WO2019087696A1 - Oral pharmaceutical composition - Google Patents

Oral pharmaceutical composition Download PDF

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Publication number
WO2019087696A1
WO2019087696A1 PCT/JP2018/037478 JP2018037478W WO2019087696A1 WO 2019087696 A1 WO2019087696 A1 WO 2019087696A1 JP 2018037478 W JP2018037478 W JP 2018037478W WO 2019087696 A1 WO2019087696 A1 WO 2019087696A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
oral pharmaceutical
active ingredient
mass
triglyceride
Prior art date
Application number
PCT/JP2018/037478
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French (fr)
Japanese (ja)
Inventor
翔 豊永
宣裕 塩野▲崎▼
辻畑　茂朝
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 JP2019550943A priority Critical patent/JP6887520B2/en
Publication of WO2019087696A1 publication Critical patent/WO2019087696A1/en

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    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • 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
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate

Definitions

  • the present disclosure relates to oral pharmaceutical compositions.
  • the active ingredient is contained in a composition having a self-emulsifying ability, and this composition and water or digestive fluid
  • a technique has been proposed in which a composition containing an active ingredient spontaneously emulsifies and disperses by simply contacting with.
  • JP-A-2015-120700 and JP-A-2016-74677 disclose preparations containing testosterone undecanoate in a solution containing monoglyceride and / or diglyceride and polyoxyethylene hydrogenated hydrogenated castor oil. It is disclosed.
  • JP-T-2017-518294 discloses a preparation containing testosterone undecanoate in a solution containing triglyceride and polyoxyl 35 castor oil.
  • Japanese Patent Application Publication No. 2013-516433 discloses a preparation containing testosterone undecanoate in a solution containing triglyceride and polyoxyethylene hydrogenated castor oil.
  • Japanese Patent No. 5313343 discloses a preparation containing ethyl ester of ⁇ 3 polyunsaturated fatty acid such as icosapentic acid (EPA) and polyoxyethylene hydrogenated castor oil.
  • the active ingredient is distributed from the oil phase of the emulsion (ie, the emulsified preparation) into the digestive fluid which is the water phase , Is absorbed from the mucosa of the small intestine.
  • the water solubility of the active ingredient is low, the smaller the particle size of the emulsion dispersed in the digestive fluid, the more efficiently the active ingredient is distributed in the digestive fluid and the absorption from the mucosa of the small intestine, Work in favor. Also, the more stable the dispersed particles of the emulsion are in the digestive fluid, the more advantageous for absorption of the active ingredient.
  • the dispersed particles of the emulsion are stable in the digestive fluid
  • the particles of the emulsion dispersed in the digestive fluid are not only physically stable but also stable as a preparation. Some things include being stable to digestion by the digestive enzymes contained in the digestive fluid. From the above, it is desirable that the self-emulsifiable concentrate containing an active ingredient poorly soluble in water is emulsified in the digestive fluid, and then the emulsified emulsion is finely and stably dispersed in the digestive fluid.
  • the problem to be solved by the embodiments of the present invention is to provide an oral pharmaceutical composition capable of spontaneously and rapidly forming an emulsion in a digestive fluid, and the emulsion being finely and stably dispersed in the digestive fluid. It is.
  • the content of the hydrophilic solvent (D) is 10 parts by mass to 50 parts by mass with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D)
  • An oral pharmaceutical composition is 10 parts by mass to 50 parts by mass with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated
  • the oral pharmaceutical composition as described in ⁇ 1> whose ⁇ 2> triglyceride (C) is a long chain fatty acid triglyceride whose average carbon number of a fatty acid chain is 14 or more and 24 or less.
  • the oral pharmaceutical composition as described in ⁇ 1> or ⁇ 2> whose content rate of ⁇ 3> triglyceride (C) is 4 mass% or more and 25 mass% or less with respect to whole quantity of oral pharmaceutical composition.
  • the hydrophilic solvent (D) is at least one selected from the group consisting of macrogol 300, macrogol 400, propylene glycol, ethanol, concentrated glycerin, triacetin, triethyl citrate, and benzyl alcohol ⁇ 1>
  • ⁇ 6> The oral pharmaceutical composition according to any one of ⁇ 1> to ⁇ 5>, wherein the active ingredient (A) further has a ring structure having 3 to 7 carbon atoms.
  • A selected from the group consisting of a compound having a steroid skeleton, a compound having a phenothiazine skeleton, a compound having a thioxanthene skeleton, a compound having a butyrophenone skeleton, and a chloramphenicol fatty acid ester compound
  • the compound having a ⁇ 8> steroid skeleton is at least one selected from the group consisting of methenolone enanthate, testosterone enanthate, testosterone decanoate, testosterone undecanoate, nandrolone decanoate, and dexamethasone palmitate Yes
  • the compound having a phenothiazine skeleton is at least one selected from the group consisting of fluphenazine enanthate, fluphenazine decanoate, pipothiazine palmitate, and perphenazine decanoate
  • the compound having a thioxanthene skeleton is at least one selected from flupenthixol decanoate and zuclopenthixol decanoate
  • the compound having a butyrophenone skeleton is at least one selected from haloperidol decanoic acid ester and bromperidol decanoate,
  • ⁇ 9> The compound according to any one of ⁇ 1> to ⁇ 8>, wherein the active ingredient (A) is at least one compound selected from the group consisting of a compound having a steroid skeleton and a chloramphenicol fatty acid ester compound Oral pharmaceutical composition.
  • the active ingredient (A) is at least one compound selected from the group consisting of a compound having a steroid skeleton and a chloramphenicol fatty acid ester compound Oral pharmaceutical composition.
  • the active ingredient (A) is at least one selected from testosterone undecanoate and chloramphenicol palmitate.
  • the dosage form is a capsule.
  • an oral pharmaceutical composition which spontaneously and rapidly forms an emulsion in a digestive fluid, and the emulsion can be finely and stably dispersed in the digestive fluid.
  • a numerical range indicated by using “to” means a range including numerical values described before and after “to” as the minimum value and the maximum value, respectively.
  • the upper limit value or the lower limit value described in a certain numerical value range may be replaced with the upper limit value or the lower limit value of the other stepwise description numerical value range in the numerical value range described stepwise in the present disclosure.
  • the upper limit value or the lower limit value described in a certain numerical range may be replaced with the value shown in the example.
  • a combination of two or more preferred embodiments is a more preferred embodiment.
  • the amount of each component means the total amount of a plurality of types of substances unless a plurality of types of substances corresponding to each component are present.
  • the content of the hydrophilic solvent (D) is 10 parts by mass or more and 50 parts by mass or less with respect to a total of 100 parts by mass of the hydrophilic solvent (D).
  • the oral pharmaceutical composition of the present disclosure spontaneously and rapidly forms an emulsion in the digestive fluid, and the emulsion can be finely and stably dispersed in the digestive fluid.
  • the oral pharmaceutical composition of the present disclosure can produce such an effect, the present inventors speculate as follows. However, the following reasons are not to be interpreted as limiting the oral pharmaceutical composition of the present disclosure, but to be described as an example.
  • the oral pharmaceutical composition of the present disclosure is a preparation referred to as a so-called self-emulsifying preparation, and an active ingredient is contained in a composition having a self-emulsifying ability, and this composition is brought into contact with water or digestive fluid. Only by itself, the composition containing the active ingredient is devised so as to be emulsified and dispersed.
  • a self-emulsifying formulation is orally administered, the poorly water-soluble active ingredient is distributed from the oil phase of the emulsion (that is, the emulsified formulation) into the digestive fluid which is the water phase and then absorbed from the mucosa of the small intestine. Ru.
  • the smaller the particle size of the emulsion dispersed in the digestive fluid the larger the specific surface area of the particles, and the active ingredient is efficiently distributed in the digestive fluid, so absorption against the mucosa of the small intestine is more effective. Work in favor. Also, the more stable the dispersed particles of the emulsion are in the digestive fluid, the more advantageous for absorption of the active ingredient.
  • a water-insoluble active ingredient (A) which has a saturated hydrocarbon group having 7 to 18 carbon atoms and has a log P of 6 to 9 and a surfactant Volatile and hydrogenated hydrogenated castor oil (B), lipid triglyceride (C), and hydrophilic solvent (D) at a specific ratio to spontaneously and rapidly emulsify in digestive fluid And fine and stable dispersion of the emulsion in the digestive fluid.
  • the content of polyoxyethylene hydrogenated castor oil (B) which is a surfactant is larger than the content of triglyceride (C) which is a lipid, that is, polyoxyethylene hydrogenated castor oil (B)
  • the content of the hydrophilic solvent (D) is 10 parts by mass or more with respect to a total of 100 parts by mass of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D). Since the entire pharmaceutical composition exhibits appropriate hydrophilicity, the time required for touching and emulsifying and dispersing the digestive fluid (i.e., the time required for dispersion) is shortened, that is, the oral pharmaceutical composition is in the digestive fluid. It is presumed that they can be emulsified and dispersed spontaneously and rapidly.
  • the content of the hydrophilic solvent (D) is 50 parts by mass or less with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D)
  • the content of polyoxyethylene hydrogenated castor oil (B) and triglyceride (C) relatively increases due to the formation of fine emulsion dispersed particles when the oral pharmaceutical composition is in contact with the digestive fluid. It is guessed to get.
  • the preparation described in JP-A-2015-120700 and the preparation described in JP-A-2016-74677 contain monoglycerides and / or diglycerides as lipids and do not contain triglycerides. .
  • the present inventors can not form dispersed particles of a fine emulsion in a digestive fluid, as in the oral pharmaceutical composition of the present disclosure, in a preparation containing monoglyceride instead of triglyceride, and triglyceride It has been confirmed that emulsions formed by preparations containing monoglycerides instead can not be stably dispersed in the digestive fluid, as emulsions formed by oral pharmaceutical compositions of the present disclosure (e.g.
  • the lipids form the oil phase of the emulsion after self-emulsification and can retain the active ingredient. Since monoglycerides and diglycerides are more soluble in water than triglycerides, they are likely to be distributed from the oil phase of the emulsion after self-emulsification into the digestive fluid which is the water phase, and it is thought that the oil phase of the emulsion decreases over time.
  • an active ingredient having a relatively high lipid solubility such as the active ingredient (A)
  • it can not stay in the emulsion when the oil phase of the emulsion decreases, and it is deposited after being distributed in the digestive fluid which is the aqueous phase.
  • monoglycerides and diglycerides have less acyl groups near the ester bond and less steric hindrance than triglycerides, so the active centers of lipases, which are digestive enzymes, easily come close to one another and are easily degraded by lipases.
  • the preparation described in JP-A-2017-518294 contains polyoxyl 35 castor oil as a surfactant and does not contain polyoxyethylene hydrogenated castor oil.
  • the inventors formed an emulsion formed by a preparation containing polyoxyl 35 castor oil instead of polyoxyethylene hydrogenated castor oil in a digestive fluid, as an emulsion formed by the oral pharmaceutical composition of the present disclosure. It has been confirmed that the dispersion can not be stably carried out (see, for example, Comparative Example 19, Comparative Example 27, and Comparative Example 35 described later).
  • the oral pharmaceutical composition of the present disclosure contains more triglycerides than polyoxyethylene hydrogenated castor oil. It is different from In a preparation having a higher content of triglycerides, which is lipid, relative to the content of polyoxyethylene hydrogenated castor oil, which is a surfactant, dispersion of a fine emulsion in digestive fluid as in the oral pharmaceutical composition of the present disclosure It is speculated that particles can not be formed.
  • 5313343 is an active ingredient, and contains ethyl ester of ⁇ 3 polyunsaturated fatty acid such as icosapentonic acid (EPA) which is a lipid, but triglyceride which is a lipid separately from the active ingredient And the content of polyoxyethylene hydrogenated castor oil which is a surfactant, and an ethyl ester of ⁇ 3 polyunsaturated fatty acid such as icosapentic acid (EPA) which is an active ingredient and which is a lipid It differs from the oral pharmaceutical composition of the present disclosure in that it has a high content of Therefore, it is assumed that the preparation described in Patent No. 5313343 can not form dispersed particles of a fine emulsion in a digestive fluid as in the oral pharmaceutical composition of the present disclosure.
  • EPA icosapentonic acid
  • EPA icosapentic acid
  • JP-A-2015-120700 JP-A-2017-518294, JP-A-2013-516433, Patent No. 5313343, and JP-A-2016-74677
  • JP-A-2015-7120700 JP-A-2017-518294, JP-A-2013-516433, Patent No. 5313343, and JP-A-2016-74677
  • JP-A-2015-7120700 JP-A-2017-518294, JP-A-2013-516433, Patent No. 5313343, and JP-A-2016-74677.
  • the oral pharmaceutical composition of the present disclosure has a saturated hydrocarbon group having a carbon number of 7 to 18 and an octanol / water partition coefficient (so-called concentration of solute in octanol phase relative to concentration of solute in aqueous phase) And the active ingredient (A) having a log P of 6 or more and 9 or less.
  • the active ingredient (A) preferably has a saturated hydrocarbon group having 7 to 18 carbon atoms and has a 10 to 16 carbon saturated hydrocarbon group.
  • the active ingredient (A) having a saturated hydrocarbon group having 7 or more and 18 or less carbon atoms has good affinity to triglyceride (C), so after self emulsification, the active ingredient (A) is the oil phase of the emulsion It is easy to be held by.
  • the carbon number of the saturated hydrocarbon group of the active ingredient (A) is 7 or more, after the active ingredient is absorbed in the small intestine epithelium, it can be expected to be transferred to lymphatic vessels in addition to blood vessels.
  • the transfer of the active ingredient to the lymphatic vessels is effective in addition to the case where it is desired to deliver the drug to the lymphatic vessels, the reduction of the systemic exposure of the active ingredient by first pass of the liver can be avoided.
  • the drug can be delivered to a low flow rate lymphatic vessel to delay the transfer of the active ingredient to systemic circulation, and it is expected that the active ingredient exhibits a sustained action.
  • the carbon number of the saturated hydrocarbon group which an active ingredient (A) has is 18 or less, there exists a tendency to be excellent in the solubility in a formulation.
  • the active ingredient having a carbon number of more than 18 and / or the active ingredient having an unsaturated hydrocarbon group tends to have poor solubility in the preparation.
  • the log P of the active ingredient (A) is 6 or more and 9 or less, preferably 6.5 or more and 8.7 or less, and more preferably 7 or more and 8.5 or less.
  • the oral pharmaceutical composition of the present disclosure is a so-called self-emulsifying formulation, and the active ingredient is distributed from the oil phase of the emulsion (ie, the emulsified oral pharmaceutical composition) into the digestive fluid which is the water phase. , Is absorbed from the mucosa of the small intestine. Whether the active ingredient is distributed in the aqueous phase (i.e., the digestive juice) or the oil phase of the emulsion depends on the logP of the active ingredient. Active ingredients with logP too low are difficult to partition into the oil phase of the emulsion.
  • the active ingredient having a logP too high does not partition into the digestive fluid which is the water phase from the oil phase of the emulsion, it is discharged without being absorbed from the mucous membrane of the small intestine.
  • the active ingredient is distributed in the oil phase of the emulsion when the oral pharmaceutical composition is self-emulsified in the digestive fluid, and then in the digestive fluid which is the aqueous phase over time. It needs to be distributed.
  • the oral pharmaceutical composition of the present disclosure contains an active ingredient (A) having a logP of 6 or more and 9 or less.
  • logP which is the common logarithm of octanol / water partition coefficient, is Viswanadhan, V. N .; Ghose, A. K .; Revankar, G. R. and Robins, R. K., J. Chem. Klopman, G .; Li, Ju-Yun .; Wang, S .; Dimayuga, M .: J. Chem. Inf. Comput. Sci., Inf. Comput. Sci., 1989, 29, 3, 163-172; , 1994, 34, 752 and is a value determined using ChemAxon.
  • the melting point of the active ingredient (A) is not particularly limited, but is preferably, for example, 0 ° C. or more and 100 ° C. or less.
  • the melting point of the active ingredient (A) is less than 0 ° C., components other than the active ingredient may coagulate and separation of the active ingredient may occur. On the other hand, such a possibility may be reduced if the melting point of the active ingredient (A) is 0 ° C. or higher. It is required to dissolve the active ingredient (A) in polyoxyethylene hydrogenated castor oil (B), triglyceride (C) and hydrophilic solvent (D) as the melting point of the active ingredient (A) is 100 ° C. or less Energy can be reduced more.
  • the melting point of the active ingredient when it is manufactured as a solid pharmaceutical composition and stored, the active ingredient may melt as the temperature rises.
  • the oral pharmaceutical composition of the present disclosure is a liquid pharmaceutical composition, it is easy to handle even when the melting point of the active ingredient (A) is 100 ° C. or less.
  • the active ingredient (A) preferably further has a ring structure having 3 or more and 7 or less carbon atoms, for example, from the viewpoint of solubility in triglyceride (C).
  • the ring structure having 3 to 7 carbon atoms is a ring such as cyclopentane ring, cyclohexane ring, benzene ring, piperidine ring, piperazine ring, thiaane ring, cyclohexenone ring, 2,5-cyclohexadien-1-one ring, etc. The structure is mentioned.
  • a compound having a steroid skeleton, a compound having a phenothiazine skeleton from the viewpoint of being more excellent in solubility in triglyceride (C) a compound having a thioxanthene skeleton, a compound having a butyrophenone skeleton, and at least one compound selected from the group consisting of a chloramphenicol fatty acid ester compound are more preferable, and a compound having a steroid skeleton and a chloramphenicol fatty acid ester compound Further preferred is at least one compound selected from the group consisting of
  • the compound having a steroid skeleton include methenolone enanthate, testosterone enanthate, testosterone decanoate, testosterone undecanoate, nandrolone decanoate, dexamethasone palmitate, and the like.
  • Specific examples of the compound having a phenothiazine skeleton include fluphenazine enanthate, fluphenazine decanoate, pipothiazine palmitate, perphenazine decanoate and the like.
  • Specific examples of the compound having a thioxanthene skeleton include flupenthixol decanoate and zuclopenthixol decanoate.
  • the compound having a butyrophenone skeleton include haloperidol decanoic acid ester and bromoperidol decanoate.
  • Specific examples of the chloramphenicol fatty acid ester compound include chloramphenicol palmitic acid ester, chloramphenicol stearic acid ester and the like.
  • the active ingredient (A) is selected from testosterone undecanoate and chloramphenicol palmitate as the active ingredient (A) from the viewpoint of being more excellent in solubility in triglyceride (C) and having more suitable log P and melting point. At least one is particularly preferred.
  • the active ingredient (A) in addition to the above-mentioned compounds, compounds such as clindamycin palmitate, neomycin palmitate, paliperidone palmitate, valomaciclovir stearate, rananinamivir octanoate hydrate and the like can be mentioned. .
  • the compounds other than paliperidone palmitic acid ester (melting point: 114 ° C.) and raninamivir octanoate hydrate (melting point: 224 ° C.) all have a melting point of 0 ° C. or more and 100 ° C. or less is there.
  • the oral pharmaceutical composition of the present disclosure may contain only one type of active ingredient (A), or may contain two or more types.
  • the content rate of the active ingredient (A) in the oral pharmaceutical composition of the present disclosure is not particularly limited.
  • the content of the active ingredient (A) in the oral pharmaceutical composition of the present disclosure is preferably 5% by mass or more, more preferably 8% by mass or more, based on the total amount of the oral pharmaceutical composition. % Or more is more preferable.
  • the upper limit of the content of the active ingredient (A) in the oral pharmaceutical composition of the present disclosure is not particularly limited. For example, from the viewpoint that the active ingredient hardly precipitates during storage, relative to the total amount of the oral pharmaceutical composition. 60 mass% or less is preferable, 55 mass% or less is more preferable, and 50 mass% or less is still more preferable.
  • the oral pharmaceutical composition of the present disclosure comprises polyoxyethylene hydrogenated castor oil (B).
  • polyoxyethylene hydrogenated castor oil (B) contributes to the refinement of dispersed particles of the emulsion in the digestive fluid.
  • polyoxyethylene hydrogenated castor oil (B) contributes to the improvement of the stability of the dispersed particles of the emulsion in the digestive fluid.
  • polyoxyethylene hydrogenated castor oil (B) contributes to the improvement of the concentration of the active ingredient (A).
  • the polyoxyethylene hydrogenated castor oil (B) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil.
  • the average polymerization degree of ethylene oxide in the polyoxyethylene hydrogenated castor oil (B) is preferably 20 to 100, more preferably 40 to 100, and still more preferably 40 to 60.
  • the average degree of polymerization of ethylene oxide is 20 or more, the stability of dispersed particles of the emulsion in the digestive fluid tends to be further improved.
  • the average degree of polymerization of ethylene oxide is 100 or less, dispersed particles of the emulsion in the digestive fluid tend to be finer.
  • polyoxyethylene hydrogenated castor oil (B) having an average polymerization degree of ethylene oxide of 20 to 100 include polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (100) hydrogenated castor oil and the like.
  • the numerical value in a parenthesis shows the average polymerization degree of ethylene oxide.
