの医薬添加物は、本発明の固体分散体組成物１００重量部に対して、医薬添加成分を１～１００００重量部配合することができる。 Pharmaceutical additives include binders (eg, carmellose, hydroxypropyl cellulose, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, dextrin, etc.), excipients (eg, starch, D-mannitol, lactose , Trehalose, crystalline cellulose, magnesium aluminate metasilicate, calcium hydrogen phosphate, hydrotalcite, anhydrous silicic acid, etc.), disintegrant (eg, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, etc.), interface Activators (eg polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, sodium lauryl sulfate), lubricant (sucrose Acid esters, magnesium stearate, talc, sodium stearyl fumarate, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweeteners (eg For example, saccharin sodium, glycyrrhizin dipotassium, aspartame, stevia, thaumatin, etc.), fragrance (eg, lemon oil, orange oil, menthol, etc.), colorant (eg, edible red No. 2, edible blue No. 2, edible yellow No. 5, Food rake pigments, iron sesquioxide, astaxanthin, etc.), stabilizers (for example, sodium edetate, tocopherol, tocotrienol, cyclodextrin, etc.), flavoring agents, flavoring agents and the like. In these pharmaceutical additives, 1 to 10,000 parts by weight of the pharmaceutical additive component can be blended with 100 parts by weight of the solid dispersion composition of the present invention.

　本発明のエキセメスタン固体分散体からなる医薬組成物は、エキセメスタンの溶解濃度向上により、投与量を減らしても、従来の結晶エキセメスタンと同等のＡＵＣが期待できる。 The pharmaceutical composition comprising the exemestane solid dispersion of the present invention can be expected to have an AUC equivalent to that of conventional crystalline exemestane even if the dosage is reduced due to an increase in the dissolution concentration of exemestane.

　以下に、本発明を実施例により説明するが、これらの実施例は本発明の範囲を限定するものではない。 Hereinafter, the present invention will be described by way of examples, but these examples do not limit the scope of the present invention.

　［実施例１］　溶媒留去法
　結晶エキセメスタン（RPG Life Sciences 社製）１０ｍｇとヒドロキシプロピルメチルセルロースフタレート（信越化学工業（株）製：ＨＰＭＣＰ　ＨＰ－５５）１０ｍｇとエチルセルロース（ダウケミカル社製）２ｍｇを５０ｍｌのナス型フラスコに入れ、ジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。アスピレーター減圧下、温度３７℃で溶媒を留去した後、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体を得た。 [Example 1] Solvent evaporation method 50 mg of 10 mg of crystalline exemestane (manufactured by RPG Life Sciences), 10 mg of hydroxypropylmethylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd .: HPMCP HP-55) and 2 mg of ethylcellulose (manufactured by Dow Chemical Company) Was added to 30 ml of an 8: 2 solution of dichloromethane and methanol and dissolved at room temperature. The solvent was distilled off at 37 ° C. under reduced pressure of an aspirator, and then dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain an exemestane solid dispersion.

　［実施例２］　溶媒留去法
　結晶エキセメスタン１０ｍｇとヒドロキシプロピルメチルセルロースフタレート１０ｍｇとメタクリル酸コポリマー（オイドラギットＲＳ：Ｒｏｈｍ社製）２ｍｇを５０ｍｌのナス型フラスコに入れ、ジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。アスピレーター減圧下、温度３７℃で溶媒を留去した後、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体を得た。 [Example 2] Solvent evaporation method 10 mg of crystalline exemestane, 10 mg of hydroxypropylmethylcellulose phthalate and 2 mg of methacrylic acid copolymer (Eudragit RS: manufactured by Rohm) were placed in a 50 ml eggplant-shaped flask, and 30 ml of an 8: 2 solution of dichloromethane and methanol was added. In addition, it was dissolved at room temperature. The solvent was distilled off at 37 ° C. under reduced pressure of an aspirator, and then dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain an exemestane solid dispersion.