  • polyoxyethylene hydrogenated castor oil B
  • Various polyoxyethylene hydrogenated castor oils are commercially available depending on the average degree of polymerization of ethylene oxide.
  • polyoxyethylene hydrogenated castor oil (B) NIKKOL (registered trademark) HCO-20 (polyoxyethylene (20) hydrogenated castor oil, Nikko Chemicals Co., Ltd.), NIKKOL (registered trademark) HCO- 40 (polyoxyethylene (40) hydrogenated castor oil, Nikko Chemicals Co., Ltd.), Kollinphor (registered trademark) RH 40 (polyoxyethylene (40) hydrogenated castor oil, BASF Corporation), NIKKOL (registered trademark) HCO-50 (poly) Oxyethylene (50) hydrogenated castor oil, Nikko Chemicals Co., Ltd., NIKKOL® HCO-60 (Polyoxyethylene (60) hydrogenated castor oil, Nikko Chemicals Co., Ltd.), NIKKOL® HCO-100 (Poly
  • the oral pharmaceutical composition of the present disclosure may contain only one type of polyoxyethylene hydrogenated castor oil (B), or may contain two or more types.
  • the mass ratio of the content of polyoxyethylene hydrogenated castor oil (B) to the content of triglyceride (C) is the content of polyoxyethylene hydrogenated castor oil (B): triglyceride
  • the content of (C) is 3: 1 to 9: 1, preferably 4: 1 to 9: 1, and more preferably 5: 1 to 9: 1.
  • triglyceride (C) contains triglyceride (C).
  • triglyceride (C) is contained in the oil phase of the emulsion after self-emulsification, and may contribute to retention of the active ingredient (A).
  • a triglyceride is an acylglycerol in which three molecules of fatty acid are ester bonded to one molecule of glycerol.
  • the triglyceride (C) may be medium chain fatty acid triglyceride or long chain fatty acid triglyceride, but the oral pharmaceutical composition can form dispersed particles of finer emulsion in digestive fluid From the viewpoint, long chain fatty acid triglyceride is preferred.
  • “medium-chain fatty acid triglyceride” means triglycerides in which the average carbon number of fatty acid chains is 6 or more and 12 or less.
  • the average carbon number of the fatty acid chain is 8 if the carbon number of the fatty acid constituting the triglyceride (ie, constituent fatty acid) (for example, caprylic acid (IUPAC family name: octanoic acid) 8 and capric acid (IUPAC family name: decanoic acid) 10, and 12) lauric acid (IUPAC strain name: dodecanoic acid) by the composition ratio of the constituent fatty acids.
  • the constituent fatty acids may be saturated fatty acids or unsaturated fatty acids, preferably saturated fatty acids.
  • the medium chain fatty acid triglyceride may be derived from natural products or may be a triglyceride of synthetic fatty acid.
  • long-chain fatty acid triglyceride means triglycerides in which the average carbon number of the fatty acid chain exceeds 12.
  • long-chain fatty acid triglycerides long-chain fatty acid triglycerides in which the average carbon number of fatty acid chains is 14 or more and 24 or less are preferable.
  • the constituent fatty acids of the long chain fatty acid triglyceride may be saturated fatty acids or unsaturated fatty acids.
  • the long chain fatty acid triglyceride may be a vegetable oil corresponding to natural long chain fatty acid triglyceride, or may be a synthetic fatty acid triglyceride. Vegetable oils are oils derived from plant seeds or nuts.
  • soybean oil examples include soybean oil, cottonseed oil, rapeseed oil, sesame oil, safflower oil, corn oil, peanut oil, olive oil, coconut oil, perilla oil, castor oil and the like.
  • soybean oil is preferable as long-chain fatty acid triglyceride from the viewpoint of availability and oral administration results.
  • a commercial item can be used as triglyceride (C).
  • Examples of commercially available medium-chain fatty acid triglycerides include "Miglyol (registered trademark) 812" (tri (caprylic acid / capric acid) glyceryl) from Sasol, "Miglyol (registered trademark) 810" (tri (caprylic acid / caprin) Acid) glyceryl), Kao Corporation “Coconard (registered trademark) RK” (glyceryl tricaprylate), “Coconard (registered trademark) MT” (tri (caprylic acid / capric acid) glyceryl), “Coconard (registered trademark)” MT-N "(tri (caprylic acid / capric acid) glyceryl),” Coconard (registered trademark) ML "(tri (caprylic acid / capric acid / lauric acid) glyceryl), and the like.
  • the oral pharmaceutical composition of the present disclosure may contain only one type of triglyceride (C), or may contain two or more types.
  • the content rate of triglyceride (C) in the oral pharmaceutical composition of the present disclosure is an oral phase from the viewpoint that the active ingredient (A) can be more stably maintained in the emulsion after self-emulsification of the oral pharmaceutical composition. 4 mass% or more is preferable with respect to whole quantity of a pharmaceutical composition, 5 mass% or more is more preferable, and 6 mass% or more is still more preferable.
  • the content ratio of triglyceride (C) in the oral pharmaceutical composition of the present disclosure is an oral pharmaceutical composition from the viewpoint that the oral pharmaceutical composition can form dispersed particles of a finer emulsion in digestive fluid. 25 mass% or less is preferable with respect to the whole quantity of, 20 mass% or less is more preferable, and 15 mass% or less is still more preferable.
  • the oral pharmaceutical composition of the present disclosure comprises a hydrophilic solvent (D).
  • the hydrophilic solvent (D) contributes to shortening of the time required for the oral pharmaceutical composition to contact the digestive fluid and then to be emulsified and dispersed (so-called, the required dispersion time).
  • the hydrophilic solvent (D) is not particularly limited as long as it is a pharmacologically acceptable hydrophilic solvent.
  • Specific examples of the hydrophilic solvent (D) include alcohols such as ethanol, absolute ethanol and benzyl alcohol, polyols such as glycerin, concentrated glycerin, propylene glycol and butylene glycol, Macrogol 100, Macrogol 300, Macrogol 400 Etc., triacetin, esters such as triethyl citrate, water, and the like.
  • the hydrophilic solvent (D) for example, macrogol 300, macrogol 400, propylene glycol, ethanol, absolute ethanol, glycerin, concentrated glycerin, triacetin, citric acid from the viewpoint of safety and oral administration results It is preferably at least one selected from the group consisting of triethyl and benzyl alcohol, and is selected from the group consisting of macrogol 300, macrogol 400, propylene glycol, ethanol, concentrated glycerin, triacetin, triethyl citrate, and benzyl alcohol. More preferably, it is at least one of The hydrophilic solvent (D) further preferably includes Macrogol 400, and particularly preferably Macrogol 400, from the viewpoint of, for example, shortening the dispersion required time and making the dispersed particles finer.
  • the oral pharmaceutical composition of the present disclosure may contain only one type of hydrophilic solvent (D), or may contain two or more types.
  • the content of the hydrophilic solvent (D) in the oral pharmaceutical composition of the present disclosure is 100 parts by mass in total of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D). 10 parts by mass or more and 50 parts by mass or less, preferably 15 parts by mass or more and 50 parts by mass or less, and more preferably 20 parts by mass or more and 50 parts by mass or less.
  • the content of the hydrophilic solvent (D) in the oral pharmaceutical composition of the present disclosure is 100 parts by mass to the total of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D).
  • the entire oral pharmaceutical composition exhibits appropriate hydrophilicity, and hence the time required for the emulsion liquid to contact and be emulsified and dispersed (that is, the time required for dispersion) is shortened. That is, the oral pharmaceutical composition can be emulsified spontaneously and rapidly in the digestive fluid and dispersed.
  • the content of the hydrophilic solvent (D) in the oral pharmaceutical composition of the present disclosure is 100 parts by mass to the total of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D).
  • the amount is 50 parts by mass or less, the content of polyoxyethylene hydrogenated castor oil (B) and triglyceride (C) relatively increases, so when the oral pharmaceutical composition is in contact with a digestive fluid, a fine emulsion is obtained. Can form dispersed particles. Moreover, precipitation of an active ingredient (A) can be suppressed.
  • the oral pharmaceutical composition of the present disclosure can contain other components as needed, as long as the effects are not impaired, in addition to the components described above.
  • antioxidants ascorbic acid, D- ⁇ -tocopherol, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), etc.
  • stabilizers eg, Sodium citrate
  • preservatives methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.
  • perfumes coloring agents and the like can be mentioned.
  • the dosage form of the oral pharmaceutical composition of the present disclosure is not particularly limited, but is preferably, for example, an oral solution or a capsule, and more preferably a capsule.
  • the stability of each component contained in the oral pharmaceutical composition of the present disclosure can be maintained.
  • the dosage form is a capsule, the effect of spontaneously and rapidly emulsifying the oral pharmaceutical composition of the present disclosure in digestive fluid is better exhibited.
  • the method for producing the capsule is not particularly limited, and can be produced by a known method. That is, the capsule preparation can be produced by preparing the oral pharmaceutical composition of the present disclosure and then filling the capsule in a conventional manner.
  • the capsule may be a soft capsule or a hard capsule.
  • the active ingredient (A) is “component (A)” or “(A)”
  • the polyoxyethylene hydrogenated castor oil (B) is “component (B)” or “(B)”
  • the triglyceride (C) may be referred to as “component (C)” or “(C)”
  • the hydrophilic solvent (D) may be referred to as “component (D)” or "(D)”.
  • C Medium-chain fatty acid triglyceride (trade name: Coconado (registered trademark) RK, average carbon number of fatty acid chain: 8, Kao Corporation) ⁇ Soybean oil (trade name: Japanese Pharmacopoeia soybean oil, average carbon number of fatty acid chain: 17.8, triglyceride content: 97% by mass, Kaneda Co., Ltd.) -Lipids other than triglyceride (C)- ⁇ Oleic acid (brand name: oleic acid special grade, Fujifilm Wako Pure Chemical Industries, Ltd.) -Glycerol monooleate (trade name: Capmul GMO, Abitec) -Glyceryl monocaprylic acid (trade name: Capmul MCM C8, Abitec)
  • Example 1 11.25 parts by mass of medium-chain fatty acid triglyceride (component (C)) which is a lipid, 56.25 parts by mass of polyoxyethylene hydrogenated castor oil 50 which is a surfactant (component (B)) in a glass container, hydrophilic solvent 11.25 parts by mass of propylene glycol (component (D)) and 11.25 parts by mass of macrogol 400 (component (D)), which is a hydrophilic solvent, at 60.degree. C., 500 rpm using a hot plate stirrer. The mixture was stirred and mixed for 30 minutes under the conditions of revolutions per minute (same below).
  • composition 10 parts by mass of testosterone enanthate (component (A)) as an active ingredient is added to the obtained mixture, and the mixture is further stirred and mixed for 30 minutes under conditions of 60 ° C. and 500 rpm to obtain an oral pharmaceutical composition. (So-called preparation) was obtained.
  • Example 2 and Example 3 The same operation as in Example 1 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 1, to obtain an oral pharmaceutical composition (so-called formulation).
  • Comparative Examples 1 to 7 The same operation as in Example 1 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 1, to obtain an oral pharmaceutical composition (so-called formulation).
  • Example 4 to Example 6 The same operation as in Example 1 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 2, to obtain an oral pharmaceutical composition (so-called preparation).
  • the dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) and particles in the scattering intensity distribution under the conditions of an atmosphere temperature of 25 ° C. A particle diameter (d90) corresponding to 90% of the integrated value of the diameter distribution was determined. The results are shown in Tables 1 and 2.
  • the d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
  • Table 1 and Table 2 the unit of the numerical value which shows the quantity of each component is a mass part.
  • "-" described in the column indicating the amount of each component means that the corresponding component is not included.
  • "-" described in the column showing the dispersed particle size means that the measurement was not performed because the solubility of the active ingredient in the preparation was poor.
  • an active ingredient having a saturated hydrocarbon group having 7 to 18 carbon atoms and having a log P, which is a common logarithm of the octanol / water partition coefficient, of 6 to 9 (A ) could be contained in an oral pharmaceutical composition (so-called formulation) in a 10% by mass solution (see Examples 1 to 6).
  • an active ingredient (A) having a saturated hydrocarbon group having 7 to 18 carbon atoms and having log P which is a common logarithm of octanol / water distribution coefficient is 6 to 9 as an active ingredient.
  • the oral pharmaceutical compositions (so-called preparations) of Examples 1 to 6 were confirmed to form fine dispersed particles in the first dissolution test of the Japanese Pharmacopoeia (so-called liquid simulating gastric juice). .
  • Example 7 100 parts by mass of medium-chain fatty acid triglyceride (component (C)) which is a lipid, 500 parts by mass of polyoxyethylene hydrogenated castor oil 50 (component (B)) which is a surfactant, in a glass container, propylene glycol which is a hydrophilic solvent 100 parts by mass of (Component (D)) and 100 parts by mass of Macrogol 400 (component (D)) which is a hydrophilic solvent are stirred and mixed for 30 minutes at 60 ° C. and 500 rpm using a hot plate stirrer The mixture was obtained.
  • component (C) medium-chain fatty acid triglyceride
  • component (B) polyoxyethylene hydrogenated castor oil 50
  • component (D) polyoxyethylene hydrogenated castor oil 50
  • component (A) chloramphenicol palmitic acid ester
  • component (A) which is an active ingredient
  • Example 8 to Example 10 The same operation as in Example 7 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 3, to obtain an oral pharmaceutical composition (so-called formulation).
  • the d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less.
  • 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
  • an aqueous digestive enzyme solution 4 mL of an aqueous digestive enzyme solution was added to a buffer in which the oral pharmaceutical composition (so-called preparation) obtained above was dispersed, and 1 mL each was sampled over time.
  • a 10% by mass 4-bromophenylboronic acid / methanol solution was added to inhibit digestive enzymes. After 120 minutes from the start of addition of the digestive enzyme aqueous solution, the sampled solution was ultracentrifuged at 32,000 rpm and maximum rotation radius of 9 cm for 30 minutes, and the supernatant was recovered.
  • the active ingredient present in the recovered supernatant corresponds to the active ingredient which was stably present in the digestive fluid.
  • the more stable the emulsion of the oral pharmaceutical composition (so-called preparation) in the digestive fluid the more the active ingredient can be distributed in the emulsion, and the residual rate approaches 100%.
  • the measurement of the concentration of the active ingredient in the buffer and the concentration of the active ingredient in the supernatant was measured by high performance liquid chromatography (HPLC). The measurement conditions are shown below.
  • Table 3 the unit of the numerical value which shows the quantity of each component is a mass part.
  • "-" described in the column indicating the amount of each component means that the corresponding component is not included.
  • the oral pharmaceutical compositions (so-called preparations) of Examples 7 to 10 containing triglycerides were finely divided in the Japanese Pharmacopoeia Dissolution Test First Liquid (so-called liquid simulating gastric juice). Formation of dispersed particles. Moreover, it was confirmed that the dispersed particles formed were stable in the digestive fluid.
  • the oral pharmaceutical compositions (so-called, preparations) of Comparative Examples 15 to 18 containing lipids other than triglycerides are finely dispersed in the first dissolution test of the Japanese Pharmacopoeia (so-called, liquid simulating gastric juice) It was not possible to form particles.
  • the dispersed particles formed by the oral pharmaceutical composition (so-called preparation) of Comparative Examples 15 to 17 containing oleic acid, glyceryl monooleate or glyceryl monocaprylate as a lipid other than triglyceride are triglycerides.
  • the stability in digestive fluid was inferior.
  • Example 11 to Example 13 An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 4. .
  • the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C.
  • the results are shown in Table 4.
  • the d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less.
  • 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
  • Example 7 and Example 8 described in Table 4 are described for comparison with other Examples and Comparative Examples, and are the same as Example 7 and Example 8 described in the above-mentioned Table. It is an oral pharmaceutical composition.
  • an oral pharmaceutical composition (so-called formulation) containing soybean oil in which the proportion of long-chain fatty acid triglyceride is 97% by mass is combined with an oral pharmaceutical composition (so-called formulation) containing medium-chain fatty acid triglyceride In comparison, it was confirmed that finer dispersed particles can be formed.
  • Example 14 The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 6, and an oral pharmaceutical composition (so-called formulation) was obtained. .
  • Example 15 An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 7. .
  • Example 16 and Example 17 An oral pharmaceutical composition (so-called preparation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 8. .
  • the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C.
  • the results are shown in Tables 5-8.
  • the d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less.
  • 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
  • the active ingredient present in the recovered supernatant corresponds to the active ingredient which was stably present in the digestive fluid.
  • the more stable the emulsion of the oral pharmaceutical composition (so-called preparation) in the digestive fluid the more the active ingredient can be distributed in the emulsion, and the residual rate approaches 100%.
  • Example 7 described in Table 5 Example 8 described in Table 6, Example 9 described in Table 7, and Example 10 described in Table 8 are for comparison with other Examples and Comparative Examples.
  • the oral pharmaceutical compositions (so-called formulations) of Examples 7 to 10 and Examples 14 to 17 containing polyoxyethylene hydrogenated castor oil (B) are active ingredients. It was excellent in the solubility of Further, the oral pharmaceutical compositions (so-called preparations) of Examples 7 to 10 and Examples 14 to 17 were finely divided in the first dissolution test of the Japanese Pharmacopoeia (so-called liquid simulating gastric juice). Formation of dispersed particles. Furthermore, the dispersed particles formed were confirmed to be stable in the digestive fluid.
  • Comparative Example 19 to Comparative Example 25 Comparative Example 27 to Comparative Example 33, Comparative Example 35 to Comparative Example 41, and Comparative Example 43 to Comparative Example 47 containing surfactants other than polyoxyethylene hydrogenated castor oil
  • the oral pharmaceutical composition of the present invention has poor solubility of the active ingredient, does not disperse, or can not form finely dispersed particles even if dispersed, or stability in digestive fluid Or at least one of the above.
  • the oral pharmaceutical composition (so-called preparation) of Comparative Example 26, Comparative Example 34, Comparative Example 42, and Comparative Example 48 which does not contain a surfactant is the Japanese Pharmacopoeia Dissolution Test First Solution (so-called gastric juice). It did not disperse in the simulated solution).
  • Example 18 to Example 21 An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 9. .
  • Example 22 to Example 26 The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 10 to obtain an oral pharmaceutical composition (so-called preparation). .
  • Comparative Example 49 and Comparative Example 50 The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 10 to obtain an oral pharmaceutical composition (so-called preparation). .
  • Example 27 The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 11, and an oral pharmaceutical composition (so-called preparation) was obtained. .
  • Example 31 to Example 37 The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 12, and an oral pharmaceutical composition (so-called preparation) was obtained. .
  • the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C.
  • the results are shown in Tables 9-12.
  • the d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less.
  • 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
  • Tables 9 to 12 units of numerical values indicating the amount of each component are parts by mass.
  • "-" described in the column indicating the amount of each component means that the corresponding component is not included.
  • Example 7 and Example 8 described in Table 9 and Example 9 and Example 10 described in Table 11 are described for comparison with other Examples and Comparative Examples, and have already been described. It is the same oral pharmaceutical composition as Example 7, Example 8, Example 9, and Example 10 as described in the above-mentioned table
  • the oral pharmaceutical compositions (so-called formulations) of Examples 7 to 10 and Examples 18 to 37 containing a hydrophilic solvent are the Japanese Pharmacopoeia Dissolution Test First Liquid It was confirmed that fine dispersed particles were formed in (a so-called liquid simulating gastric juice).
  • the oral pharmaceutical compositions (so-called preparations) of Examples 7 to 10 and Examples 18 to 37 are rapidly obtained in the first dissolution test of the Japanese Pharmacopoeia (so-called liquid simulating gastric juice). It was confirmed that the product was emulsified and dispersed.
  • Example 38 In a glass container, 23.75 parts by mass of soybean oil (component (C)) as a lipid, polyoxyethylene hydrogenated castor oil 50 as a surfactant (component (B)) 71.25 parts by mass, a hydrophilic solvent Using a hot plate stirrer, 5 parts by mass of propylene glycol (component (D)) and 5 parts by mass of macrogol 400 (component (D)) which is a hydrophilic solvent, for 30 minutes at 60 ° C. and 500 rpm Stir and mix to obtain a mixture.
  • Example 39 to Example 41> The same operation as in Example 38 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 13, to obtain an oral pharmaceutical composition (so-called preparation).
  • Comparative Example 53 and Comparative Example 54 The same operation as in Example 38 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 13, to obtain an oral pharmaceutical composition (so-called preparation).
  • Example 42 to Example 45 The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 14, to obtain an oral pharmaceutical composition (so-called formulation).
  • Example 46 to Example 49 The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 15, to obtain an oral pharmaceutical composition (so-called preparation).
  • Comparative Example 58 The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 15, to obtain an oral pharmaceutical composition (so-called preparation).
  • Examples 50 to 53 The same procedure as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 16, to obtain an oral pharmaceutical composition (so-called preparation).
  • the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C.
  • the results are shown in Tables 13-16.
  • the d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less.
  • 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
  • Example 41 described in Table 14 and Example 49 described in Table 16 are described for comparison with other Examples and Comparative Examples, and Example 41 described in the above-mentioned Table. And the same oral pharmaceutical composition as Example 49.
  • the mass ratio of the polyoxyethylene hydrogenated castor oil (B) content to the triglyceride (C) content is the polyoxyethylene hydrogenated castor oil (B) content:
  • the content of triglyceride (C) is 3: 1 to 9: 1, and based on 100 parts by mass in total of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D)
  • the oral pharmaceutical compositions (so-called formulations) of Examples 38 to 53 in which the content of the hydrophilic solvent (D) is 10 parts by mass or more and 50 parts by mass or less were excellent in the solubility of the active ingredient.
  • the oral pharmaceutical compositions (so-called preparations) of Examples 38 to 53 can form fine dispersed particles in Japanese Pharmacopoeia dissolution test first liquid (so-called liquid simulating gastric juice). confirmed. Furthermore, the oral pharmaceutical composition (so-called preparation) of Example 38 to Example 53 can be rapidly emulsified and dispersed in Japanese Pharmacopoeia Dissolution Test First Liquid (so-called liquid simulating gastric juice). confirmed.

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Abstract

This oral pharmaceutical composition comprises: an active ingredient (A) that has a saturated hydrocarbon group having 7-18 carbon atoms and having a logP, which is the common logarithm of octanol/water partition coefficient, of 6-9; a polyoxyethylene hydrogenated castor oil (B); triglyceride (C); and a hydrophilic solvent (D), wherein the mass ratio between the content of polyoxyethylene hydrogenated castor oil (B) and the content of triglyceride (C) is 3:1 to 9:1, and the hydrophobic solvent (D) is contained in an amount of 10-50 parts by mass with respect to 100 parts by mass of the sum of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D).

Description

経口医薬組成物Oral pharmaceutical composition
　本開示は、経口医薬組成物に関する。 The present disclosure relates to oral pharmaceutical compositions.
　従来、水に難溶性の医薬上の有効成分について、体内での吸収性を改善するための技術として、有効成分を、自己乳化能を有する組成物に含有させ、この組成物と水又は消化液とが接触するだけで、自然に有効成分を含有する組成物が乳化して分散するように工夫した技術が提案されている。 Conventionally, as a technique for improving the absorbability in the body of a pharmaceutically active ingredient poorly soluble in water, the active ingredient is contained in a composition having a self-emulsifying ability, and this composition and water or digestive fluid A technique has been proposed in which a composition containing an active ingredient spontaneously emulsifies and disperses by simply contacting with.
　例えば、特開２０１５－１２０７００号公報及び特開２０１６－７４６７７号公報には、モノグリセリド及び／又はジグリセリドと、ポリオキシエチレ硬化ヒマシ油と、を含む溶液中に、ウンデカン酸テストステロンを含有させた製剤が開示されている。
　特表２０１７－５１８２９４号公報には、トリグリセリドと、ポリオキシル３５ヒマシ油と、を含む溶液中に、ウンデカン酸テストステロンを含有させた製剤が開示されている。
　特表２０１３－５１６４３３号公報には、トリグリセリドと、ポリオキシエチレン硬化ヒマシ油と、を含む溶液中に、ウンデカン酸テストステロンを含有させた製剤が開示されている。
　特許第５３１３３４３号公報には、イコサペント酸（ＥＰＡ）等のω３多価不飽和脂肪酸のエチルエステルと、ポリオキシエチレン硬化ヒマシ油と、を含む製剤が開示されている。 For example, JP-A-2015-120700 and JP-A-2016-74677 disclose preparations containing testosterone undecanoate in a solution containing monoglyceride and / or diglyceride and polyoxyethylene hydrogenated hydrogenated castor oil. It is disclosed.
JP-T-2017-518294 discloses a preparation containing testosterone undecanoate in a solution containing triglyceride and polyoxyl 35 castor oil.
Japanese Patent Application Publication No. 2013-516433 discloses a preparation containing testosterone undecanoate in a solution containing triglyceride and polyoxyethylene hydrogenated castor oil.
Japanese Patent No. 5313343 discloses a preparation containing ethyl ester of ω3 polyunsaturated fatty acid such as icosapentic acid (EPA) and polyoxyethylene hydrogenated castor oil.
　上記の技術を適用した製剤（所謂、自己乳化型製剤）を経口投与した場合、有効成分は、乳化物（即ち、乳化した製剤）の油相中から水相である消化液中に分配した後、小腸の粘膜から吸収される。有効成分の水溶性が低い場合には、消化液中で分散している乳化物の粒子径が小さいほど、有効成分が効率的に消化液中に分配し、小腸の粘膜からの吸収に対し、有利に働く。
　また、乳化物の分散粒子が消化液中で安定であるほど、有効成分の吸収に有利である。ここで、「乳化物の分散粒子が消化液中で安定である」ことは、消化液中で分散している乳化物の粒子が、物理的に安定であることのみならず、製剤として安定であること、即ち、消化液中に含まれる消化酵素による消化に対して安定であることを含む。
　以上のことから、水に難溶性の有効成分を含む自己乳化型製剤は、消化液中で乳化した後、その乳化した乳化物が消化液中で微細かつ安定に分散することが望ましい。 When a preparation to which the above technology is applied (so-called self-emulsifying preparation) is orally administered, the active ingredient is distributed from the oil phase of the emulsion (ie, the emulsified preparation) into the digestive fluid which is the water phase , Is absorbed from the mucosa of the small intestine. When the water solubility of the active ingredient is low, the smaller the particle size of the emulsion dispersed in the digestive fluid, the more efficiently the active ingredient is distributed in the digestive fluid and the absorption from the mucosa of the small intestine, Work in favor.
Also, the more stable the dispersed particles of the emulsion are in the digestive fluid, the more advantageous for absorption of the active ingredient. Here, "the dispersed particles of the emulsion are stable in the digestive fluid" means that the particles of the emulsion dispersed in the digestive fluid are not only physically stable but also stable as a preparation. Some things include being stable to digestion by the digestive enzymes contained in the digestive fluid.
From the above, it is desirable that the self-emulsifiable concentrate containing an active ingredient poorly soluble in water is emulsified in the digestive fluid, and then the emulsified emulsion is finely and stably dispersed in the digestive fluid.
　上述の点に関し、特開２０１５－１２０７００号公報、特表２０１７－５１８２９４号公報、特表２０１３－５１６４３３号公報、特許第５３１３３４３号公報、及び特開２０１６－７４６７７号公報では、消化液中で微細な乳化物を得るための技術について明確な記載はなく、また、消化液中での乳化物の分散粒子の安定性については何ら着目していない。 Regarding the above-mentioned points, in JP-A-2015-120700, JP-A-2017-518294, JP-A-2013-516433, Patent No. 5313343, and JP-A-2016-74677, fine particles are contained in digestive fluid. There is no clear description of the technique for obtaining such emulsions, and no attention is paid to the stability of the dispersed particles of the emulsion in the digestive fluid.
　本発明の実施形態が解決しようとする課題は、消化液中で自発的かつ速やかに乳化物を形成し、その乳化物が消化液中で微細かつ安定に分散し得る経口医薬組成物を提供することである。 The problem to be solved by the embodiments of the present invention is to provide an oral pharmaceutical composition capable of spontaneously and rapidly forming an emulsion in a digestive fluid, and the emulsion being finely and stably dispersed in the digestive fluid. It is.
　上記課題を解決するための手段には、以下の態様が含まれる。
　＜１＞　炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、オクタノール／水分配係数の常用対数であるｌｏｇＰが６以上９以下の有効成分（Ａ）と、
　ポリオキシエチレン硬化ヒマシ油（Ｂ）と、
　トリグリセリド（Ｃ）と、
　親水性溶媒（Ｄ）と、を含み、
　ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリドの含有量（Ｃ）＝３：１～９：１であり、
　ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が１０質量部以上５０質量部以下である経口医薬組成物。
　＜２＞　トリグリセリド（Ｃ）が、脂肪酸鎖の平均炭素数が１４以上２４以下の長鎖脂肪酸トリグリセリドである＜１＞に記載の経口医薬組成物。
　＜３＞　トリグリセリド（Ｃ）の含有率が、経口医薬組成物の全量に対し、４質量％以上２５質量％以下である＜１＞又は＜２＞に記載の経口医薬組成物。
　＜４＞　親水性溶媒（Ｄ）が、マクロゴール３００、マクロゴール４００、プロピレングリコール、エタノール、濃グリセリン、トリアセチン、クエン酸トリエチル、及びベンジルアルコールからなる群より選ばれる少なくとも１種である＜１＞～＜３＞のいずれか１つに記載の経口医薬組成物。
　＜５＞　有効成分（Ａ）の融点が０℃以上１００℃以下である＜１＞～＜４＞のいずれか１つに記載の経口医薬組成物。
　＜６＞　有効成分（Ａ）が、炭素数が３以上７以下の環構造を更に有する＜１＞～＜５＞のいずれか１つに記載の経口医薬組成物。
　＜７＞　有効成分（Ａ）が、ステロイド骨格を有する化合物、フェノチアジン骨格を有する化合物、チオキサンテン骨格を有する化合物、ブチロフェノン骨格を有する化合物、及びクロラムフェニコール脂肪酸エステル化合物からなる群より選ばれる少なくとも１種の化合物である＜１＞～＜６＞のいずれか１つに記載の経口医薬組成物。
　＜８＞　ステロイド骨格を有する化合物が、メテノロンエナント酸エステル、テストステロンエナント酸エステル、テストステロンデカノアート、ウンデカン酸テストステロン、ナンドロロンデカン酸エステル、及びデキサメタゾンパルミチン酸エステルからなる群より選ばれる少なくとも１種であり、
　フェノチアジン骨格を有する化合物が、フルフェナジンエナント酸エステル、フルフェナジンデカン酸エステル、パルミチン酸ピポチアジン、及びペルフェナジンデカノアートからなる群より選ばれる少なくとも１種であり、
　チオキサンテン骨格を有する化合物が、フルペンチキソールデカノアート及びズクロペンチキソールデカノアートから選ばれる少なくとも１種であり、
　ブチロフェノン骨格を有する化合物が、ハロペリドールデカン酸エステル及びデカン酸ブロムペリドールから選ばれる少なくとも１種であり、
　クロラムフェニコール脂肪酸エステル化合物が、クロラムフェニコールパルミチン酸エステル及びクロラムフェニコールステアリン酸エステルから選ばれる少なくとも１種である＜７＞に記載の経口医薬組成物。
　＜９＞　有効成分（Ａ）が、ステロイド骨格を有する化合物及びクロラムフェニコール脂肪酸エステル化合物からなる群より選ばれる少なくとも１種の化合物である＜１＞～＜８＞のいずれか１つに記載の経口医薬組成物。
　＜１０＞　有効成分（Ａ）が、ウンデカン酸テストステロン及びクロラムフェニコールパルミチン酸エステルから選ばれる少なくとも１種である＜１＞～＜９＞のいずれか１つに記載の経口医薬組成物。
　＜１１＞　剤形が、カプセル剤である＜１＞～＜１０＞のいずれか１つに記載の経口医薬組成物。 Means for solving the above problems include the following aspects.
<1> An active ingredient (A) having a saturated hydrocarbon group having 7 to 18 carbon atoms and having a log P of 6 to 9 which is a common logarithm of the octanol / water distribution coefficient,
Polyoxyethylene hydrogenated castor oil (B),
Triglyceride (C),
Containing a hydrophilic solvent (D),
The mass ratio of the content of polyoxyethylene hydrogenated castor oil (B) to the content of triglyceride (C) is the content of polyoxyethylene hydrogenated castor oil (B): content of triglyceride (C) = 3: 1 to 9: 1,
The content of the hydrophilic solvent (D) is 10 parts by mass to 50 parts by mass with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D) An oral pharmaceutical composition.
The oral pharmaceutical composition as described in <1> whose <2> triglyceride (C) is a long chain fatty acid triglyceride whose average carbon number of a fatty acid chain is 14 or more and 24 or less.
The oral pharmaceutical composition as described in <1> or <2> whose content rate of <3> triglyceride (C) is 4 mass% or more and 25 mass% or less with respect to whole quantity of oral pharmaceutical composition.
<4> The hydrophilic solvent (D) is at least one selected from the group consisting of macrogol 300, macrogol 400, propylene glycol, ethanol, concentrated glycerin, triacetin, triethyl citrate, and benzyl alcohol <1> The oral pharmaceutical composition according to any one of to <3>.
The oral pharmaceutical composition as described in any one of <1>-<4> whose melting | fusing point of <5> active ingredient (A) is 0 degreeC or more and 100 degrees C or less.
<6> The oral pharmaceutical composition according to any one of <1> to <5>, wherein the active ingredient (A) further has a ring structure having 3 to 7 carbon atoms.
<7> At least an active ingredient (A) selected from the group consisting of a compound having a steroid skeleton, a compound having a phenothiazine skeleton, a compound having a thioxanthene skeleton, a compound having a butyrophenone skeleton, and a chloramphenicol fatty acid ester compound The oral pharmaceutical composition according to any one of <1> to <6>, which is one compound.
The compound having a <8> steroid skeleton is at least one selected from the group consisting of methenolone enanthate, testosterone enanthate, testosterone decanoate, testosterone undecanoate, nandrolone decanoate, and dexamethasone palmitate Yes,
The compound having a phenothiazine skeleton is at least one selected from the group consisting of fluphenazine enanthate, fluphenazine decanoate, pipothiazine palmitate, and perphenazine decanoate,
The compound having a thioxanthene skeleton is at least one selected from flupenthixol decanoate and zuclopenthixol decanoate,
The compound having a butyrophenone skeleton is at least one selected from haloperidol decanoic acid ester and bromperidol decanoate,
The oral pharmaceutical composition according to <7>, wherein the chloramphenicol fatty acid ester compound is at least one selected from chloramphenicol palmitic acid ester and chloramphenicol stearic acid ester.
<9> The compound according to any one of <1> to <8>, wherein the active ingredient (A) is at least one compound selected from the group consisting of a compound having a steroid skeleton and a chloramphenicol fatty acid ester compound Oral pharmaceutical composition.
<10> The oral pharmaceutical composition according to any one of <1> to <9>, wherein the active ingredient (A) is at least one selected from testosterone undecanoate and chloramphenicol palmitate.
<11> The oral pharmaceutical composition according to any one of <1> to <10>, wherein the dosage form is a capsule.
　本発明の実施形態によれば、消化液中で自発的かつ速やかに乳化物を形成し、その乳化物が消化液中で微細かつ安定に分散し得る経口医薬組成物が提供される。 According to an embodiment of the present invention, there is provided an oral pharmaceutical composition which spontaneously and rapidly forms an emulsion in a digestive fluid, and the emulsion can be finely and stably dispersed in the digestive fluid.
　以下、本発明を適用した経口医薬組成物の実施形態の一例について説明する。但し、本発明は、以下の実施形態に何ら限定されるものではなく、本発明の目的の範囲内において、適宜、変更を加えて実施することができる。 Hereinafter, an example of embodiment of the oral pharmaceutical composition to which this invention is applied is demonstrated. However, the present invention is not limited to the following embodiments at all, and modifications can be made as appropriate within the scope of the object of the present invention.
　本開示において「～」を用いて示された数値範囲は、「～」の前後に記載される数値をそれぞれ最小値及び最大値として含む範囲を意味する。
　本開示に段階的に記載されている数値範囲において、ある数値範囲で記載された上限値又は下限値は、他の段階的な記載の数値範囲の上限値又は下限値に置き換えてもよい。また、本開示に記載されている数値範囲において、ある数値範囲で記載された上限値又は下限値は、実施例に示されている値に置き換えてもよい。
　本開示において、２以上の好ましい態様の組み合わせは、より好ましい態様である。
　本開示において、各成分の量は、各成分に該当する物質が複数種存在する場合には、特に断らない限り、複数種の物質の合計量を意味する。 In the present disclosure, a numerical range indicated by using “to” means a range including numerical values described before and after “to” as the minimum value and the maximum value, respectively.
The upper limit value or the lower limit value described in a certain numerical value range may be replaced with the upper limit value or the lower limit value of the other stepwise description numerical value range in the numerical value range described stepwise in the present disclosure. Further, in the numerical range described in the present disclosure, the upper limit value or the lower limit value described in a certain numerical range may be replaced with the value shown in the example.
In the present disclosure, a combination of two or more preferred embodiments is a more preferred embodiment.
In the present disclosure, the amount of each component means the total amount of a plurality of types of substances unless a plurality of types of substances corresponding to each component are present.
［経口医薬組成物］
　本開示の経口医薬組成物は、炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、オクタノール／水分配係数の常用対数であるｌｏｇＰが６以上９以下の有効成分（Ａ）と、ポリオキシエチレン硬化ヒマシ油（Ｂ）と、トリグリセリド（Ｃ）と、親水性溶媒（Ｄ）と、を含み、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリドの含有量（Ｃ）＝３：１～９：１であり、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が１０質量部以上５０質量部以下である。 [Oral pharmaceutical composition]
The oral pharmaceutical composition of the present disclosure has a saturated hydrocarbon group having 7 to 18 carbon atoms, and an active ingredient (A) having a log P of 6 to 9 which is a common logarithm of octanol / water partition coefficient And polyoxyethylene hydrogenated castor oil (B), triglyceride (C) and hydrophilic solvent (D), and the content of polyoxyethylene hydrogenated castor oil (B) and the content of triglyceride (C) Weight ratio of polyoxyethylene hydrogenated castor oil (B): triglyceride content (C) = 3: 1 to 9: 1, polyoxyethylene hydrogenated castor oil (B), triglyceride (C) The content of the hydrophilic solvent (D) is 10 parts by mass or more and 50 parts by mass or less with respect to a total of 100 parts by mass of the hydrophilic solvent (D).
　本開示の経口医薬組成物は、消化液中で自発的かつ速やかに乳化物を形成し、その乳化物が消化液中で微細かつ安定に分散し得る。
　本開示の経口医薬組成物がこのような効果を奏し得る理由については明らかではないが、本発明者らは、以下のように推測している。但し、以下の理由は、本開示の経口医薬組成物を限定的に解釈するものではなく、一例として説明するものである。 The oral pharmaceutical composition of the present disclosure spontaneously and rapidly forms an emulsion in the digestive fluid, and the emulsion can be finely and stably dispersed in the digestive fluid.
Although it is not clear why the oral pharmaceutical composition of the present disclosure can produce such an effect, the present inventors speculate as follows. However, the following reasons are not to be interpreted as limiting the oral pharmaceutical composition of the present disclosure, but to be described as an example.
　本開示の経口医薬組成物は、所謂、自己乳化型製剤と称される製剤であり、有効成分を、自己乳化能を有する組成物に含有させ、この組成物と水又は消化液とが接触するだけで、自然に有効成分を含有する組成物が乳化して分散するように工夫されたものである。
　自己乳化型製剤を経口投与すると、水に難溶性の有効成分は、乳化物（即ち、乳化した製剤）の油相中から水相である消化液中に分配した後、小腸の粘膜から吸収される。この場合、消化液中で分散している乳化物の粒子径が小さいほど、粒子の比表面積が大きくなり、有効成分が効率的に消化液中に分配するため、小腸の粘膜からの吸収に対し、有利に働く。また、乳化物の分散粒子が消化液中で安定であるほど、有効成分の吸収に有利である。 The oral pharmaceutical composition of the present disclosure is a preparation referred to as a so-called self-emulsifying preparation, and an active ingredient is contained in a composition having a self-emulsifying ability, and this composition is brought into contact with water or digestive fluid. Only by itself, the composition containing the active ingredient is devised so as to be emulsified and dispersed.
When a self-emulsifying formulation is orally administered, the poorly water-soluble active ingredient is distributed from the oil phase of the emulsion (that is, the emulsified formulation) into the digestive fluid which is the water phase and then absorbed from the mucosa of the small intestine. Ru. In this case, the smaller the particle size of the emulsion dispersed in the digestive fluid, the larger the specific surface area of the particles, and the active ingredient is efficiently distributed in the digestive fluid, so absorption against the mucosa of the small intestine is more effective. Work in favor. Also, the more stable the dispersed particles of the emulsion are in the digestive fluid, the more advantageous for absorption of the active ingredient.