　［比較例２］　
　結晶エキセメスタン１０ｍｇを５０ｍｌのナス型フラスコに入れ、ジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。アスピレーター減圧下、温度３７℃で溶媒を留去した後、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの非晶質体を得た。 [Comparative Example 2]
10 mg of crystalline exemestane was placed in a 50 ml eggplant-shaped flask, and 30 ml of an 8: 2 solution of dichloromethane and methanol was added and dissolved at room temperature. The solvent was distilled off at a temperature of 37 ° C. under reduced pressure of an aspirator, followed by drying at 40 ° C. under reduced pressure (5 Torr or less) overnight to obtain an exemestane amorphous substance.

　［比較例３］　
　結晶エキセメスタン１０ｍｇとヒドロキシプロピルメチルセルロースフタレート１０ｍｇを５０ｍｌのナス型フラスコに入れ、ジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。アスピレーター減圧下、温度３７℃で溶媒を留去した後、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体を得た。 [Comparative Example 3]
10 mg of crystalline exemestane and 10 mg of hydroxypropylmethylcellulose phthalate were placed in a 50 ml eggplant-shaped flask, and 30 ml of an 8: 2 solution of dichloromethane and methanol was added and dissolved at room temperature. The solvent was distilled off at 37 ° C. under reduced pressure of an aspirator, and then dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain an exemestane solid dispersion.

　［比較例４］　
　結晶エキセメスタン１０ｍｇとメタクリル酸コオリマー（オイドラギットＬ１００－５５：Ｒｏｈｍ社製）１０ｍｇを５０ｍｌのナス型フラスコに入れ、ジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。アスピレーター減圧下、温度３７℃で溶媒を留去した後、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体を得た。 [Comparative Example 4]
10 mg of crystalline exemestane and 10 mg of Koorimer methacrylate (Eudragit L100-55: manufactured by Rohm) were placed in a 50 ml eggplant type flask, and 30 ml of an 8: 2 solution of dichloromethane and methanol was added and dissolved at room temperature. The solvent was distilled off at 37 ° C. under reduced pressure of an aspirator, and then dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain an exemestane solid dispersion.

（溶出試験）
　前述の実験で得た試料のエキセメスタン１０ｍｇ相当を含むナス型フラスコを３７℃の温浴に浸し、３７℃の崩壊試験液第２液（ｐＨ６．８）４０ｍｌ溶液を加えてフラスコ口をパラフィン紙で閉じ、１００回／分で震盪させながら、経時的に水溶液を採取し、水溶液エキセメスタン濃度を測定した。採取した溶液を０．４５μｍのフィルターで篩過したのち、その溶液１ｍｌをメタノールで１０ｍｌに希釈し、ＨＰＬＣ（日立製）測定により定量して溶解濃度を求めた。
比較例１は結晶エキセメスタン粉末である。 (Dissolution test)
The eggplant-shaped flask containing 10 mg of exemestane sample obtained in the above-mentioned experiment is immersed in a 37 ° C. warm bath, 40 ml of the 37 ° C. disintegration test solution second solution (pH 6.8) is added, and the flask mouth is closed with paraffin paper. The aqueous solution was sampled over time while shaking at 100 times / minute, and the aqueous exemestane concentration was measured. After the collected solution was sieved with a 0.45 μm filter, 1 ml of the solution was diluted to 10 ml with methanol and quantified by HPLC (manufactured by Hitachi) to determine the dissolution concentration.
Comparative Example 1 is a crystalline exemestane powder.

　［表１］　溶出試験結果

Figure JPOXMLDOC01-appb-I000001
単位はμｇ／ｍｌである。 [Table 1] Dissolution test results
Figure JPOXMLDOC01-appb-I000001
The unit is μg / ml.

　比較例１と２より、エキセメスタンは単独で非晶質化しても溶解度が４０μｍ／ｍｌ以下と溶解性が改善されない。比較例３と４より、エキセメスタンと溶出向上ポリマーからなる固体分散体は、５分で溶解度がピークを迎えるが、その後溶解度が大きく低下している。対して、本発明の実施例１と実施例２の溶出向上ポリマーと溶出抑制ポリマーからなるエキセメスタンの固体分散体は、３０分後においても溶解度が高く、結晶エキセメスタン対して６倍以上であり、エキセメスタン固体分散体に対して２倍以上である。 From Comparative Examples 1 and 2, even if exemestane is made amorphous alone, the solubility is 40 μm / ml or less and the solubility is not improved. From Comparative Examples 3 and 4, the solid dispersion composed of exemestane and the dissolution improving polymer reaches its peak in 5 minutes, but the solubility is greatly lowered after that. On the other hand, the solid dispersion of exemestane comprising the dissolution enhancing polymer and the dissolution inhibiting polymer of Examples 1 and 2 of the present invention has high solubility even after 30 minutes, and is 6 times or more than crystalline exemestane. It is 2 times or more with respect to the solid dispersion.