　本開示の経口医薬組成物では、炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、ｌｏｇＰが６以上９以下である、水に難溶性の有効成分（Ａ）と、界面活性剤であるポリオキシエチレン硬化ヒマシ油（Ｂ）と、脂質であるトリグリセリド（Ｃ）と、親水性溶媒（Ｄ）と、を特定比率で含むことにより、消化液中での自発的かつ速やかな乳化、及び、乳化物の消化液中での微細かつ安定な分散を実現し得る。
　詳細には、界面活性剤であるポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量を、脂質であるトリグリセリド（Ｃ）の含有量よりも多く含む、即ち、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリドの含有量（Ｃ）＝３：１～９：１であることにより、経口医薬組成物が消化液中で速やかに乳化物を形成し、その乳化物が消化液中で微細に分散し得ると推測される。
　また、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対する親水性溶媒（Ｄ）の含有量が１０質量部以上であることにより、経口医薬組成物全体が適度な親水性を示すため、消化液に触れてから乳化して分散するまでに要する時間（即ち、分散所要時間）が短くなる、即ち、経口医薬組成物が、消化液中で自発的にかつ速やかに乳化して分散し得ると推測される。
　さらに、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が５０質量部以下であることにより、相対的にポリオキシエチレン硬化ヒマシ油（Ｂ）及びトリグリセリド（Ｃ）の含有量が多くなるため、経口医薬組成物が消化液に触れた際に、微細な乳化物の分散粒子を形成し得ると推測される。 In the oral pharmaceutical composition of the present disclosure, a water-insoluble active ingredient (A) which has a saturated hydrocarbon group having 7 to 18 carbon atoms and has a log P of 6 to 9 and a surfactant Volatile and hydrogenated hydrogenated castor oil (B), lipid triglyceride (C), and hydrophilic solvent (D) at a specific ratio to spontaneously and rapidly emulsify in digestive fluid And fine and stable dispersion of the emulsion in the digestive fluid.
Specifically, the content of polyoxyethylene hydrogenated castor oil (B) which is a surfactant is larger than the content of triglyceride (C) which is a lipid, that is, polyoxyethylene hydrogenated castor oil (B) The mass ratio of the content to the content of triglyceride (C) is: content of polyoxyethylene hydrogenated castor oil (B): content of triglyceride (C) = 3: 1 to 9: 1, It is speculated that the oral pharmaceutical composition will rapidly form an emulsion in the digestive fluid and that the emulsion may be finely dispersed in the digestive fluid.
In addition, the content of the hydrophilic solvent (D) is 10 parts by mass or more with respect to a total of 100 parts by mass of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D). Since the entire pharmaceutical composition exhibits appropriate hydrophilicity, the time required for touching and emulsifying and dispersing the digestive fluid (i.e., the time required for dispersion) is shortened, that is, the oral pharmaceutical composition is in the digestive fluid. It is presumed that they can be emulsified and dispersed spontaneously and rapidly.
Furthermore, the content of the hydrophilic solvent (D) is 50 parts by mass or less with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D) As the content of polyoxyethylene hydrogenated castor oil (B) and triglyceride (C) relatively increases due to the formation of fine emulsion dispersed particles when the oral pharmaceutical composition is in contact with the digestive fluid. It is guessed to get.
　本開示の経口医薬組成物に対し、特開２０１５－１２０７００号公報に記載の製剤及び特開２０１６－７４６７７号公報に記載の製剤は、脂質としてモノグリセリド及び／又はジグリセリドを含み、トリグリセリドを含んでいない。
　本発明者らは、トリグリセリドの代わりにモノグリセリドを含む製剤では、本開示の経口医薬組成物のように、消化液中で微細な乳化物の分散粒子を形成することができないこと、また、トリグリセリドの代わりにモノグリセリドを含む製剤により形成された乳化物は、本開示の経口医薬組成物により形成された乳化物のように、消化液中で安定に分散することができないことを確認している（例えば、後述の比較例１６及び比較例１７参照）。
　なお、トリグリセリドの代わりにモノグリセリドを含む製剤により形成された乳化物が、消化液中で安定に分散することができない理由については、以下のように推測される。
　自己乳化型製剤において、脂質は、自己乳化後の乳化物の油相を形成し、有効成分を保持し得る。モノグリセリド及びジグリセリドは、トリグリセリドに比べて水溶性が高いため、自己乳化後の乳化物の油相中から水相である消化液中へと分配しやすく、乳化物の油相が経時で減ると考えられる。有効成分（Ａ）のような脂溶性が比較的高い有効成分の場合、乳化物の油相が減ると乳化物中に留まることができず、水相である消化液中に分配後、析出してしまうと推測される。また、モノグリセリド及びジグリセリドは、トリグリセリドに比べて、エステル結合近傍のアシル基が少なく、立体障害が少ないため、消化酵素であるリパーゼの活性中心が近接しやすく、リパーゼによる分解を受けやすい。モノグリセリド及びジグリセリドがリパーゼによる分解を受けると、水溶性が更に高くなり、自己乳化後の乳化物の油相中から水相である消化液中へとより分配しやすくなるため、乳化物の油相が更に減少し、有効成分を保持することができなくなると推測される。 In contrast to the oral pharmaceutical composition of the present disclosure, the preparation described in JP-A-2015-120700 and the preparation described in JP-A-2016-74677 contain monoglycerides and / or diglycerides as lipids and do not contain triglycerides. .
The present inventors can not form dispersed particles of a fine emulsion in a digestive fluid, as in the oral pharmaceutical composition of the present disclosure, in a preparation containing monoglyceride instead of triglyceride, and triglyceride It has been confirmed that emulsions formed by preparations containing monoglycerides instead can not be stably dispersed in the digestive fluid, as emulsions formed by oral pharmaceutical compositions of the present disclosure (e.g. (See Comparative Example 16 and Comparative Example 17 described later).
The reason why the emulsion formed by the preparation containing monoglyceride instead of triglyceride can not be stably dispersed in the digestive fluid is presumed as follows.
In self-emulsifying formulations, the lipids form the oil phase of the emulsion after self-emulsification and can retain the active ingredient. Since monoglycerides and diglycerides are more soluble in water than triglycerides, they are likely to be distributed from the oil phase of the emulsion after self-emulsification into the digestive fluid which is the water phase, and it is thought that the oil phase of the emulsion decreases over time. Be In the case of an active ingredient having a relatively high lipid solubility such as the active ingredient (A), it can not stay in the emulsion when the oil phase of the emulsion decreases, and it is deposited after being distributed in the digestive fluid which is the aqueous phase. It is presumed that In addition, monoglycerides and diglycerides have less acyl groups near the ester bond and less steric hindrance than triglycerides, so the active centers of lipases, which are digestive enzymes, easily come close to one another and are easily degraded by lipases. When monoglycerides and diglycerides are degraded by lipase, their water solubility is further enhanced, and they are more easily distributed in the oil phase of the emulsion after self-emulsification into the digestive fluid which is the water phase, so the oil phase of the emulsion Is further reduced, and it is presumed that the active ingredient can not be retained.
　特表２０１７－５１８２９４号公報に記載の製剤は、界面活性剤としてポリオキシル３５ヒマシ油を含み、ポリオキシエチレン硬化ヒマシ油を含んでいない。
　本発明者らは、ポリオキシエチレン硬化ヒマシ油の代わりにポリオキシル３５ヒマシ油を含む製剤により形成された乳化物は、本開示の経口医薬組成物により形成された乳化物のように、消化液中で安定に分散することができないことを確認している（例えば、後述の比較例１９、比較例２７、及び比較例３５参照）。
　特表２０１３－５１６４３３号公報に記載の製剤は、ポリオキシエチレン硬化ヒマシ油とトリグリセリドとを含むが、ポリオキシエチレン硬化ヒマシ油よりもトリグリセリドを多く含んでいる点で、本開示の経口医薬組成物とは異なる。
　界面活性剤であるポリオキシエチレン硬化ヒマシ油の含有量に対し、脂質であるトリグリセリドの含有量が多い製剤では、本開示の経口医薬組成物のように、消化液中で微細な乳化物の分散粒子を形成することができないと推測される。
　特許第５３１３３４３号公報に記載の製剤は、有効成分であり、かつ、脂質であるイコサペント酸（ＥＰＡ）等のω３多価不飽和脂肪酸のエチルエステルを含むが、有効成分とは別に脂質であるトリグリセリドを含んでいない点、及び界面活性剤であるポリオキシエチレン硬化ヒマシ油の含有量に対し、有効成分であり、かつ、脂質であるイコサペント酸（ＥＰＡ）等のω３多価不飽和脂肪酸のエチルエステルの含有量が多い点で、本開示の経口医薬組成物とは異なる。
　したがって、特許第５３１３３４３号公報に記載の製剤では、本開示の経口医薬組成物のように、消化液中で微細な乳化物の分散粒子を形成することができないと推測される。 The preparation described in JP-A-2017-518294 contains polyoxyl 35 castor oil as a surfactant and does not contain polyoxyethylene hydrogenated castor oil.
The inventors formed an emulsion formed by a preparation containing polyoxyl 35 castor oil instead of polyoxyethylene hydrogenated castor oil in a digestive fluid, as an emulsion formed by the oral pharmaceutical composition of the present disclosure. It has been confirmed that the dispersion can not be stably carried out (see, for example, Comparative Example 19, Comparative Example 27, and Comparative Example 35 described later).
Although the preparation described in JP-A-2013-516433 contains polyoxyethylene hydrogenated castor oil and triglycerides, the oral pharmaceutical composition of the present disclosure contains more triglycerides than polyoxyethylene hydrogenated castor oil. It is different from
In a preparation having a higher content of triglycerides, which is lipid, relative to the content of polyoxyethylene hydrogenated castor oil, which is a surfactant, dispersion of a fine emulsion in digestive fluid as in the oral pharmaceutical composition of the present disclosure It is speculated that particles can not be formed.
The preparation described in Japanese Patent No. 5313343 is an active ingredient, and contains ethyl ester of ω3 polyunsaturated fatty acid such as icosapentonic acid (EPA) which is a lipid, but triglyceride which is a lipid separately from the active ingredient And the content of polyoxyethylene hydrogenated castor oil which is a surfactant, and an ethyl ester of ω3 polyunsaturated fatty acid such as icosapentic acid (EPA) which is an active ingredient and which is a lipid It differs from the oral pharmaceutical composition of the present disclosure in that it has a high content of
Therefore, it is assumed that the preparation described in Patent No. 5313343 can not form dispersed particles of a fine emulsion in a digestive fluid as in the oral pharmaceutical composition of the present disclosure.
　また、特開２０１５－１２０７００号公報、特表２０１７－５１８２９４号公報、特表２０１３－５１６４３３号公報、特許第５３１３３４３号公報、及び特開２０１６－７４６７７号公報では、消化液中で微細な乳化物を得るための技術について明確な記載はなく、また、消化液中での乳化物の分散粒子の安定性については何ら着目していない。 Further, in JP-A-2015-120700, JP-A-2017-518294, JP-A-2013-516433, Patent No. 5313343, and JP-A-2016-74677, it is possible to use a fine emulsion in a digestive fluid. There is no clear description of the technique for obtaining, and no attention is paid to the stability of the dispersed particles of the emulsion in the digestive fluid.
　以下、本開示の経口医薬組成物における各成分について詳細に説明する。 Hereinafter, each component in the oral pharmaceutical composition of this indication is demonstrated in detail.
＜有効成分（Ａ）＞
　本開示の経口医薬組成物は、炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、オクタノール／水分配係数（所謂、水相中における溶質の濃度に対するオクタノール相中における溶質の濃度の割合）の常用対数であるｌｏｇＰが６以上９以下の有効成分（Ａ）を含む。 <Active ingredient (A)>
The oral pharmaceutical composition of the present disclosure has a saturated hydrocarbon group having a carbon number of 7 to 18 and an octanol / water partition coefficient (so-called concentration of solute in octanol phase relative to concentration of solute in aqueous phase) And the active ingredient (A) having a log P of 6 or more and 9 or less.
　有効成分（Ａ）は、炭素数が７以上１８以下の飽和炭化水素基を有し、炭素数が１０以上１６以下の飽和炭化水素基を有することが好ましい。
　炭素数が７以上１８以下の飽和炭化水素基を有する有効成分（Ａ）は、トリグリセリド（Ｃ）との親和性が良好であるため、自己乳化後、有効成分（Ａ）が乳化物の油相に保持されやすい。
　また、有効成分（Ａ）が有する飽和炭化水素基の炭素数が７以上であると、有効成分が小腸上皮にて吸収された後に、血管に加えてリンパ管にも移行することが期待できる。リンパ管への有効成分の移行は、リンパ管に薬物を送達させたい場合に加え、肝初回通過による有効成分の全身曝露量の低下を回避できる点で有効である。また、流速の遅いリンパ管に薬物を送達させることで、有効成分が全身循環血に移行するのを遅延させることができ、有効成分が持続的な作用を示すことが期待される。
　また、有効成分（Ａ）が有する飽和炭化水素基の炭素数が１８以下であると、製剤中での溶解性に優れる傾向がある。
　なお、炭素数が１８を超える有効成分、及び／又は、不飽和炭化水素基を有する有効成分は、製剤中での溶解性に劣る傾向がある。 The active ingredient (A) preferably has a saturated hydrocarbon group having 7 to 18 carbon atoms and has a 10 to 16 carbon saturated hydrocarbon group.
The active ingredient (A) having a saturated hydrocarbon group having 7 or more and 18 or less carbon atoms has good affinity to triglyceride (C), so after self emulsification, the active ingredient (A) is the oil phase of the emulsion It is easy to be held by.
In addition, when the carbon number of the saturated hydrocarbon group of the active ingredient (A) is 7 or more, after the active ingredient is absorbed in the small intestine epithelium, it can be expected to be transferred to lymphatic vessels in addition to blood vessels. The transfer of the active ingredient to the lymphatic vessels is effective in addition to the case where it is desired to deliver the drug to the lymphatic vessels, the reduction of the systemic exposure of the active ingredient by first pass of the liver can be avoided. In addition, the drug can be delivered to a low flow rate lymphatic vessel to delay the transfer of the active ingredient to systemic circulation, and it is expected that the active ingredient exhibits a sustained action.
Moreover, when the carbon number of the saturated hydrocarbon group which an active ingredient (A) has is 18 or less, there exists a tendency to be excellent in the solubility in a formulation.
The active ingredient having a carbon number of more than 18 and / or the active ingredient having an unsaturated hydrocarbon group tends to have poor solubility in the preparation.
　有効成分（Ａ）のｌｏｇＰは、６以上９以下であり、好ましくは６．５以上８．７以下であり、より好ましくは７以上８．５以下である。
　本開示の経口医薬組成物は、所謂、自己乳化型製剤であり、有効成分は、乳化物（即ち、乳化した経口医薬組成物）の油相中から水相である消化液中に分配した後、小腸の粘膜から吸収される。有効成分が水相（即ち、消化液）又は乳化物の油相のいずれに分配されるかは、有効成分のｌｏｇＰによって決まる。ｌｏｇＰが低すぎる有効成分は、乳化物の油相に分配され難い。一方、ｌｏｇＰが高すぎる有効成分は、乳化物の油相中から水相である消化液中に分配しないため、小腸の粘膜から吸収されることなく、排出されてしまう。
　本開示の経口医薬組成物において、有効成分は、経口医薬組成物が消化液中で自己乳化した際には、乳化物の油相に分配され、その後、経時で水相である消化液中に分配される必要がある。このような観点から、本開示の経口医薬組成物では、ｌｏｇＰが６以上９以下の有効成分（Ａ）を含む。 The log P of the active ingredient (A) is 6 or more and 9 or less, preferably 6.5 or more and 8.7 or less, and more preferably 7 or more and 8.5 or less.
The oral pharmaceutical composition of the present disclosure is a so-called self-emulsifying formulation, and the active ingredient is distributed from the oil phase of the emulsion (ie, the emulsified oral pharmaceutical composition) into the digestive fluid which is the water phase. , Is absorbed from the mucosa of the small intestine. Whether the active ingredient is distributed in the aqueous phase (i.e., the digestive juice) or the oil phase of the emulsion depends on the logP of the active ingredient. Active ingredients with logP too low are difficult to partition into the oil phase of the emulsion. On the other hand, since the active ingredient having a logP too high does not partition into the digestive fluid which is the water phase from the oil phase of the emulsion, it is discharged without being absorbed from the mucous membrane of the small intestine.
In the oral pharmaceutical composition of the present disclosure, the active ingredient is distributed in the oil phase of the emulsion when the oral pharmaceutical composition is self-emulsified in the digestive fluid, and then in the digestive fluid which is the aqueous phase over time. It needs to be distributed. From such a viewpoint, the oral pharmaceutical composition of the present disclosure contains an active ingredient (A) having a logP of 6 or more and 9 or less.
　本開示において、オクタノール／水分配係数の常用対数である「ｌｏｇＰ」は、Viswanadhan, V. N.; Ghose, A. K.; Revankar, G. R. and Robins, R. K., J. Chem. Inf. Comput.Sci., 1989, 29, 3, 163-172; Klopman, G.; Li, Ju-Yun.; Wang, S.; Dimayuga, M.: J. Chem. Inf. Comput. Sci., 1994, 34, 752の記載に基づき、ChemAxonを用いて求めた値である。 In the present disclosure, “logP”, which is the common logarithm of octanol / water partition coefficient, is Viswanadhan, V. N .; Ghose, A. K .; Revankar, G. R. and Robins, R. K., J. Chem. Klopman, G .; Li, Ju-Yun .; Wang, S .; Dimayuga, M .: J. Chem. Inf. Comput. Sci., Inf. Comput. Sci., 1989, 29, 3, 163-172; , 1994, 34, 752 and is a value determined using ChemAxon.
　有効成分（Ａ）の融点は、特に制限されないが、例えば、０℃以上１００℃以下であることが好ましい。
　有効成分の融点が０℃未満であると、経口医薬組成物を冷蔵保管した際に、有効成分以外の成分が凝固し、有効成分の分離が起こる可能性がある。これに対し、有効成分（Ａ）の融点が０℃以上であると、このような可能性を低減し得る。
　有効成分（Ａ）の融点が１００℃以下であると、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）に、有効成分（Ａ）を溶解させる際に要するエネルギーをより低減し得る。
　また、有効成分の融点が１００℃以下である場合、固形状の医薬組成物として製造し、保管すると、温度上昇に伴い、有効成分が融解することがある。しかし、本開示の経口医薬組成物は、液状の医薬組成物であるため、有効成分（Ａ）の融点が１００℃以下であっても、取り扱い性が容易である。 The melting point of the active ingredient (A) is not particularly limited, but is preferably, for example, 0 ° C. or more and 100 ° C. or less.
When the oral pharmaceutical composition is stored under refrigeration, if the melting point of the active ingredient is less than 0 ° C., components other than the active ingredient may coagulate and separation of the active ingredient may occur. On the other hand, such a possibility may be reduced if the melting point of the active ingredient (A) is 0 ° C. or higher.
It is required to dissolve the active ingredient (A) in polyoxyethylene hydrogenated castor oil (B), triglyceride (C) and hydrophilic solvent (D) as the melting point of the active ingredient (A) is 100 ° C. or less Energy can be reduced more.
In addition, when the melting point of the active ingredient is 100 ° C. or less, when it is manufactured as a solid pharmaceutical composition and stored, the active ingredient may melt as the temperature rises. However, since the oral pharmaceutical composition of the present disclosure is a liquid pharmaceutical composition, it is easy to handle even when the melting point of the active ingredient (A) is 100 ° C. or less.
　有効成分（Ａ）は、例えば、トリグリセリド（Ｃ）に対する溶解性の観点から、炭素数が３以上７以下の環構造を更に有することが好ましい。
　炭素数が３以上７以下の環構造としては、シクロペンタン環、シクロヘキサン環、ベンゼン環、ピペリジン環、ピペラジン環、チアン環、シクロヘキセノン環、２，５－シクロヘキサジエン－１－オン環等の環構造が挙げられる。
　炭素数が３以上７以下の環構造を更に有する化合物の中でも、有効成分（Ａ）としては、トリグリセリド（Ｃ）に対する溶解性により優れるとの観点から、ステロイド骨格を有する化合物、フェノチアジン骨格を有する化合物、チオキサンテン骨格を有する化合物、ブチロフェノン骨格を有する化合物、及びクロラムフェニコール脂肪酸エステル化合物からなる群より選ばれる少なくとも１種の化合物がより好ましく、ステロイド骨格を有する化合物及びクロラムフェニコール脂肪酸エステル化合物からなる群より選ばれる少なくとも１種の化合物が更に好ましい。 The active ingredient (A) preferably further has a ring structure having 3 or more and 7 or less carbon atoms, for example, from the viewpoint of solubility in triglyceride (C).
The ring structure having 3 to 7 carbon atoms is a ring such as cyclopentane ring, cyclohexane ring, benzene ring, piperidine ring, piperazine ring, thiaane ring, cyclohexenone ring, 2,5-cyclohexadien-1-one ring, etc. The structure is mentioned.
Among the compounds further having a ring structure having 3 to 7 carbon atoms, as the active ingredient (A), a compound having a steroid skeleton, a compound having a phenothiazine skeleton from the viewpoint of being more excellent in solubility in triglyceride (C) , A compound having a thioxanthene skeleton, a compound having a butyrophenone skeleton, and at least one compound selected from the group consisting of a chloramphenicol fatty acid ester compound are more preferable, and a compound having a steroid skeleton and a chloramphenicol fatty acid ester compound Further preferred is at least one compound selected from the group consisting of
　ステロイド骨格を有する化合物の具体例としては、メテノロンエナント酸エステル、テストステロンエナント酸エステル、テストステロンデカノアート、ウンデカン酸テストステロン、ナンドロロンデカン酸エステル、デキサメタゾンパルミチン酸エステル等が挙げられる。
　フェノチアジン骨格を有する化合物の具体例としては、フルフェナジンエナント酸エステル、フルフェナジンデカン酸エステル、パルミチン酸ピポチアジン、ペルフェナジンデカノアート等が挙げられる。
　チオキサンテン骨格を有する化合物の具体例としては、フルペンチキソールデカノアート、ズクロペンチキソールデカノアート等が挙げられる。
　ブチロフェノン骨格を有する化合物の具体例としては、ハロペリドールデカン酸エステル、デカン酸ブロムペリドール等が挙げられる。
　クロラムフェニコール脂肪酸エステル化合物の具体例としては、クロラムフェニコールパルミチン酸エステル、クロラムフェニコールステアリン酸エステル等が挙げられる。 Specific examples of the compound having a steroid skeleton include methenolone enanthate, testosterone enanthate, testosterone decanoate, testosterone undecanoate, nandrolone decanoate, dexamethasone palmitate, and the like.
Specific examples of the compound having a phenothiazine skeleton include fluphenazine enanthate, fluphenazine decanoate, pipothiazine palmitate, perphenazine decanoate and the like.
Specific examples of the compound having a thioxanthene skeleton include flupenthixol decanoate and zuclopenthixol decanoate.
Specific examples of the compound having a butyrophenone skeleton include haloperidol decanoic acid ester and bromoperidol decanoate.
Specific examples of the chloramphenicol fatty acid ester compound include chloramphenicol palmitic acid ester, chloramphenicol stearic acid ester and the like.
　有効成分（Ａ）のトリグリセリドに対する溶解性が高いほど、経口医薬組成物中に有効成分（Ａ）をより高濃度に含ませることができる。経口医薬組成物中に含ませることができる有効成分（Ａ）の濃度が高いほど、製剤の質量を小さくすることが可能となるため、服用性が良好な製剤とすることができる。 The higher the solubility of the active ingredient (A) in triglycerides, the higher the concentration of the active ingredient (A) can be contained in the oral pharmaceutical composition. The higher the concentration of the active ingredient (A) that can be contained in the oral pharmaceutical composition, the smaller the mass of the preparation, and therefore, the preparation can be made more favorable for taking.
　例えば、トリグリセリド（Ｃ）に対する溶解性により優れ、かつ、ｌｏｇＰ及び融点がより好適であるとの観点からは、有効成分（Ａ）としては、ウンデカン酸テストステロン及びクロラムフェニコールパルミチン酸エステルから選ばれる少なくとも１種が特に好ましい。 For example, the active ingredient (A) is selected from testosterone undecanoate and chloramphenicol palmitate as the active ingredient (A) from the viewpoint of being more excellent in solubility in triglyceride (C) and having more suitable log P and melting point. At least one is particularly preferred.
　有効成分（Ａ）としては、上記の化合物以外にも、塩酸パルミチン酸クリンダマイシン、パルミチン酸ネオマイシン、パリペリドンパルミチン酸エステル、ステアリン酸バロマシクロビル、ラニナミビルオクタン酸エステル水和物等の化合物が挙げられる。
　なお、既述の化合物のうち、パリペリドンパルミチン酸エステル（融点：１１４℃）及びラニナミビルオクタン酸エステル水和物（融点：２２４℃）以外の化合物は、全て融点が０℃以上１００℃以下である。 As the active ingredient (A), in addition to the above-mentioned compounds, compounds such as clindamycin palmitate, neomycin palmitate, paliperidone palmitate, valomaciclovir stearate, rananinamivir octanoate hydrate and the like can be mentioned. .
Among the compounds described above, the compounds other than paliperidone palmitic acid ester (melting point: 114 ° C.) and raninamivir octanoate hydrate (melting point: 224 ° C.) all have a melting point of 0 ° C. or more and 100 ° C. or less is there.
　本開示の経口医薬組成物は、有効成分（Ａ）を１種のみ含んでいてもよく、２種以上含んでいてもよい。 The oral pharmaceutical composition of the present disclosure may contain only one type of active ingredient (A), or may contain two or more types.
　本開示の経口医薬組成物中における有効成分（Ａ）の含有率は、特に制限されない。
　有効成分の濃度が高いほど、製剤の質量を小さくできるため、服用性が良好な製剤を実現できる。このような観点から、本開示の経口医薬組成物中における有効成分（Ａ）の含有率は、経口医薬組成物の全量に対し、５質量％以上が好ましく、８質量％以上がより好ましく、１０質量％以上が更に好ましい。
　本開示の経口医薬組成物中における有効成分（Ａ）の含有率の上限は、特に制限されず、例えば、保管中に有効成分が析出し難いとの観点から、経口医薬組成物の全量に対し、６０質量％以下が好ましく、５５質量％以下がより好ましく、５０質量％以下が更に好ましい。 The content rate of the active ingredient (A) in the oral pharmaceutical composition of the present disclosure is not particularly limited.
The higher the concentration of the active ingredient, the smaller the mass of the preparation, so that a preparation with good administration can be realized. From such a viewpoint, the content of the active ingredient (A) in the oral pharmaceutical composition of the present disclosure is preferably 5% by mass or more, more preferably 8% by mass or more, based on the total amount of the oral pharmaceutical composition. % Or more is more preferable.
The upper limit of the content of the active ingredient (A) in the oral pharmaceutical composition of the present disclosure is not particularly limited. For example, from the viewpoint that the active ingredient hardly precipitates during storage, relative to the total amount of the oral pharmaceutical composition. 60 mass% or less is preferable, 55 mass% or less is more preferable, and 50 mass% or less is still more preferable.
＜ポリオキシエチレン硬化ヒマシ油（Ｂ）＞
　本開示の経口医薬組成物は、ポリオキシエチレン硬化ヒマシ油（Ｂ）を含む。
　本開示の経口医薬組成物において、ポリオキシエチレン硬化ヒマシ油（Ｂ）は、消化液中での乳化物の分散粒子の微細化に寄与する。また、ポリオキシエチレン硬化ヒマシ油（Ｂ）は、消化液中での乳化物の分散粒子の安定性の向上に寄与する。さらに、ポリオキシエチレン硬化ヒマシ油（Ｂ）は、有効成分（Ａ）の濃度の向上に寄与する。 <Polyoxyethylene Cured Castor Oil (B)>
The oral pharmaceutical composition of the present disclosure comprises polyoxyethylene hydrogenated castor oil (B).
In the oral pharmaceutical composition of the present disclosure, polyoxyethylene hydrogenated castor oil (B) contributes to the refinement of dispersed particles of the emulsion in the digestive fluid. Moreover, polyoxyethylene hydrogenated castor oil (B) contributes to the improvement of the stability of the dispersed particles of the emulsion in the digestive fluid. Furthermore, polyoxyethylene hydrogenated castor oil (B) contributes to the improvement of the concentration of the active ingredient (A).
　ポリオキシエチレン硬化ヒマシ油（Ｂ）は、ヒマシ油に水素を添加した硬化ヒマシ油に酸化エチレンが付加重合した化合物である。 The polyoxyethylene hydrogenated castor oil (B) is a compound obtained by addition polymerization of ethylene oxide to hydrogenated castor oil obtained by adding hydrogen to castor oil.
　ポリオキシエチレン硬化ヒマシ油（Ｂ）における酸化エチレンの平均重合度は、２０～１００が好ましく、４０～１００がより好ましく、４０～６０が更に好ましい。
　酸化エチレンの平均重合度が２０以上であると、消化液中での乳化物の分散粒子の安定性がより向上する傾向がある。
　酸化エチレンの平均重合度が１００以下であると、消化液中での乳化物の分散粒子がより微細化する傾向がある。 The average polymerization degree of ethylene oxide in the polyoxyethylene hydrogenated castor oil (B) is preferably 20 to 100, more preferably 40 to 100, and still more preferably 40 to 60.
When the average degree of polymerization of ethylene oxide is 20 or more, the stability of dispersed particles of the emulsion in the digestive fluid tends to be further improved.
When the average degree of polymerization of ethylene oxide is 100 or less, dispersed particles of the emulsion in the digestive fluid tend to be finer.
　酸化エチレンの平均重合度が２０～１００であるポリオキシエチレン硬化ヒマシ油（Ｂ）の具体例としては、ポリオキシエチレン（２０）硬化ヒマシ油、ポリオキシエチレン（４０）硬化ヒマシ油、ポリオキシエチレン（５０）硬化ヒマシ油、ポリオキシエチレン（６０）硬化ヒマシ油、ポリオキシエチレン（１００）硬化ヒマシ油等が挙げられる。なお、括弧内の数値は、酸化エチレンの平均重合度を示す。 Specific examples of polyoxyethylene hydrogenated castor oil (B) having an average polymerization degree of ethylene oxide of 20 to 100 include polyoxyethylene (20) hydrogenated castor oil, polyoxyethylene (40) hydrogenated castor oil, polyoxyethylene (50) hydrogenated castor oil, polyoxyethylene (60) hydrogenated castor oil, polyoxyethylene (100) hydrogenated castor oil and the like. In addition, the numerical value in a parenthesis shows the average polymerization degree of ethylene oxide.
　ポリオキシエチレン硬化ヒマシ油（Ｂ）としては、市販品を用いることができる。酸化エチレンの平均重合度により種々のポリオキシエチレン硬化ヒマシ油が市販されている。
　ポリオキシエチレン硬化ヒマシ油（Ｂ）の市販品の例としては、ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－２０（ポリオキシエチレン（２０）硬化ヒマシ油、日光ケミカルズ（株））、ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－４０（ポリオキシエチレン（４０）硬化ヒマシ油、日光ケミカルズ（株））、Ｋｏｌｌｉｎｐｈｏｒ（登録商標）　ＲＨ４０（ポリオキシエチレン（４０）硬化ヒマシ油、ＢＡＳＦ社）、ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－５０（ポリオキシエチレン（５０）硬化ヒマシ油、日光ケミカルズ（株））、ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－６０（ポリオキシエチレン（６０）硬化ヒマシ油、日光ケミカルズ（株））、ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－１００（ポリオキシエチレン（１００）硬化ヒマシ油、日光ケミカルズ（株））等が挙げられる。 A commercial item can be used as polyoxyethylene hydrogenated castor oil (B). Various polyoxyethylene hydrogenated castor oils are commercially available depending on the average degree of polymerization of ethylene oxide.
As a commercial example of polyoxyethylene hydrogenated castor oil (B), NIKKOL (registered trademark) HCO-20 (polyoxyethylene (20) hydrogenated castor oil, Nikko Chemicals Co., Ltd.), NIKKOL (registered trademark) HCO- 40 (polyoxyethylene (40) hydrogenated castor oil, Nikko Chemicals Co., Ltd.), Kollinphor (registered trademark) RH 40 (polyoxyethylene (40) hydrogenated castor oil, BASF Corporation), NIKKOL (registered trademark) HCO-50 (poly) Oxyethylene (50) hydrogenated castor oil, Nikko Chemicals Co., Ltd., NIKKOL® HCO-60 (Polyoxyethylene (60) hydrogenated castor oil, Nikko Chemicals Co., Ltd.), NIKKOL® HCO-100 (Polyoxyethylene (100) hydrogenated castor oil, Nikko Chemicals (stock ), And the like.
　本開示の経口医薬組成物は、ポリオキシエチレン硬化ヒマシ油（Ｂ）を１種のみ含んでいてもよく、２種以上含んでいてもよい。 The oral pharmaceutical composition of the present disclosure may contain only one type of polyoxyethylene hydrogenated castor oil (B), or may contain two or more types.
　本開示の経口医薬組成物は、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリド（Ｃ）の含有量＝３：１～９：１であり、好ましくは４：１～９：１であり、より好ましくは５：１～９：１である。
　ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリド（Ｃ）の含有量＝３：１～９：１であると、経口医薬組成物が消化液中で速やかに乳化物を形成し、その乳化物が消化液中で微細に分散し得る。 In the oral pharmaceutical composition of the present disclosure, the mass ratio of the content of polyoxyethylene hydrogenated castor oil (B) to the content of triglyceride (C) is the content of polyoxyethylene hydrogenated castor oil (B): triglyceride The content of (C) is 3: 1 to 9: 1, preferably 4: 1 to 9: 1, and more preferably 5: 1 to 9: 1.
The mass ratio of the polyoxyethylene hydrogenated castor oil (B) content to the triglyceride (C) content is the same as the polyoxyethylene hydrogenated castor oil (B) content: triglyceride (C) content = 3 If it is 1 to 9: 1, the oral pharmaceutical composition can rapidly form an emulsion in the digestive fluid, and the emulsion can be finely dispersed in the digestive fluid.
＜トリグリセリド（Ｃ）＞
　本開示の経口医薬組成物は、トリグリセリド（Ｃ）を含む。
　本開示の経口医薬組成物において、トリグリセリド（Ｃ）は、自己乳化後の乳化物の油相に含まれ、有効成分（Ａ）の保持に寄与し得る。 <Triglyceride (C)>
The oral pharmaceutical composition of the present disclosure contains triglyceride (C).
In the oral pharmaceutical composition of the present disclosure, triglyceride (C) is contained in the oil phase of the emulsion after self-emulsification, and may contribute to retention of the active ingredient (A).
　トリグリセリドは、１分子のグリセリンに３分子の脂肪酸がエステル結合したアシルグリセロールである。 A triglyceride is an acylglycerol in which three molecules of fatty acid are ester bonded to one molecule of glycerol.
　トリグリセリド（Ｃ）は、中鎖脂肪酸トリグリセリドであってもよく、長鎖脂肪酸トリグリセリドであってもよいが、経口医薬組成物が消化液中でより微細な乳化物の分散粒子を形成し得るとの観点から、長鎖脂肪酸トリグリセリドが好ましい。 The triglyceride (C) may be medium chain fatty acid triglyceride or long chain fatty acid triglyceride, but the oral pharmaceutical composition can form dispersed particles of finer emulsion in digestive fluid From the viewpoint, long chain fatty acid triglyceride is preferred.
　本開示において、「中鎖脂肪酸トリグリセリド」とは、脂肪酸鎖の平均炭素数が６以上１２以下であるトリグリセリドを意味する。
　脂肪酸鎖の平均炭素数は、トリグリセリドを構成する脂肪酸（即ち、構成脂肪酸）の炭素数（例えば、カプリル酸（ＩＵＰＡＣ系統名：オクタン酸）であれば８、カプリン酸（ＩＵＰＡＣ系統名：デカン酸）であれば１０、ラウリン酸（ＩＵＰＡＣ系統名：ドデカン酸）であれば１２））を構成脂肪酸の組成比によって加重平均したものである。構成脂肪酸は、飽和脂肪酸であってもよく、不飽和脂肪酸であってもよく、好ましくは飽和脂肪酸である。中鎖脂肪酸トリグリセリドは、天然物由来であってもよく、合成脂肪酸のトリグリセリドであってもよい。 In the present disclosure, “medium-chain fatty acid triglyceride” means triglycerides in which the average carbon number of fatty acid chains is 6 or more and 12 or less.
The average carbon number of the fatty acid chain is 8 if the carbon number of the fatty acid constituting the triglyceride (ie, constituent fatty acid) (for example, caprylic acid (IUPAC family name: octanoic acid) 8 and capric acid (IUPAC family name: decanoic acid) 10, and 12) lauric acid (IUPAC strain name: dodecanoic acid) by the composition ratio of the constituent fatty acids. The constituent fatty acids may be saturated fatty acids or unsaturated fatty acids, preferably saturated fatty acids. The medium chain fatty acid triglyceride may be derived from natural products or may be a triglyceride of synthetic fatty acid.
　本開示において、「長鎖脂肪酸トリグリセリド」とは、脂肪酸鎖の平均炭素数が１２を超えるトリグリセリドを意味する。
　長鎖脂肪酸トリグリセリドとしては、脂肪酸鎖の平均炭素数が１４以上２４以下の長鎖脂肪酸トリグリセリドが好ましい。
　長鎖脂肪酸トリグリセリドの構成脂肪酸は、飽和脂肪酸であってもよく、不飽和脂肪酸であってもよい。長鎖脂肪酸トリグリセリドは、天然の長鎖脂肪酸トリグリセリドに相当する植物油であってもよく、合成脂肪酸のトリグリセリドであってもよい。
　植物油は、植物の種子又は堅果由来の油分である。植物油としては、ダイズ油、綿実油、菜種油、ゴマ油、サフラワー油、コーン油、落花生油、オリーブ油、ヤシ油、シソ油、ヒマシ油等が挙げられる。植物油の中でも、長鎖脂肪酸トリグリセリドとしては、入手容易性及び経口投与実績の観点から、ダイズ油が好ましい。 In the present disclosure, "long-chain fatty acid triglyceride" means triglycerides in which the average carbon number of the fatty acid chain exceeds 12.
As long-chain fatty acid triglycerides, long-chain fatty acid triglycerides in which the average carbon number of fatty acid chains is 14 or more and 24 or less are preferable.
The constituent fatty acids of the long chain fatty acid triglyceride may be saturated fatty acids or unsaturated fatty acids. The long chain fatty acid triglyceride may be a vegetable oil corresponding to natural long chain fatty acid triglyceride, or may be a synthetic fatty acid triglyceride.
Vegetable oils are oils derived from plant seeds or nuts. Examples of vegetable oils include soybean oil, cottonseed oil, rapeseed oil, sesame oil, safflower oil, corn oil, peanut oil, olive oil, coconut oil, perilla oil, castor oil and the like. Among vegetable oils, soybean oil is preferable as long-chain fatty acid triglyceride from the viewpoint of availability and oral administration results.
　トリグリセリド（Ｃ）としては、市販品を用いることができる。
　中鎖脂肪酸トリグリセリドの市販品の例としては、Ｓａｓｏｌ社の「Ｍｉｇｌｙｏｌ（登録商標）　８１２」（トリ（カプリル酸／カプリン酸）グリセリル）、「Ｍｉｇｌｙｏｌ（登録商標）　８１０」（トリ（カプリル酸／カプリン酸）グリセリル）、花王（株）の「ココナード（登録商標）　ＲＫ」（トリカプリル酸グリセリル）、「ココナード（登録商標）　ＭＴ」（トリ（カプリル酸／カプリン酸）グリセリル）、「ココナード（登録商標）　ＭＴ－Ｎ」（トリ（カプリル酸／カプリン酸）グリセリル）、「ココナード（登録商標）　ＭＬ」（トリ（カプリル酸／カプリン酸／ラウリン酸）グリセリル）等が挙げられる。
　長鎖脂肪酸トリグリセリドの市販品の例としては、カネダ（株）の「日本薬局方　ダイズ油」（トリグリセリドの含有率：９７質量％）等が挙げられる。 A commercial item can be used as triglyceride (C).
Examples of commercially available medium-chain fatty acid triglycerides include "Miglyol (registered trademark) 812" (tri (caprylic acid / capric acid) glyceryl) from Sasol, "Miglyol (registered trademark) 810" (tri (caprylic acid / caprin) Acid) glyceryl), Kao Corporation "Coconard (registered trademark) RK" (glyceryl tricaprylate), "Coconard (registered trademark) MT" (tri (caprylic acid / capric acid) glyceryl), "Coconard (registered trademark)" MT-N "(tri (caprylic acid / capric acid) glyceryl)," Coconard (registered trademark) ML "(tri (caprylic acid / capric acid / lauric acid) glyceryl), and the like.
Examples of commercial products of long-chain fatty acid triglycerides include Kaneda Co., Ltd.'s “Japanese Pharmacopoeia soybean oil” (triglyceride content: 97% by mass).
　本開示の経口医薬組成物は、トリグリセリド（Ｃ）を１種のみ含んでいてもよく、２種以上含んでいてもよい。 The oral pharmaceutical composition of the present disclosure may contain only one type of triglyceride (C), or may contain two or more types.
　本開示の経口医薬組成物中におけるトリグリセリド（Ｃ）の含有率は、経口医薬組成物の自己乳化後の乳化物中に、有効成分（Ａ）をより安定に保持し得るとの観点から、経口医薬組成物の全量に対し、４質量％以上が好ましく、５質量％以上がより好ましく、６質量％以上が更に好ましい。
　また、本開示の経口医薬組成物中におけるトリグリセリド（Ｃ）の含有率は、経口医薬組成物が消化液中でより微細な乳化物の分散粒子を形成し得るとの観点から、経口医薬組成物の全量に対し、２５質量％以下が好ましく、２０質量％以下がより好ましく、１５質量％以下が更に好ましい。 The content rate of triglyceride (C) in the oral pharmaceutical composition of the present disclosure is an oral phase from the viewpoint that the active ingredient (A) can be more stably maintained in the emulsion after self-emulsification of the oral pharmaceutical composition. 4 mass% or more is preferable with respect to whole quantity of a pharmaceutical composition, 5 mass% or more is more preferable, and 6 mass% or more is still more preferable.
In addition, the content ratio of triglyceride (C) in the oral pharmaceutical composition of the present disclosure is an oral pharmaceutical composition from the viewpoint that the oral pharmaceutical composition can form dispersed particles of a finer emulsion in digestive fluid. 25 mass% or less is preferable with respect to the whole quantity of, 20 mass% or less is more preferable, and 15 mass% or less is still more preferable.