　［実施例３］　噴霧乾燥
　結晶エキセメスタン１００ｍｇとヒドロキシプロピルメチルセルロースフタレート３００ｍｇとエチルセルロース５０ｍｇをジクロロメタンとメタノールの８：２溶液１７．５ｍｌを加えて常温で溶解させた。ついで、入熱温度８０℃、排熱温度５０℃、噴霧速度６ｍｌ／分で噴霧乾燥を行ったのち、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体の粉末を得た。 [Example 3] Spray drying Crystal exemestane (100 mg), hydroxypropylmethylcellulose phthalate (300 mg) and ethylcellulose (50 mg) were dissolved at room temperature by adding 17.5 ml of an 8: 2 solution of dichloromethane and methanol. Next, spray drying was performed at a heat input temperature of 80 ° C., exhaust heat temperature of 50 ° C., and a spray rate of 6 ml / min, followed by drying overnight at 40 ° C. under reduced pressure (5 Torr or less), and a powder of a solid dispersion of exemestane Got.

　［実施例４］　噴霧乾燥
　結晶エキセメスタン１００ｍｇとヒドロキシプロピルメチルセルロースフタレート３００ｍｇとエチルセルロース２００ｍｇをジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。ついで、入熱温度８０℃、排熱温度５０℃、噴霧速度６ｍｌ／分で噴霧乾燥を行ったのち、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体の粉末を得た。 [Example 4] Spray drying Crystal exemestane 100 mg, hydroxypropylmethylcellulose phthalate 300 mg, and ethylcellulose 200 mg were dissolved in an 8: 2 solution of dichloromethane and methanol at room temperature. Next, spray drying was performed at a heat input temperature of 80 ° C., exhaust heat temperature of 50 ° C., and a spray rate of 6 ml / min, followed by drying overnight at 40 ° C. under reduced pressure (5 Torr or less), and a powder of a solid dispersion of exemestane Got.

　［比較例５］　物理混合
　結晶エキセメスタン２０ｍｇとヒドロキシプロピルメチルセルロースフタレート６０ｍｇとエチルセルロース１０ｍｇをビニール袋に入れて混合し、エキセメスタンの混合粉末を得た。 Comparative Example 5 Physical Mixing Crystal Exemestane 20 mg, Hydroxypropyl Methylcellulose Phthalate 60 mg, and Ethylcellulose 10 mg were mixed in a plastic bag to obtain a mixed powder of exemestane.

　［比較例６］　噴霧乾燥
　結晶エキセメスタン１００ｍｇとヒドロキシプロピルメチルセルロースフタレート３００ｍｇをジクロロメタンとメタノールの８：２溶液２０ｍｌを加えて常温で溶解させた。ついで、入熱温度８０℃、排熱温度５０℃、噴霧速度６ｍｌ／分で噴霧乾燥を行ったのち、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体の粉末を得た。 [Comparative Example 6] Spray drying Crystal exemestane 100 mg and hydroxypropylmethylcellulose phthalate 300 mg were added with 20 ml of an 8: 2 solution of dichloromethane and methanol and dissolved at room temperature. Next, spray drying was performed at a heat input temperature of 80 ° C., exhaust heat temperature of 50 ° C., and a spray rate of 6 ml / min. Got.