＜親水性溶媒（Ｄ）＞
　本開示の経口医薬組成物は、親水性溶媒（Ｄ）を含む。
　本開示の経口医薬組成物において、親水性溶媒（Ｄ）は、経口医薬組成物が消化液に触れてから乳化して分散するまでに要する時間（所謂、分散所要時間）の短縮に寄与する。 <Hydrophilic solvent (D)>
The oral pharmaceutical composition of the present disclosure comprises a hydrophilic solvent (D).
In the oral pharmaceutical composition of the present disclosure, the hydrophilic solvent (D) contributes to shortening of the time required for the oral pharmaceutical composition to contact the digestive fluid and then to be emulsified and dispersed (so-called, the required dispersion time).
　親水性溶媒（Ｄ）は、薬理学的に許容される親水性溶媒であれば、特に制限されない。
　親水性溶媒（Ｄ）の具体例としては、エタノール、無水エタノール、ベンジルアルコール等のアルコール類、グリセリン、濃グリセリン、プロピレングリコール、ブチレングリコール等のポリオール類、マクロゴール１００、マクロゴール３００、マクロゴール４００、等のマクロゴール類、トリアセチン、クエン酸トリエチル等のエステル類、水などが挙げられる。
　これらの中でも、親水性溶媒（Ｄ）としては、例えば、安全性及び経口投与実績の観点から、マクロゴール３００、マクロゴール４００、プロピレングリコール、エタノール、無水エタノール、グリセリン、濃グリセリン、トリアセチン、クエン酸トリエチル、及びベンジルアルコールからなる群より選ばれる少なくとも１種であることが好ましく、マクロゴール３００、マクロゴール４００、プロピレングリコール、エタノール、濃グリセリン、トリアセチン、クエン酸トリエチル、及びベンジルアルコールからなる群より選ばれる少なくとも１種であることがより好ましい。
　また、親水性溶媒（Ｄ）は、例えば、分散所要時間の短縮及び分散粒子の微細化の観点から、マクロゴール４００を含むことが更に好ましく、マクロゴール４００であることが特に好ましい。 The hydrophilic solvent (D) is not particularly limited as long as it is a pharmacologically acceptable hydrophilic solvent.
Specific examples of the hydrophilic solvent (D) include alcohols such as ethanol, absolute ethanol and benzyl alcohol, polyols such as glycerin, concentrated glycerin, propylene glycol and butylene glycol, Macrogol 100, Macrogol 300, Macrogol 400 Etc., triacetin, esters such as triethyl citrate, water, and the like.
Among these, as the hydrophilic solvent (D), for example, macrogol 300, macrogol 400, propylene glycol, ethanol, absolute ethanol, glycerin, concentrated glycerin, triacetin, citric acid from the viewpoint of safety and oral administration results It is preferably at least one selected from the group consisting of triethyl and benzyl alcohol, and is selected from the group consisting of macrogol 300, macrogol 400, propylene glycol, ethanol, concentrated glycerin, triacetin, triethyl citrate, and benzyl alcohol. More preferably, it is at least one of
The hydrophilic solvent (D) further preferably includes Macrogol 400, and particularly preferably Macrogol 400, from the viewpoint of, for example, shortening the dispersion required time and making the dispersed particles finer.
　本開示の経口医薬組成物は、親水性溶媒（Ｄ）を１種のみ含んでいてもよく、２種以上含んでいてもよい。 The oral pharmaceutical composition of the present disclosure may contain only one type of hydrophilic solvent (D), or may contain two or more types.
　本開示の経口医薬組成物中における親水性溶媒（Ｄ）の含有量は、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、１０質量部以上５０質量部以下であり、１５質量部以上５０質量部以下であることが好ましく、２０質量部以上５０質量部以下であることがより好ましい。
　本開示の経口医薬組成物中における親水性溶媒（Ｄ）の含有量が、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して１０質量部以上であると、経口医薬組成物全体が適度な親水性を示すため、消化液に触れてから乳化して分散するまでに要する時間（即ち、分散所要時間）が短くなる。すなわち、経口医薬組成物が、消化液中で自発的かつ速やかに乳化して分散し得る。
　本開示の経口医薬組成物中における親水性溶媒（Ｄ）の含有量が、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して５０質量部以下であると、相対的にポリオキシエチレン硬化ヒマシ油（Ｂ）及びトリグリセリド（Ｃ）の含有量が多くなるため、経口医薬組成物が消化液に触れた際に、微細な乳化物の分散粒子を形成し得る。また、有効成分（Ａ）の析出を抑制し得る。 The content of the hydrophilic solvent (D) in the oral pharmaceutical composition of the present disclosure is 100 parts by mass in total of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D). 10 parts by mass or more and 50 parts by mass or less, preferably 15 parts by mass or more and 50 parts by mass or less, and more preferably 20 parts by mass or more and 50 parts by mass or less.
The content of the hydrophilic solvent (D) in the oral pharmaceutical composition of the present disclosure is 100 parts by mass to the total of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D). When the amount is 10 parts by mass or more, the entire oral pharmaceutical composition exhibits appropriate hydrophilicity, and hence the time required for the emulsion liquid to contact and be emulsified and dispersed (that is, the time required for dispersion) is shortened. That is, the oral pharmaceutical composition can be emulsified spontaneously and rapidly in the digestive fluid and dispersed.
The content of the hydrophilic solvent (D) in the oral pharmaceutical composition of the present disclosure is 100 parts by mass to the total of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D). When the amount is 50 parts by mass or less, the content of polyoxyethylene hydrogenated castor oil (B) and triglyceride (C) relatively increases, so when the oral pharmaceutical composition is in contact with a digestive fluid, a fine emulsion is obtained. Can form dispersed particles. Moreover, precipitation of an active ingredient (A) can be suppressed.
＜他の成分＞
　本開示の経口医薬組成物は、既述の成分以外に、効果を損なわない範囲において、必要に応じて、他の成分を含むことができる。
　他の成分としては、医薬品の添加物として使用可能な、酸化防止剤（アスコルビン酸、Ｄ－α－トコフェロール、ブチルヒドロキシアニソール（ＢＨＡ）、ジブチルヒドロキシトルエン（ＢＨＴ）等）、安定化剤（例えば、クエン酸ナトリウム）、防腐剤（パラオキシ安息香酸メチル、パラオキシ安息香酸プロピル等）、香料、着色剤等が挙げられる。 <Other ingredients>
The oral pharmaceutical composition of the present disclosure can contain other components as needed, as long as the effects are not impaired, in addition to the components described above.
As other components, antioxidants (ascorbic acid, D-α-tocopherol, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), etc.) which can be used as additives for pharmaceuticals, stabilizers (eg, Sodium citrate), preservatives (methyl parahydroxybenzoate, propyl parahydroxybenzoate, etc.), perfumes, coloring agents and the like can be mentioned.
＜剤形＞
　本開示の経口医薬組成物の剤形は、特に制限されないが、例えば、経口液剤又はカプセル剤であることが好ましく、カプセル剤であることがより好ましい。
　剤形がカプセル剤であると、本開示の経口医薬組成物に含まれる各成分の安定性を保持することができる。また、剤形がカプセル剤であると、本開示の経口医薬組成物が消化液中で自発的かつ速やかに乳化するとの効果がより良好に奏される。
　カプセル剤の製造方法は、特に制限されず、公知の方法により製造することができる。すなわち、カプセル剤は、本開示の経口医薬組成物を調製した後、常法により、カプセルに充填することにより、製造することができる。
　カプセルは、ソフトカプセルであってもよく、ハードカプセルであってもよい。 <Dosage form>
The dosage form of the oral pharmaceutical composition of the present disclosure is not particularly limited, but is preferably, for example, an oral solution or a capsule, and more preferably a capsule.
When the dosage form is a capsule, the stability of each component contained in the oral pharmaceutical composition of the present disclosure can be maintained. In addition, when the dosage form is a capsule, the effect of spontaneously and rapidly emulsifying the oral pharmaceutical composition of the present disclosure in digestive fluid is better exhibited.
The method for producing the capsule is not particularly limited, and can be produced by a known method. That is, the capsule preparation can be produced by preparing the oral pharmaceutical composition of the present disclosure and then filling the capsule in a conventional manner.
The capsule may be a soft capsule or a hard capsule.
　以下、本発明を実施例により更に具体的に説明するが、本発明はその主旨を超えない限り、以下の実施例に限定されるものではない。
　以下の実施例では、有効成分（Ａ）を「成分（Ａ）」又は「（Ａ）」と、ポリオキシエチレン硬化ヒマシ油（Ｂ）を「成分（Ｂ）」又は「（Ｂ）」と、トリグリセリド（Ｃ）を「成分（Ｃ）」又は「（Ｃ）」と、また、親水性溶媒（Ｄ）を「成分（Ｄ）」又は「（Ｄ）」と称する場合がある。 EXAMPLES Hereinafter, the present invention will be more specifically described by way of examples. However, the present invention is not limited to the following examples as long as the gist thereof is not exceeded.
In the following examples, the active ingredient (A) is “component (A)” or “(A)”, the polyoxyethylene hydrogenated castor oil (B) is “component (B)” or “(B)”, The triglyceride (C) may be referred to as "component (C)" or "(C)", and the hydrophilic solvent (D) may be referred to as "component (D)" or "(D)".
　本実施例において用いた各成分の詳細を以下に示す。 The detail of each component used in the present Example is shown below.
＜有効成分＞
－有効成分（Ａ）－
・テストステロンエナント酸エステル（ステロイド骨格を有する化合物、ｌｏｇＰ：６．３、飽和炭化水素基の炭素数：７、富士フイルム和光純薬（株））
・ウンデカン酸テストステロン（ステロイド骨格を有する化合物、ｌｏｇＰ：８．１、飽和炭化水素基の炭素数：１１、Ｍｅｄｃｈｅｍｅｘｐｒｅｓｓ社）
・クロラムフェニコールパルミチン酸エステル（ｌｏｇＰ：７．８、飽和炭化水素基の炭素数：１６、東京化成工業（株））
－有効成分（Ａ）以外の有効成分－
・シクロスポリンＡ（東京化成工業（株））
・ダナゾール（東京化成工業（株））
・リトナビル（東京化成工業（株））
・クロファミジン（富士フイルム和光純薬（株））
・テストステロン（富士フイルム和光純薬（株））
・プロピオン酸テストステロン（富士フイルム和光純薬（株））
・ユビキノン（富士フイルム和光純薬（株）） <Active ingredient>
-Active ingredient (A)-
Testosterone enanthate (compound having a steroid skeleton, log P: 6.3, carbon number of saturated hydrocarbon group: 7, Fujifilm Wako Pure Chemical Industries, Ltd.)
Undecanoic acid testosterone (compound having a steroid skeleton, log P: 8.1, carbon number of saturated hydrocarbon group: 11, Medchemexpress)
-Chloramphenicol palmitate (log P: 7.8, carbon number of saturated hydrocarbon group: 16, Tokyo Chemical Industry Co., Ltd.)
-Active ingredients other than active ingredient (A)-
・ Cyclosporin A (Tokyo Chemical Industry Co., Ltd.)
-Danazol (Tokyo Chemical Industry Co., Ltd.)
・ Ritona Building (Tokyo Chemical Industry Co., Ltd.)
・ Chlofamidine (Fujifilm Wako Pure Chemical Industries, Ltd.)
Testosterone (Fujifilm Wako Pure Chemical Industries, Ltd.)
・ Testosterone propionate (Fujifilm Wako Pure Chemical Industries, Ltd.)
・ Ubiquinone (Fujifilm Wako Pure Chemical Industries, Ltd.)
＜界面活性剤＞
－ポリオキシエチレン硬化ヒマシ油（Ｂ）－
・ポリオキシエチレン硬化ヒマシ油４０（商品名：ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－４０、日光ケミカルズ（株））
・ポリオキシエチレン硬化ヒマシ油５０（商品名：ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－５０、日光ケミカルズ（株））
・ポリオキシエチレン硬化ヒマシ油６０（商品名：ＮＩＫＫＯＬ（登録商標）　ＨＣＯ－６０、日光ケミカルズ（株））
－ポリオキシエチレン硬化ヒマシ油（Ｂ）以外の界面活性剤－
・ポリオキシル３５ヒマシ油（Ｋｏｌｌｉｐｈｏｒ（登録商標）　ＥＬ、ＢＡＳＦ社）
・ポリグリセリル－３　ジオレエート（Ｐｌｕｒｏｌ（登録商標）　Ｏｌｅｉｑｕｅ　ＣＣ　４９７、Ｇａｔｔｅｆｏｓｓｅ社）
・モノラウリン酸ソルビタン（富士フイルム和光純薬（株））
・カプリロカプロイルマクロゴールグリセリド（Ｌａｂｒａｓｏｌ（登録商標）、Ｇａｔｔｅｆｏｓｓｅ社）
・ラウロマクロゴール（ＮＩＫＫＯＬ（登録商標）　ＢＬ－９ＥＸ、日光ケミカルズ（株））
・ポリソルベート８０（日油（株））
・ステアリン酸ポリオキシル４０（ＮＩＫＫＯＬ（登録商標）　ＭＹＳ－４０ＭＶ、日光ケミカルズ（株）） <Surfactant>
-Polyoxyethylene Cured Castor Oil (B)-
・ Polyoxyethylene hydrogenated castor oil 40 (trade name: NIKKOL® HCO-40, Nikko Chemicals Co., Ltd.)
・ Polyoxyethylene hydrogenated castor oil 50 (Brand name: NIKKOL (registered trademark) HCO-50, Nikko Chemicals Co., Ltd.)
・ Polyoxyethylene hydrogenated castor oil 60 (trade name: NIKKOL (registered trademark) HCO-60, Nikko Chemicals Co., Ltd.)
-Surfactants other than polyoxyethylene hydrogenated castor oil (B)-
Polyoxyl 35 castor oil (Kolliphor (registered trademark) EL, BASF)
Polyglyceryl-3 dioleate (Plurol (registered trademark) Oleique CC 497, Gattefosse)
・ Sorbitan monolaurate (Fujifilm Wako Pure Chemical Industries, Ltd.)
-Caprilo caproyl macrogol glyceride (Labrasol (registered trademark), Gattefosse)
・ Lauro Macrogol (NIKKOL® BL-9EX, Nikko Chemicals Co., Ltd.)
・ Polysorbate 80 (NOF Corporation)
-Polyoxyl stearate (NIKKOL (R) MYS-40 MV, Nikko Chemicals Co., Ltd.)
＜脂質＞
－トリグリセリド（Ｃ）－
・中鎖脂肪酸トリグリセリド（商品名：ココナード（登録商標）　ＲＫ、脂肪酸鎖の平均炭素数：８、花王（株））
・ダイズ油（商品名：日本薬局方　ダイズ油、脂肪酸鎖の平均炭素数：１７．８、トリグリセリドの含有率：９７質量％、カネダ（株））
－トリグリセリド（Ｃ）以外の脂質－
・オレイン酸（商品名：オレイン酸　特級、富士フイルム和光純薬（株））
・モノオレイン酸グリセリン（商品名：Ｃａｐｍｕｌ　ＧＭＯ、Ａｂｉｔｅｃ社）
・モノカプリル酸グリセリン（商品名：Ｃａｐｍｕｌ　ＭＣＭ　Ｃ８、Ａｂｉｔｅｃ社） <Lipid>
-Triglyceride (C)-
Medium-chain fatty acid triglyceride (trade name: Coconado (registered trademark) RK, average carbon number of fatty acid chain: 8, Kao Corporation)
・ Soybean oil (trade name: Japanese Pharmacopoeia soybean oil, average carbon number of fatty acid chain: 17.8, triglyceride content: 97% by mass, Kaneda Co., Ltd.)
-Lipids other than triglyceride (C)-
・ Oleic acid (brand name: oleic acid special grade, Fujifilm Wako Pure Chemical Industries, Ltd.)
-Glycerol monooleate (trade name: Capmul GMO, Abitec)
-Glyceryl monocaprylic acid (trade name: Capmul MCM C8, Abitec)
＜親水性溶媒＞
－親水性溶媒（Ｄ）－
・マクロゴール３００（富士フイルム和光純薬（株））
・マクロゴール４００（メルクミリポア社）
・プロピレングリコール（商品名：コリソルブ　ＰＧ、ＢＡＳＦ社）
・エタノール（富士フイルム和光純薬（株））
・濃グリセリン（メルクミリポア社）
・トリアセチン（メルクミリポア社）
・クエン酸トリエチル（森村商事）
・ベンジルアルコール（富士フイルム和光純薬（株）） <Hydrophilic solvent>
-Hydrophilic solvent (D)-
・ Macrogol 300 (Fujifilm Wako Pure Chemical Industries, Ltd.)
Macrogol 400 (Merck Millipore)
・ Propylene glycol (Brand name: Corisorb PG, BASF)
・ Ethanol (Fujifilm Wako Pure Chemical Industries, Ltd.)
・ Concentrated glycerin (Merck Millipore)
Triacetin (Merck Millipore)
・ Triethyl citrate (Morimura Corporation)
・ Benzyl alcohol (Fujifilm Wako Pure Chemical Industries, Ltd.)
［経口医薬組成物の製造（１）］
＜実施例１＞
　ガラス容器に、脂質である中鎖脂肪酸トリグリセリド（成分（Ｃ））１１．２５質量部、界面活性剤であるポリオキシエチレン硬化ヒマシ油５０（成分（Ｂ））５６．２５質量部、親水性溶媒であるプロピレングリコール（成分（Ｄ））１１．２５質量部、及び親水性溶媒であるマクロゴール４００（成分（Ｄ））１１．２５質量部を、ホットプレートスターラーを用いて、６０℃、５００ｒｐｍ（revolutions per minute；以下同じ。）の条件にて、３０分間撹拌混合し、混合物を得た。
　次いで、得られた混合物に、有効成分であるテストステロンエナント酸エステル（成分（Ａ））１０質量部を加えて、更に、６０℃、５００ｒｐｍの条件にて、３０分間撹拌混合し、経口医薬組成物（所謂、製剤）を得た。 [Production of Oral Pharmaceutical Composition (1)]
Example 1
11.25 parts by mass of medium-chain fatty acid triglyceride (component (C)) which is a lipid, 56.25 parts by mass of polyoxyethylene hydrogenated castor oil 50 which is a surfactant (component (B)) in a glass container, hydrophilic solvent 11.25 parts by mass of propylene glycol (component (D)) and 11.25 parts by mass of macrogol 400 (component (D)), which is a hydrophilic solvent, at 60.degree. C., 500 rpm using a hot plate stirrer. The mixture was stirred and mixed for 30 minutes under the conditions of revolutions per minute (same below).
Next, 10 parts by mass of testosterone enanthate (component (A)) as an active ingredient is added to the obtained mixture, and the mixture is further stirred and mixed for 30 minutes under conditions of 60 ° C. and 500 rpm to obtain an oral pharmaceutical composition. (So-called preparation) was obtained.
＜実施例２及び実施例３＞
　経口医薬組成物（所謂、製剤）の組成を、表１に示す組成に変更したこと以外は、実施例１と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 2 and Example 3
The same operation as in Example 1 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 1, to obtain an oral pharmaceutical composition (so-called formulation).
＜比較例１～比較例７＞
　経口医薬組成物（所謂、製剤）の組成を、表１に示す組成に変更したこと以外は、実施例１と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Comparative Examples 1 to 7
The same operation as in Example 1 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 1, to obtain an oral pharmaceutical composition (so-called formulation).
＜実施例４～実施例６＞
　経口医薬組成物（所謂、製剤）の組成を、表２に示す組成に変更したこと以外は、実施例１と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 4 to Example 6
The same operation as in Example 1 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 2, to obtain an oral pharmaceutical composition (so-called preparation).
＜比較例８～比較例１４＞
　経口医薬組成物（所謂、製剤）の組成を、表２に示す組成に変更したこと以外は、実施例１と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 8 to Comparative Example 14>
The same operation as in Example 1 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 2, to obtain an oral pharmaceutical composition (so-called preparation).
［評価及び測定（１）］
１．溶解性の評価
　上記にて得られた経口医薬組成物（所謂、製剤）を室温まで冷却した。次いで、冷却後の経口医薬組成物（所謂、製剤）を観察し、有効成分が溶解しているか否かを目視にて確認した。
　具体的には、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物のいずれも確認されなかった場合には、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解していると判断し、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物の少なくとも一方が確認された場合には、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していないと判断した。
　結果を表１及び表２に示す。
　なお、表１及び表２では、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解している場合を「良好」と表記し、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していない場合を「不良」と表記した。 [Evaluation and Measurement (1)]
1. Evaluation of Solubility The oral pharmaceutical composition (so-called formulation) obtained above was cooled to room temperature. Then, the oral pharmaceutical composition (so-called, preparation) after cooling was observed to visually confirm whether the active ingredient was dissolved.
Specifically, when neither undissolved crystals nor crystalline precipitates are confirmed in the oral pharmaceutical composition (so-called preparation), the active ingredient is contained in the oral pharmaceutical composition (so-called preparation). An oral pharmaceutical composition (so-called formulation) when it is judged that the composition is sufficiently dissolved and at least one of undissolved crystals and crystalline precipitates is confirmed in the oral pharmaceutical composition (so-called formulation) It was determined that the active ingredient was not completely dissolved therein.