　［比較例７］　噴霧乾燥と混合
　結晶エキセメスタン１００ｍｇとヒドロキシプロピルメチルセルロースフタレート３００ｍｇをジクロロメタンとメタノールの８：２溶液３０ｍｌを加えて常温で溶解させた。ついで、入熱温度８０℃、排熱温度５０℃、噴霧速度６ｍｌ／分で噴霧乾燥を行ったのち、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、エキセメスタンの固体分散体の粉末を得た。この粉末２００ｍｇにエチルセルロース２５ｍｇを混合し、エキセメスタンの混合粉末を得た。 [Comparative Example 7] Spray drying and mixing 100 mg of crystalline exemestane and 300 mg of hydroxypropylmethylcellulose phthalate were added at 30 ml of an 8: 2 solution of dichloromethane and methanol and dissolved at room temperature. Next, spray drying was performed at a heat input temperature of 80 ° C., exhaust heat temperature of 50 ° C., and a spray rate of 6 ml / min. Got. 200 mg of this powder was mixed with 25 mg of ethyl cellulose to obtain a mixed powder of exemestane.

（溶出試験）
　前述の実験で得た試料のエキセメスタン７．５ｍｇ相当をナス型フラスコに入れて３７℃の温浴に浸し、３７℃の崩壊試験液第２液３０ｍｌ溶液を加えてフラスコ口をパラフィン紙で閉じ、１００回／分で震盪させながら、経時的に水溶液を採取し、水溶液のエキセメスタン濃度を測定した。採取した溶液を０．４５μｍのフィルターで篩過したのち、その溶液１ｍｌをメタノールで１０ｍｌに希釈し、ＨＰＬＣ測定により定量して溶解濃度を求めた。
結果を表２、図２に示す。比較例１は結晶エキセメスタン粉末である。 (Dissolution test)
Exemestane equivalent to 7.5 mg of the sample obtained in the above-mentioned experiment is placed in a eggplant-shaped flask, immersed in a 37 ° C. warm bath, the 37 ° C. disintegration test solution second solution 30 ml solution is added, and the flask mouth is closed with paraffin paper. The aqueous solution was collected over time while shaking at times / minute, and the exemestane concentration of the aqueous solution was measured. After the collected solution was sieved with a 0.45 μm filter, 1 ml of the solution was diluted to 10 ml with methanol, and quantified by HPLC measurement to obtain the dissolution concentration.
The results are shown in Table 2 and FIG. Comparative Example 1 is a crystalline exemestane powder.

　［表２］　溶出試験結果

Figure JPOXMLDOC01-appb-I000002
単位はμｇ／ｍｌである。 [Table 2] Dissolution test results

Figure JPOXMLDOC01-appb-I000002
The unit is μg / ml.

　本発明のエキセメスタン固体分散体の実施例３と実施例４は、溶出試験の２～３０分の間において、比較例１の結晶エキセメスタンに対して６倍以上の溶解度を維持している。比較例１の結晶エキセメスタンと比較例５の結晶エキセメスタンとポリマーの物理混合品の溶解度に差はなく、単なるポリマーの混合は溶解度の向上に効果がない。比較例６のエキセメスタンとヒドロキシプロピルメチルセルロースフタレートとの固体分散体は、２分後に溶解度の一時的な上昇が見られるが５分以降ではその半分程度に溶解度が低下した。比較例６の固体分散体にエチルセルロースを添加した比較例７の溶解度は、実施例３や４の半部以下であった。 Example 3 and Example 4 of the exemestane solid dispersion of the present invention maintain a solubility of 6 times or more with respect to the crystal exemestane of Comparative Example 1 during 2 to 30 minutes of the dissolution test. There is no difference in the solubility of the physical mixture of crystalline exemestane of Comparative Example 1 and crystalline exemestane of Comparative Example 5 and the polymer, and mere polymer mixing has no effect on improving the solubility. The solid dispersion of exemestane and hydroxypropylmethylcellulose phthalate of Comparative Example 6 showed a temporary increase in solubility after 2 minutes, but the solubility decreased to about half after 5 minutes. The solubility of Comparative Example 7 in which ethyl cellulose was added to the solid dispersion of Comparative Example 6 was less than half of Examples 3 and 4.