The results are shown in Tables 1 and 2.
In Tables 1 and 2, the case where the active ingredient is sufficiently dissolved in the oral pharmaceutical composition (so-called preparation) is described as "good", and it is effective in the oral pharmaceutical composition (so-called preparation) The case where the components were not completely dissolved was described as "poor".
２．分散粒子径の測定
　上記の「１．溶解性の評価」において、経口医薬組成物（所謂、製剤）中での有効成分の溶解性が「良好」と評価された実施例１～実施例６及び比較例６の各経口医薬組成物（所謂、製剤）について、自己乳化させた後、分散粒子径を測定した。
　具体的には、日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて３０分間穏やかに撹拌し、分散した。
　得られた分散物１０質量部を、日本薬局方溶出試験第１液（所謂、胃液を模した液）３０質量部を用いて希釈し、分散物の希釈液を得た。
　得られた分散物の希釈液を用いて、動的光散乱法により、分散粒子径を測定した。具体的には、測定装置として、濃厚系粒径アナライザー　ＦＰＡＲ－１０００（製品名、大塚電子（株））を用い、雰囲気温度２５℃の条件下、散乱強度分布における中位径（ｄ５０）及び粒子径分布の積算値が９０％に相当する粒子径（ｄ９０）を求めた。
　結果を表１及び表２に示す。
　ｄ５０は、３００ｎｍ以下が好ましく、２００ｎｍ以下がより好ましく、１００ｎｍ以下が更に好ましい。また、ｄ９０は、１０００ｎｍ以下が好ましく、６００ｎｍ以下がより好ましく、３００ｎｍ以下が更に好ましい。 2. Measurement of dispersed particle size In the above-mentioned "1. evaluation of solubility", the solubility of the active ingredient in the oral pharmaceutical composition (so-called preparation) was evaluated as "good" in Examples 1 to 6 and About each oral pharmaceutical composition (so-called, formulation) of Comparative Example 6, the dispersed particle size was measured after self emulsification.
Specifically, 10 parts by mass of an oral pharmaceutical composition (so-called preparation) is brought into contact with 90 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called solution simulating gastric juice) and then added to 37 ° C. The mixture was warmed, and gently stirred and dispersed for 30 minutes at 500 rpm using a hot stirrer.
Ten parts by mass of the obtained dispersion was diluted with 30 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called liquid simulating gastric juice) to obtain a diluted solution of the dispersion.
The dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) and particles in the scattering intensity distribution under the conditions of an atmosphere temperature of 25 ° C. A particle diameter (d90) corresponding to 90% of the integrated value of the diameter distribution was determined.
The results are shown in Tables 1 and 2.
The d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表１及び表２中、各成分の量を示す数値の単位は、質量部である。
　表１及び表２中、各成分の量を示す欄に記載の「－」は、該当する成分を含まないことを意味する。
　表１及び表２中、分散粒子径を示す欄に記載の「－」は、製剤中での有効成分の溶解性が不良であったため、測定を行わなかったことを意味する。 In Table 1 and Table 2, the unit of the numerical value which shows the quantity of each component is a mass part.
In Tables 1 and 2, "-" described in the column indicating the amount of each component means that the corresponding component is not included.
In Tables 1 and 2, "-" described in the column showing the dispersed particle size means that the measurement was not performed because the solubility of the active ingredient in the preparation was poor.
　表１及び表２に示すように、炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、オクタノール／水分配係数の常用対数であるｌｏｇＰが６以上９以下である有効成分（Ａ）は、経口医薬組成物（所謂、製剤）中に１０質量％溶解した状態で含むことができた（実施例１～実施例６参照）。
　また、有効成分として、炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、オクタノール／水分配係数の常用対数であるｌｏｇＰが６以上９以下である有効成分（Ａ）を含む実施例１～実施例６の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、微細な分散粒子を形成することが確認された。 As shown in Tables 1 and 2, an active ingredient having a saturated hydrocarbon group having 7 to 18 carbon atoms and having a log P, which is a common logarithm of the octanol / water partition coefficient, of 6 to 9 (A ) Could be contained in an oral pharmaceutical composition (so-called formulation) in a 10% by mass solution (see Examples 1 to 6).
In addition, an active ingredient (A) having a saturated hydrocarbon group having 7 to 18 carbon atoms and having log P which is a common logarithm of octanol / water distribution coefficient is 6 to 9 as an active ingredient. The oral pharmaceutical compositions (so-called preparations) of Examples 1 to 6 were confirmed to form fine dispersed particles in the first dissolution test of the Japanese Pharmacopoeia (so-called liquid simulating gastric juice). .
　一方、有効成分（Ａ）以外の有効成分は、有効成分（Ａ）と比較して、経口医薬組成物（所謂、製剤）中での溶解性に劣ることが確認された（比較例１～比較例１４参照）。 On the other hand, it was confirmed that the active ingredient other than the active ingredient (A) is inferior to the active ingredient (A) in solubility in an oral pharmaceutical composition (so-called preparation) (Comparative Example 1-Comparative) See Example 14).
［経口医薬組成物の製造（２）］
＜実施例７＞
　ガラス容器に、脂質である中鎖脂肪酸トリグリセリド（成分（Ｃ））１００質量部、界面活性剤であるポリオキシエチレン硬化ヒマシ油５０（成分（Ｂ））５００質量部、親水性溶媒であるプロピレングリコール（成分（Ｄ））１００質量部、及び親水性溶媒であるマクロゴール４００（成分（Ｄ））１００質量部を、ホットプレートスターラーを用いて、６０℃、５００ｒｐｍの条件にて、３０分間撹拌混合し、混合物を得た。
　次いで、得られた混合物に、有効成分であるクロラムフェニコールパルミチン酸エステル（成分（Ａ））１００質量部を加えて、更に、６０℃、５００ｒｐｍの条件にて、３０分間撹拌混合し、経口医薬組成物（所謂、製剤）を得た。 [Production of Oral Pharmaceutical Composition (2)]
Example 7
100 parts by mass of medium-chain fatty acid triglyceride (component (C)) which is a lipid, 500 parts by mass of polyoxyethylene hydrogenated castor oil 50 (component (B)) which is a surfactant, in a glass container, propylene glycol which is a hydrophilic solvent 100 parts by mass of (Component (D)) and 100 parts by mass of Macrogol 400 (component (D)) which is a hydrophilic solvent are stirred and mixed for 30 minutes at 60 ° C. and 500 rpm using a hot plate stirrer The mixture was obtained.
Next, 100 parts by mass of chloramphenicol palmitic acid ester (component (A)), which is an active ingredient, is added to the obtained mixture, and the mixture is further stirred and mixed for 30 minutes under conditions of 60 ° C. and 500 rpm. A pharmaceutical composition (so-called formulation) was obtained.
＜実施例８～実施例１０＞
　経口医薬組成物（所謂、製剤）の組成を、表３に示す組成に変更したこと以外は、実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 8 to Example 10
The same operation as in Example 7 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 3, to obtain an oral pharmaceutical composition (so-called formulation).
＜比較例１５～比較例１８＞
　経口医薬組成物（所謂、製剤）の組成を、表３に示す組成に変更したこと以外は、実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 15 to Comparative Example 18>
The same operation as in Example 7 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 3, to obtain an oral pharmaceutical composition (so-called formulation).
［評価及び測定（２）］ [Evaluation and Measurement (2)]
１．分散粒子径の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて３０分間穏やかに撹拌し、分散した。
　得られた分散物１０質量部を、日本薬局方溶出試験第１液（所謂、胃液を模した液）３０質量部を用いて希釈し、分散物の希釈液を得た。
　得られた分散物の希釈液を用いて、動的光散乱法により、分散粒子径を測定した。具体的には、測定装置として、濃厚系粒径アナライザー　ＦＰＡＲ－１０００（製品名、大塚電子（株））を用い、雰囲気温度２５℃の条件下、散乱強度分布における中位径（ｄ５０）及び粒子径分布の積算値が９０％に相当する粒子径（ｄ９０）を求めた。
　結果を表３に示す。
　ｄ５０は、３００ｎｍ以下が好ましく、２００ｎｍ以下がより好ましく、１００ｎｍ以下が更に好ましい。また、ｄ９０は、１０００ｎｍ以下が好ましく、６００ｎｍ以下がより好ましく、３００ｎｍ以下が更に好ましい。 1. Measurement of Dispersed Particle Size After contacting 10 parts by mass of an oral pharmaceutical composition (so-called preparation) with 90 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), addition to 37 ° C. The mixture was warmed, and gently stirred and dispersed for 30 minutes at 500 rpm using a hot stirrer.
Ten parts by mass of the obtained dispersion was diluted with 30 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called liquid simulating gastric juice) to obtain a diluted solution of the dispersion.
The dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) and particles in the scattering intensity distribution under the conditions of an atmosphere temperature of 25 ° C. A particle diameter (d90) corresponding to 90% of the integrated value of the diameter distribution was determined.
The results are shown in Table 3.
The d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
２．消化液中での安定性
　経口医薬組成物（所謂、製剤）約３５０ｍｇを３７℃に保温した下記の組成の緩衝液（所謂、空腹時の腸液を模した液）３６ｍＬに添加した後、ホットスターラーを用いて、５００ｒｐｍの条件にて２０分間穏やかに撹拌し、分散した。
　この時点の緩衝液中の有効成分の濃度を測定した。
　次に、消化酵素（パンクレアチン　ブタ膵臓由来　８×ＵＳＰ　specification、シグマアルドリッチ社）を１７質量％濃度になるように精製水に溶解した消化酵素水溶液を調製した。
　上記にて得られた経口医薬組成物（所謂、製剤）が分散した緩衝液に、消化酵素水溶液を４ｍＬ添加し、経時的に１ｍＬずつサンプリングした。サンプリングした液には、１０質量％４－ブロモフェニルボロン酸／メタノール溶液を添加し、消化酵素を阻害させた。
　消化酵素水溶液の添加開始から１２０分後、サンプリングした液を３２，０００ｒｐｍ、最大回転半径９ｃｍにて３０分間の超遠心分離し、上清を回収した。次いで、回収した上清に存在する有効成分の濃度を測定し、消化酵素水溶液を添加する前の有効成分の濃度に対する割合（以下、「残存率」ともいう。）を求めた。
　結果を表３に示す。 2. Stability in digestive fluid About 350 mg of oral pharmaceutical composition (so-called preparation) is added to 36 mL of buffer solution of the following composition (so-called solution mimicking fasting intestinal fluid) kept at 37 ° C. The mixture was gently stirred for 20 minutes under the conditions of 500 rpm and dispersed.
At this time point, the concentration of the active ingredient in the buffer solution was measured.
Next, an aqueous digestive enzyme solution was prepared by dissolving a digestive enzyme (pancreatin-swine pancreas-derived 8 × USP specification, Sigma Aldrich) in purified water to a concentration of 17% by mass.
4 mL of an aqueous digestive enzyme solution was added to a buffer in which the oral pharmaceutical composition (so-called preparation) obtained above was dispersed, and 1 mL each was sampled over time. To the sampled solution, a 10% by mass 4-bromophenylboronic acid / methanol solution was added to inhibit digestive enzymes.
After 120 minutes from the start of addition of the digestive enzyme aqueous solution, the sampled solution was ultracentrifuged at 32,000 rpm and maximum rotation radius of 9 cm for 30 minutes, and the supernatant was recovered. Next, the concentration of the active ingredient present in the collected supernatant was measured, and the ratio to the concentration of the active ingredient before addition of the digestive enzyme aqueous solution (hereinafter, also referred to as “remaining rate”) was determined.
The results are shown in Table 3.
　回収した上清に存在する有効成分は、消化液中で安定に存在していた有効成分に相当する。経口医薬組成物（所謂、製剤）の乳化物が消化液中で安定であるほど、有効成分は乳化物中に分配できるため、残存率は１００％に近い値となる。
　残存率が高いほど、消化液中で乳化物が安定に分散していることを意味し、残存率は、７０％以上であることが好ましい。 The active ingredient present in the recovered supernatant corresponds to the active ingredient which was stably present in the digestive fluid. The more stable the emulsion of the oral pharmaceutical composition (so-called preparation) in the digestive fluid, the more the active ingredient can be distributed in the emulsion, and the residual rate approaches 100%.
The higher the residual rate, the more stably the emulsion is dispersed in the digestive fluid, and the residual rate is preferably 70% or more.
－緩衝液の組成－
・５０ｍＭ　トリス／マレイン酸緩衝液
・５ｍＭ　塩化カルシウム
・３ｍＭ　タウロコール酸
・０．７５ｍＭ　レシチン
・ｐＨ７．４ -Composition of buffer solution-
-50 mM Tris / maleic acid buffer-5 mM calcium chloride-3 mM taurocholic acid-0.75 mM lecithin-pH 7.4
　緩衝液中の有効成分の濃度及び上清中の有効成分の濃度の測定は、高速液体クロマトグラフィー（ＨＰＬＣ）によって測定した。測定条件を以下に示す。 The measurement of the concentration of the active ingredient in the buffer and the concentration of the active ingredient in the supernatant was measured by high performance liquid chromatography (HPLC). The measurement conditions are shown below.
－測定条件－
　測定装置：ＳＣＬ－１０ＡＶＰ（（株）島津製作所）
　カラム：ＹＭＣ－Ｐａｃｋ　ＯＤＳ－Ａ（４．６ｍｍＩＤ×１５ｃｍ、粒子径：５μｍ、ＹＭＣ（株））
　溶離液：２ｍＭリン酸水溶液／メタノール混合溶液（２０／８０）
　流速：１ｍＬ／ｍｉｎ
　サンプル注入量：１０μＬ
　カラム温度：４０℃
　検出器：ＳＰＤ－１０ＡＶ -Measurement condition-
Measuring device: SCL-10AVP (Shimadzu Corporation)
Column: YMC-Pack ODS-A (4.6 mm ID × 15 cm, particle diameter: 5 μm, YMC Co., Ltd.)
Eluent: 2 mM phosphoric acid aqueous solution / methanol mixed solution (20/80)
Flow rate: 1 mL / min
Sample injection volume: 10 μL
Column temperature: 40 ° C
Detector: SPD-10AV
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表３中、各成分の量を示す数値の単位は、質量部である。
　表３中、各成分の量を示す欄に記載の「－」は、該当する成分を含まないことを意味する。 In Table 3, the unit of the numerical value which shows the quantity of each component is a mass part.
In Table 3, "-" described in the column indicating the amount of each component means that the corresponding component is not included.
　表３に示すように、トリグリセリドを含む実施例７～実施例１０の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、微細な分散粒子を形成することが確認された。また、形成された分散粒子は、消化液中で安定であることが確認された。 As shown in Table 3, the oral pharmaceutical compositions (so-called preparations) of Examples 7 to 10 containing triglycerides were finely divided in the Japanese Pharmacopoeia Dissolution Test First Liquid (so-called liquid simulating gastric juice). Formation of dispersed particles. Moreover, it was confirmed that the dispersed particles formed were stable in the digestive fluid.
　一方、トリグリセリド以外の脂質を含む比較例１５～比較例１８の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、微細な分散粒子を形成することができなかった。特に、トリグリセリド以外の脂質として、オレイン酸、モノオレイン酸グリセリン、又はモノカプリル酸グリセリンを含む比較例１５～比較例１７の経口医薬組成物（所謂、製剤）により形成された分散粒子は、トリグリセリドを含む実施例７～実施例１０の経口医薬組成物（所謂、製剤）により形成された分散粒子と比較して、消化液中での安定性に劣っていた。 On the other hand, the oral pharmaceutical compositions (so-called, preparations) of Comparative Examples 15 to 18 containing lipids other than triglycerides are finely dispersed in the first dissolution test of the Japanese Pharmacopoeia (so-called, liquid simulating gastric juice) It was not possible to form particles. In particular, the dispersed particles formed by the oral pharmaceutical composition (so-called preparation) of Comparative Examples 15 to 17 containing oleic acid, glyceryl monooleate or glyceryl monocaprylate as a lipid other than triglyceride are triglycerides. Compared to the dispersed particles formed by the oral pharmaceutical composition (so-called formulation) of Examples 7 to 10, the stability in digestive fluid was inferior.
［経口医薬組成物の製造（３）］
＜実施例１１～実施例１３＞
　経口医薬組成物（所謂、製剤）の組成を、表４に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 [Production of Oral Pharmaceutical Composition (3)]
Example 11 to Example 13
An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 4. .
［評価及び測定（３）］
１．溶解性の評価
　上記にて得られた経口医薬組成物（所謂、製剤）を室温まで冷却した。次いで、冷却後の経口医薬組成物（所謂、製剤）を観察し、有効成分が溶解しているか否かを目視にて確認した。
　具体的には、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物のいずれも確認されなかった場合には、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解していると判断し、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物の少なくとも一方が確認された場合には、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していないと判断した。
　結果を表４に示す。
　なお、表４では、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解している場合を「良好」と表記し、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していない場合を「不良」と表記した。 [Evaluation and Measurement (3)]
1. Evaluation of Solubility The oral pharmaceutical composition (so-called formulation) obtained above was cooled to room temperature. Then, the oral pharmaceutical composition (so-called, preparation) after cooling was observed to visually confirm whether the active ingredient was dissolved.
Specifically, when neither undissolved crystals nor crystalline precipitates are confirmed in the oral pharmaceutical composition (so-called preparation), the active ingredient is contained in the oral pharmaceutical composition (so-called preparation). An oral pharmaceutical composition (so-called formulation) when it is judged that the composition is sufficiently dissolved and at least one of undissolved crystals and crystalline precipitates is confirmed in the oral pharmaceutical composition (so-called formulation) It was determined that the active ingredient was not completely dissolved therein.
The results are shown in Table 4.
In Table 4, the case where the active ingredient is sufficiently dissolved in the oral pharmaceutical composition (so-called preparation) is described as "good", and the active ingredient is completely contained in the oral pharmaceutical composition (so-called preparation). The case where it is not dissolved in is described as "defective".
２．分散粒子径の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて３０分間穏やかに撹拌し、分散した。
　得られた分散物１０質量部を、日本薬局方溶出試験第１液（所謂、胃液を模した液）３０質量部を用いて希釈し、分散物の希釈液を得た。
　得られた分散物の希釈液を用いて、動的光散乱法により、分散粒子径を測定した。具体的には、測定装置として、濃厚系粒径アナライザー　ＦＰＡＲ－１０００（製品名、大塚電子（株））を用い、雰囲気温度２５℃の条件下、散乱強度分布における中位径（ｄ５０）を求めた。
　結果を表４に示す。
　ｄ５０は、３００ｎｍ以下が好ましく、２００ｎｍ以下がより好ましく、１００ｎｍ以下が更に好ましい。また、ｄ９０は、１０００ｎｍ以下が好ましく、６００ｎｍ以下がより好ましく、３００ｎｍ以下が更に好ましい。 2. Measurement of Dispersed Particle Size After contacting 10 parts by mass of an oral pharmaceutical composition (so-called preparation) with 90 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), addition to 37 ° C. The mixture was warmed, and gently stirred and dispersed for 30 minutes at 500 rpm using a hot stirrer.
Ten parts by mass of the obtained dispersion was diluted with 30 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called liquid simulating gastric juice) to obtain a diluted solution of the dispersion.
The dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C. The
The results are shown in Table 4.
The d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表４中、各成分の量を示す数値の単位は、質量部である。
　表４中、各成分の量を示す欄に記載の「－」は、該当する成分を含まないことを意味する。
　表４に記載の実施例７及び実施例８は、他の実施例及び比較例との対比のために記載したものであり、それぞれ既述の表に記載の実施例７及び実施例８と同じ経口医薬組成物である。 In Table 4, the unit of the numerical value which shows the quantity of each component is a mass part.
In Table 4, "-" described in the column indicating the amount of each component means that the corresponding component is not included.
Example 7 and Example 8 described in Table 4 are described for comparison with other Examples and Comparative Examples, and are the same as Example 7 and Example 8 described in the above-mentioned Table. It is an oral pharmaceutical composition.
　表４に示すように、長鎖脂肪酸トリグリセリドの割合が９７質量％であるダイズ油を含む経口医薬組成物（所謂、製剤）は、中鎖脂肪酸トリグリセリドを含む経口医薬組成物（所謂、製剤）と比較して、より微細な分散粒子を形成できることが確認された。 As shown in Table 4, an oral pharmaceutical composition (so-called formulation) containing soybean oil in which the proportion of long-chain fatty acid triglyceride is 97% by mass is combined with an oral pharmaceutical composition (so-called formulation) containing medium-chain fatty acid triglyceride In comparison, it was confirmed that finer dispersed particles can be formed.
［経口医薬組成物の製造（４）］
＜比較例１９～比較例２６＞
　経口医薬組成物（所謂、製剤）の組成を、表５に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 [Production of oral pharmaceutical composition (4)]
<Comparative Example 19 to Comparative Example 26>
An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 5. .