　実施例３～４、比較例６～７について、Ｘ'Ｐｅｒｔ－ＭＰＤ型（フィリップス社製）によりＸ線測定（Ｘ－ＲＤ）した。エキセメスタンの結晶ピークが表れず、固体分散体を形成していることを確認した。実施例３と比較例１のＸ－ＲＤパターンを図３に示す。比較例１の結晶エキセメスタンはピークが顕著に表れているが、実施例３の固体分散体は明確なピークがないハローパターンを示している。 Examples 3 to 4 and Comparative Examples 6 to 7 were subjected to X-ray measurement (X-RD) using an X′Pert-MPD type (manufactured by Philips). The crystal peak of exemestane did not appear and it was confirmed that a solid dispersion was formed. The X-RD patterns of Example 3 and Comparative Example 1 are shown in FIG. The crystal exemestane of Comparative Example 1 shows a significant peak, but the solid dispersion of Example 3 shows a halo pattern without a clear peak.

　以上の結果より、エチルセルロースの効果はエキセメスタン溶解平衡の増加効果ではなく、溶出向上ポリマーであるヒドロキシプロピルセルロースフタレートンと溶出抑制ポリマーのエチルセルロースとエキセメスタンの３成分が固体分散体を形成していることが、エキセメスタンの再析出による溶解度の低下を防止し、溶解度を長時間にわたって維持していることがわかる。 Based on the above results, the effect of ethyl cellulose is not the effect of increasing the dissolution equilibrium of exemestane, but the three components of hydroxypropyl cellulose phthalate, which is an elution improving polymer, and ethyl cellulose and exemestane, which is an elution inhibiting polymer, form a solid dispersion. It can be seen that the decrease in solubility due to reprecipitation of exemestane is prevented and the solubility is maintained for a long time.

Claims (16)

エキセメスタン、溶出向上ポリマー及び溶出抑制ポリマーからなる固体分散体組成物。 A solid dispersion composition comprising exemestane, an elution enhancing polymer and an elution inhibiting polymer. エキセメスタンと溶出向上ポリマーの配合比が１：０．１～１：１０である請求項１に記載の組成物。 The composition according to claim 1, wherein the mixing ratio of exemestane and the dissolution enhancing polymer is 1: 0.1 to 1:10. エキセメスタンと溶出向上ポリマーの配合比が１：０．５～１：５である請求項１に記載の組成物。 The composition according to claim 1, wherein the blending ratio of exemestane and the dissolution enhancing polymer is 1: 0.5 to 1: 5. 溶出向上ポリマーと溶出抑制ポリマーの重量比が１：０．０１～１：２である請求項１～２のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 2, wherein the weight ratio of the dissolution enhancing polymer to the dissolution inhibiting polymer is 1: 0.01 to 1: 2. 溶出向上ポリマーと溶出抑制ポリマーの重量比が１：０．０５～１：１である請求項１～２のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 2, wherein the weight ratio of the dissolution enhancing polymer to the dissolution inhibiting polymer is 1: 0.05 to 1: 1. 溶出向上ポリマーがセルロース系ポリマー、合成高分子モノポリマー、合成高分子コポリマー、天然高分子のうち水に溶解するポリマーの一種以上からなる請求項１～５のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 5, wherein the elution improving polymer comprises at least one of a cellulose-based polymer, a synthetic polymer monopolymer, a synthetic polymer copolymer, and a natural polymer that dissolves in water. 溶出向上ポリマーが、ヒプロメロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルメチルセルロースフタレート、ヒドロキシプロピルメチルセルロースアセテートサクシネート、ポリビニルピロリドン、ポリビニルピロリドンコポリマー、メタクリル酸コポリマーの一種以上からなる請求項１～５のいずれか１項に記載の組成物。 The elution improving polymer is composed of one or more of hypromellose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl pyrrolidone, polyvinyl pyrrolidone copolymer, and methacrylic acid copolymer. Composition. 溶出抑制ポリマーが、水に溶解しないポリマーの一種以上からなる請求項１～７のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 7, wherein the elution-inhibiting polymer comprises at least one polymer that does not dissolve in water. 溶出抑制ポリマーが、エチルセルロース、オイドラギット、カルボキシメチルエチルセルロース、ポリビニルアセタールジエチルアミノアセテート、ポリビニルアルコールポリエチレングリコールグラフトコポリマーの一種以上からなる請求項１～７のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 7, wherein the elution inhibiting polymer comprises one or more of ethyl cellulose, Eudragit, carboxymethyl ethyl cellulose, polyvinyl acetal diethylaminoacetate, and polyvinyl alcohol polyethylene glycol graft copolymer. エキセメスタンの水への溶解度が、エキセメスタンの結晶物の水への溶解度に対し、溶出試験の３０分後において２倍以上である請求項１～９のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 9, wherein the solubility of exemestane in water is at least twice as high as the solubility of exemestane crystal in water 30 minutes after the dissolution test. エキセメスタンの水への溶解度が、エキセメスタンの結晶物の水への溶解度に対し、溶出試験の３０分後において４倍以上である請求項１～９のいずれか１項に記載の組成物。 The composition according to any one of claims 1 to 9, wherein the solubility of exemestane in water is 4 times or more 30 minutes after the dissolution test with respect to the solubility of exemestane crystal in water. 粉末Ｘ線構造解析で実質的にエキセメスタンの結晶が確認されない請求項１～１１に記載の組成物。 The composition according to any one of claims 1 to 11, wherein substantially no exemestane crystals are confirmed by powder X-ray structural analysis. 請求項１～１２のいずれか１項に記載の組成物１００重量部に対して、医薬添加成分を１～１００００重量部含有する医薬組成物。 A pharmaceutical composition comprising 1 to 10,000 parts by weight of a pharmaceutical additive component per 100 parts by weight of the composition according to any one of claims 1 to 12. 請求項１～１２のいずれか１項に記載の組成物の製造方法であって、エキセメスタン、溶出向上ポリマー及び溶出抑制ポリマーを溶液に溶解又は分散し、溶媒を除去する組成物の製造方法。 The method for producing a composition according to any one of claims 1 to 12, wherein the exemestane, the dissolution enhancing polymer and the dissolution inhibiting polymer are dissolved or dispersed in a solution and the solvent is removed. 溶媒の除去が噴霧によって１０分以内である請求項１４に記載の製造方法。 The process according to claim 14, wherein the solvent is removed by spraying within 10 minutes. 請求項１～１２のいずれか１項に記載の組成物の製造方法であって、エキセメスタン、溶出向上ポリマー及び溶出抑制ポリマーを加熱により溶融した後、冷却する組成物の製造方法。 The method for producing a composition according to any one of claims 1 to 12, wherein the exemestane, the dissolution enhancing polymer and the dissolution inhibiting polymer are melted by heating and then cooled.
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JP2015007116A (en) * 2012-10-12 2015-01-15 味の素株式会社 Pharmaceutical preparation containing calcium antagonist / angiotensin II receptor antagonist
CN114948901A (en) * 2022-05-06 2022-08-30 郑州大学第一附属医院 Exemestane nanoparticles and preparation for synergistically treating breast cancer and preparation method thereof
JP2023536128A (en) * 2020-07-28 2023-08-23 ビアル－ポルテラ エ コンパニア，ソシエダッド アノニマ Solid dispersion of opicapon

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US20060003002A1 (en) * 2003-11-03 2006-01-05 Lipocine, Inc. Pharmaceutical compositions with synchronized solubilizer release
CA2552925A1 (en) * 2004-01-30 2005-08-18 Pfizer Italia S.R.L. Semisolid matrix pharmaceutical formulations
JP2009502969A (en) * 2005-07-28 2009-01-29 アイエスピー インヴェストメンツ インコーポレイテッド Amorphous efavirenz and its manufacture
JP2009155282A (en) * 2007-12-27 2009-07-16 Kowa Co Pharmaceutical composition containing solid dispersion

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2015007116A (en) * 2012-10-12 2015-01-15 味の素株式会社 Pharmaceutical preparation containing calcium antagonist / angiotensin II receptor antagonist
JP5854371B2 (en) * 2012-10-12 2016-02-09 味の素株式会社 Pharmaceutical preparation containing calcium antagonist / angiotensin II receptor antagonist
JP2023536128A (en) * 2020-07-28 2023-08-23 ビアル－ポルテラ エ コンパニア，ソシエダッド アノニマ Solid dispersion of opicapon
CN114948901A (en) * 2022-05-06 2022-08-30 郑州大学第一附属医院 Exemestane nanoparticles and preparation for synergistically treating breast cancer and preparation method thereof

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