＜実施例１４＞
　経口医薬組成物（所謂、製剤）の組成を、表６に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 14
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 6, and an oral pharmaceutical composition (so-called formulation) was obtained. .
＜比較例２７～比較例３４＞
　経口医薬組成物（所謂、製剤）の組成を、表６に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 27 to Comparative Example 34>
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 6, and an oral pharmaceutical composition (so-called formulation) was obtained. .
＜実施例１５＞
　経口医薬組成物（所謂、製剤）の組成を、表７に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 15
An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 7. .
＜比較例３５～比較例４２＞
　経口医薬組成物（所謂、製剤）の組成を、表７に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 35 to Comparative Example 42>
An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 7. .
＜実施例１６及び実施例１７＞
　経口医薬組成物（所謂、製剤）の組成を、表８に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 16 and Example 17
An oral pharmaceutical composition (so-called preparation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 8. .
＜比較例４３～比較例４８＞
　経口医薬組成物（所謂、製剤）の組成を、表８に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 43 to Comparative Example 48>
An oral pharmaceutical composition (so-called preparation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 8. .
［評価及び測定（４）］
１．溶解性の評価
　上記にて得られた経口医薬組成物（所謂、製剤）を室温まで冷却した。次いで、冷却後の経口医薬組成物（所謂、製剤）を観察し、有効成分が溶解しているか否かを目視にて確認した。
　具体的には、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物のいずれも確認されなかった場合には、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解していると判断し、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物の少なくとも一方が確認された場合には、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していないと判断した。
　結果を表５～表８に示す。
　なお、表５～表８では、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解している場合を「良好」と表記し、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していない場合を「不良」と表記した。 [Evaluation and Measurement (4)]
1. Evaluation of Solubility The oral pharmaceutical composition (so-called formulation) obtained above was cooled to room temperature. Then, the oral pharmaceutical composition (so-called, preparation) after cooling was observed to visually confirm whether the active ingredient was dissolved.
Specifically, when neither undissolved crystals nor crystalline precipitates are confirmed in the oral pharmaceutical composition (so-called preparation), the active ingredient is contained in the oral pharmaceutical composition (so-called preparation). An oral pharmaceutical composition (so-called formulation) when it is judged that the composition is sufficiently dissolved and at least one of undissolved crystals and crystalline precipitates is confirmed in the oral pharmaceutical composition (so-called formulation) It was determined that the active ingredient was not completely dissolved therein.
The results are shown in Tables 5-8.
In Tables 5 to 8, the case where the active ingredient is sufficiently dissolved in the oral pharmaceutical composition (so-called preparation) is described as "good", and is effective in the oral pharmaceutical composition (so-called preparation). The case where the components were not completely dissolved was described as "poor".
２．分散粒子径の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて３０分間穏やかに撹拌し、分散した。
　得られた分散物１０質量部を、日本薬局方溶出試験第１液（所謂、胃液を模した液）３０質量部を用いて希釈し、分散物の希釈液を得た。
　得られた分散物の希釈液を用いて、動的光散乱法により、分散粒子径を測定した。具体的には、測定装置として、濃厚系粒径アナライザー　ＦＰＡＲ－１０００（製品名、大塚電子（株））を用い、雰囲気温度２５℃の条件下、散乱強度分布における中位径（ｄ５０）を求めた。
　結果を表５～表８に示す。
　ｄ５０は、３００ｎｍ以下が好ましく、２００ｎｍ以下がより好ましく、１００ｎｍ以下が更に好ましい。また、ｄ９０は、１０００ｎｍ以下が好ましく、６００ｎｍ以下がより好ましく、３００ｎｍ以下が更に好ましい。 2. Measurement of Dispersed Particle Size After contacting 10 parts by mass of an oral pharmaceutical composition (so-called preparation) with 90 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), addition to 37 ° C. The mixture was warmed, and gently stirred and dispersed for 30 minutes at 500 rpm using a hot stirrer.
Ten parts by mass of the obtained dispersion was diluted with 30 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called liquid simulating gastric juice) to obtain a diluted solution of the dispersion.
The dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C. The
The results are shown in Tables 5-8.
The d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
３．消化液中での安定性
　経口医薬組成物（所謂、製剤）約３５０ｍｇを３７℃に保温した既述の組成の緩衝液（所謂、空腹時の腸液を模した液）３６ｍＬに添加した後、ホットスターラーを用いて、５００ｒｐｍの条件にて２０分間穏やかに撹拌し、分散した。
　この時点の緩衝液中の有効成分の濃度を測定した。
　次に、消化酵素（パンクレアチン　ブタ膵臓由来　８×ＵＳＰ　specification、メルク社）を１７質量％濃度になるように精製水に溶解した消化酵素水溶液を調製した。
　上記にて得られた経口医薬組成物（所謂、製剤）が分散した緩衝液に、消化酵素水溶液を４ｍＬ添加し、経時的に１ｍＬずつサンプリングした。サンプリングした液には、１０質量％４－ブロモフェニルボロン酸／メタノール溶液を添加し、消化酵素を阻害させた。
　消化酵素水溶液の添加開始から１２０分後、サンプリングした液を３２，０００ｒｐｍ、最大回転半径９ｃｍにて３０分間の超遠心分離し、上清を回収した。次いで、回収した上清に存在する有効成分の濃度を測定し、消化酵素水溶液を添加する前の有効成分の濃度に対する割合（所謂、残存率）を求めた。
　結果を表５～表８に示す。 3. Stability in digestive fluid About 350 mg of oral pharmaceutical composition (so-called preparation) is added to 36 mL of buffer solution (so-called solution mimicking fasting intestinal fluid) kept at 37 ° C and then hot The mixture was gently stirred and dispersed at 500 rpm for 20 minutes using a stirrer.
At this time point, the concentration of the active ingredient in the buffer solution was measured.
Next, an aqueous digestive enzyme solution was prepared by dissolving a digestive enzyme (pancreatin-swine pancreas-derived 8 × USP specification, Merck & Co., Inc.) in purified water to a concentration of 17% by mass.
4 mL of an aqueous digestive enzyme solution was added to a buffer in which the oral pharmaceutical composition (so-called preparation) obtained above was dispersed, and 1 mL each was sampled over time. To the sampled solution, a 10% by mass 4-bromophenylboronic acid / methanol solution was added to inhibit digestive enzymes.
After 120 minutes from the start of addition of the digestive enzyme aqueous solution, the sampled solution was ultracentrifuged at 32,000 rpm and maximum rotation radius of 9 cm for 30 minutes, and the supernatant was recovered. Next, the concentration of the active ingredient present in the collected supernatant was measured, and the ratio (so-called residual rate) to the concentration of the active ingredient before the addition of the digestive enzyme aqueous solution was determined.
The results are shown in Tables 5-8.
　回収した上清に存在する有効成分は、消化液中で安定に存在していた有効成分に相当する。経口医薬組成物（所謂、製剤）の乳化物が消化液中で安定であるほど、有効成分は乳化物中に分配できるため、残存率は１００％に近い値となる。
　残存率が高いほど、消化液中で乳化物が安定に分散していることを意味し、残存率は、７０％以上であることが好ましい。 The active ingredient present in the recovered supernatant corresponds to the active ingredient which was stably present in the digestive fluid. The more stable the emulsion of the oral pharmaceutical composition (so-called preparation) in the digestive fluid, the more the active ingredient can be distributed in the emulsion, and the residual rate approaches 100%.
The higher the residual rate, the more stably the emulsion is dispersed in the digestive fluid, and the residual rate is preferably 70% or more.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　表５～表８中、各成分の量を示す数値の単位は、質量部である。
　表５～表８中、各成分の量を示す欄に記載の「－」は、該当する成分を含まないことを意味する。
　表５～表８中、分散粒子径及び有効成分の残存率を示す欄に記載の「－」は、分散しなかったため、測定できなかったことを意味する。
　表５に記載の実施例７、表６に記載の実施例８、表７に記載の実施例９、及び表８に記載の実施例１０は、他の実施例及び比較例との対比のために記載したものであり、それぞれ既述の表に記載の実施例７、実施例８、実施例９、及び実施例１０と同じ経口医薬組成物である。 In Tables 5 to 8, the unit of the numerical value indicating the amount of each component is parts by mass.
In Tables 5 to 8, "-" described in the column indicating the amount of each component means that the corresponding component is not included.
In Tables 5 to 8, "-" described in the column showing the dispersed particle size and the residual ratio of the active ingredient means that it could not be measured because it did not disperse.
Example 7 described in Table 5, Example 8 described in Table 6, Example 9 described in Table 7, and Example 10 described in Table 8 are for comparison with other Examples and Comparative Examples. The same oral pharmaceutical composition as in Example 7, Example 8, Example 9, and Example 10 described in the above-mentioned table.
　表５～表８に示すように、ポリオキシエチレン硬化ヒマシ油（Ｂ）を含む実施例７～実施例１０及び実施例１４～実施例１７の経口医薬組成物（所謂、製剤）は、有効成分の溶解性に優れていた。
　また、実施例７～実施例１０及び実施例１４～実施例１７の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、微細な分散粒子を形成することが確認された。
　さらに、形成された分散粒子は、消化液中で安定であることが確認された。 As shown in Tables 5 to 8, the oral pharmaceutical compositions (so-called formulations) of Examples 7 to 10 and Examples 14 to 17 containing polyoxyethylene hydrogenated castor oil (B) are active ingredients. It was excellent in the solubility of
Further, the oral pharmaceutical compositions (so-called preparations) of Examples 7 to 10 and Examples 14 to 17 were finely divided in the first dissolution test of the Japanese Pharmacopoeia (so-called liquid simulating gastric juice). Formation of dispersed particles.
Furthermore, the dispersed particles formed were confirmed to be stable in the digestive fluid.
　一方、ポリオキシエチレン硬化ヒマシ油（Ｂ）以外の界面活性剤を含む比較例１９～比較例２５、比較例２７～比較例３３、比較例３５～比較例４１、及び比較例４３～比較例４７の経口医薬組成物（所謂、製剤）は、有効成分の溶解性に劣るか、分散しないか、分散しても微細な分散粒子を形成することができないか、又は、消化液中での安定性に劣っているか、の少なくともいずれかであることが確認された。
　また、界面活性剤を含まない比較例２６、比較例３４、比較例４２、及び比較例４８の、経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、分散しなかった。 On the other hand, Comparative Example 19 to Comparative Example 25, Comparative Example 27 to Comparative Example 33, Comparative Example 35 to Comparative Example 41, and Comparative Example 43 to Comparative Example 47 containing surfactants other than polyoxyethylene hydrogenated castor oil (B) The oral pharmaceutical composition of the present invention (so-called preparation) has poor solubility of the active ingredient, does not disperse, or can not form finely dispersed particles even if dispersed, or stability in digestive fluid Or at least one of the above.
The oral pharmaceutical composition (so-called preparation) of Comparative Example 26, Comparative Example 34, Comparative Example 42, and Comparative Example 48 which does not contain a surfactant is the Japanese Pharmacopoeia Dissolution Test First Solution (so-called gastric juice). It did not disperse in the simulated solution).
［経口医薬組成物の製造（５）］
＜実施例１８～実施例２１＞
　経口医薬組成物（所謂、製剤）の組成を、表９に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 [Production of oral pharmaceutical composition (5)]
Example 18 to Example 21
An oral pharmaceutical composition (so-called formulation) was obtained by performing the same operation as in Example 7 described above except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 9. .
＜実施例２２～実施例２６＞
　経口医薬組成物（所謂、製剤）の組成を、表１０に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 22 to Example 26
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 10 to obtain an oral pharmaceutical composition (so-called preparation). .
＜比較例４９及び比較例５０＞
　経口医薬組成物（所謂、製剤）の組成を、表１０に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Comparative Example 49 and Comparative Example 50
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 10 to obtain an oral pharmaceutical composition (so-called preparation). .
＜実施例２７～実施例３０＞
　経口医薬組成物（所謂、製剤）の組成を、表１１に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Examples 27 to 30
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 11, and an oral pharmaceutical composition (so-called preparation) was obtained. .
＜実施例３１～実施例３７＞
　経口医薬組成物（所謂、製剤）の組成を、表１２に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 31 to Example 37
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 12, and an oral pharmaceutical composition (so-called preparation) was obtained. .
＜比較例５１及び比較例５２＞
　経口医薬組成物（所謂、製剤）の組成を、表１２に示す組成に変更したこと以外は、既述の実施例７と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 51 and Comparative Example 52>
The same procedure as in Example 7 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 12, and an oral pharmaceutical composition (so-called preparation) was obtained. .
［評価及び測定（５）］
１．分散所要時間の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて穏やかに撹拌した。撹拌物を目視にて観察し、経口医薬組成物（所謂、製剤）に由来する１ｍｍ以上の大きさの固まりが確認されなくなるまでの時間を、分散に要する時間（即ち、分散所要時間）として計測した。
　結果を表９～表１２に示す。 [Evaluation and measurement (5)]
1. Measurement of the time required for dispersion After contacting 10 parts by weight of an oral pharmaceutical composition (so-called preparation) with 90 parts by weight of the Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), add to 37 ° C. The mixture was warmed and gently stirred at 500 rpm using a hot stirrer. The substance to be stirred is visually observed, and the time taken for the lump having a size of 1 mm or more derived from the oral pharmaceutical composition (so-called preparation) not to be confirmed is measured as the time required for dispersion (that is, the time required for dispersion). did.
The results are shown in Tables 9-12.
２．分散粒子径の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて３０分間穏やかに撹拌し、分散した。
　得られた分散物１０質量部を、日本薬局方溶出試験第１液（所謂、胃液を模した液）３０質量部を用いて希釈し、分散物の希釈液を得た。
　得られた分散物の希釈液を用いて、動的光散乱法により、分散粒子径を測定した。具体的には、測定装置として、濃厚系粒径アナライザー　ＦＰＡＲ－１０００（製品名、大塚電子（株））を用い、雰囲気温度２５℃の条件下、散乱強度分布における中位径（ｄ５０）を求めた。
　結果を表９～表１２に示す。
　ｄ５０は、３００ｎｍ以下が好ましく、２００ｎｍ以下がより好ましく、１００ｎｍ以下が更に好ましい。また、ｄ９０は、１０００ｎｍ以下が好ましく、６００ｎｍ以下がより好ましく、３００ｎｍ以下が更に好ましい。 2. Measurement of Dispersed Particle Size After contacting 10 parts by mass of an oral pharmaceutical composition (so-called preparation) with 90 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), addition to 37 ° C. The mixture was warmed, and gently stirred and dispersed for 30 minutes at 500 rpm using a hot stirrer.
Ten parts by mass of the obtained dispersion was diluted with 30 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called liquid simulating gastric juice) to obtain a diluted solution of the dispersion.
The dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C. The
The results are shown in Tables 9-12.
The d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000011
Figure JPOXMLDOC01-appb-T000012
Figure JPOXMLDOC01-appb-T000012
　表９～表１２中、各成分の量を示す数値の単位は、質量部である。
　表９～表１２中、各成分の量を示す欄に記載の「－」は、該当する成分を含まないことを意味する。
　表９に記載の実施例７及び実施例８、並びに、表１１に記載の実施例９及び実施例１０は、他の実施例及び比較例との対比のために記載したものであり、それぞれ既述の表に記載の実施例７、実施例８、実施例９、及び実施例１０と同じ経口医薬組成物である。 In Tables 9 to 12, units of numerical values indicating the amount of each component are parts by mass.
In Tables 9 to 12, "-" described in the column indicating the amount of each component means that the corresponding component is not included.
Example 7 and Example 8 described in Table 9 and Example 9 and Example 10 described in Table 11 are described for comparison with other Examples and Comparative Examples, and have already been described. It is the same oral pharmaceutical composition as Example 7, Example 8, Example 9, and Example 10 as described in the above-mentioned table | surface.
　表９～表１２に示すように、親水性溶媒を含む実施例７～実施例１０及び実施例１８～実施例３７の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、微細な分散粒子を形成することが確認された。
　また、実施例７～実施例１０及び実施例１８～実施例３７の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、速やかに乳化し、分散することが確認された。 As shown in Tables 9 to 12, the oral pharmaceutical compositions (so-called formulations) of Examples 7 to 10 and Examples 18 to 37 containing a hydrophilic solvent are the Japanese Pharmacopoeia Dissolution Test First Liquid It was confirmed that fine dispersed particles were formed in (a so-called liquid simulating gastric juice).
In addition, the oral pharmaceutical compositions (so-called preparations) of Examples 7 to 10 and Examples 18 to 37 are rapidly obtained in the first dissolution test of the Japanese Pharmacopoeia (so-called liquid simulating gastric juice). It was confirmed that the product was emulsified and dispersed.
　一方、親水性溶媒を含まない比較例４９～比較例５２の経口医薬組成物（所謂、製剤）では、分散所要時間が長くなることが確認された。 On the other hand, in the oral pharmaceutical compositions (so-called, preparations) of Comparative Examples 49 to 52 which do not contain a hydrophilic solvent, it was confirmed that the time required for dispersion becomes long.
［経口医薬組成物の製造（６）］
＜実施例３８＞
　ガラス容器に、脂質であるダイズ油（成分（Ｃ））２３．７５質量部、界面活性剤であるポリオキシエチレン硬化ヒマシ油５０（成分（Ｂ））７１．２５質量部、親水性溶媒であるプロピレングリコール（成分（Ｄ））５質量部、及び親水性溶媒であるマクロゴール４００（成分（Ｄ））５質量部を、ホットプレートスターラーを用いて、６０℃、５００ｒｐｍの条件にて、３０分間撹拌混合し、混合物を得た。
　次いで、得られた混合物に、有効成分であるクロラムフェニコールパルミチン酸エステル（成分（Ａ））１２．５質量部を加えて、更に、６０℃、５００ｒｐｍの条件にて、３０分間撹拌混合し、経口医薬組成物（所謂、製剤）を得た。 [Production of Oral Pharmaceutical Composition (6)]
Example 38
In a glass container, 23.75 parts by mass of soybean oil (component (C)) as a lipid, polyoxyethylene hydrogenated castor oil 50 as a surfactant (component (B)) 71.25 parts by mass, a hydrophilic solvent Using a hot plate stirrer, 5 parts by mass of propylene glycol (component (D)) and 5 parts by mass of macrogol 400 (component (D)) which is a hydrophilic solvent, for 30 minutes at 60 ° C. and 500 rpm Stir and mix to obtain a mixture.
Next, 12.5 parts by mass of chloramphenicol palmitic acid ester (component (A)) as an active ingredient is added to the obtained mixture, and the mixture is further stirred and mixed for 30 minutes under conditions of 60 ° C. and 500 rpm. An oral pharmaceutical composition (so-called formulation) was obtained.
＜実施例３９～実施例４１＞
　経口医薬組成物（所謂、製剤）の組成を、表１３に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Example 39 to Example 41>
The same operation as in Example 38 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 13, to obtain an oral pharmaceutical composition (so-called preparation).
＜比較例５３及び比較例５４＞
　経口医薬組成物（所謂、製剤）の組成を、表１３に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Comparative Example 53 and Comparative Example 54
The same operation as in Example 38 was performed except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 13, to obtain an oral pharmaceutical composition (so-called preparation).
＜実施例４２～実施例４５＞
　経口医薬組成物（所謂、製剤）の組成を、表１４に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Example 42 to Example 45
The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 14, to obtain an oral pharmaceutical composition (so-called formulation).
＜比較例５５～比較例５７＞
　経口医薬組成物（所謂、製剤）の組成を、表１４に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 55 to Comparative Example 57>
The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called formulation) was changed to the composition shown in Table 14, to obtain an oral pharmaceutical composition (so-called formulation).
＜実施例４６～実施例４９＞
　経口医薬組成物（所謂、製剤）の組成を、表１５に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Example 46 to Example 49>
The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 15, to obtain an oral pharmaceutical composition (so-called preparation).
＜比較例５８＞
　経口医薬組成物（所謂、製剤）の組成を、表１５に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Comparative Example 58
The same operation as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 15, to obtain an oral pharmaceutical composition (so-called preparation).
＜実施例５０～実施例５３＞
　経口医薬組成物（所謂、製剤）の組成を、表１６に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 Examples 50 to 53
The same procedure as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 16, to obtain an oral pharmaceutical composition (so-called preparation).
＜比較例５９～比較例６１＞
　経口医薬組成物（所謂、製剤）の組成を、表１６に示す組成に変更したこと以外は、実施例３８と同様の操作を行い、経口医薬組成物（所謂、製剤）を得た。 <Comparative Example 59 to Comparative Example 61>
The same procedure as in Example 38 was carried out except that the composition of the oral pharmaceutical composition (so-called preparation) was changed to the composition shown in Table 16, to obtain an oral pharmaceutical composition (so-called preparation).
［評価及び測定（６）］
１．溶解性の評価
　上記にて得られた経口医薬組成物（所謂、製剤）を室温まで冷却した。次いで、冷却後の経口医薬組成物（所謂、製剤）を観察し、有効成分が溶解しているか否かを目視にて確認した。
　具体的には、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物のいずれも確認されなかった場合には、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解していると判断し、経口医薬組成物（所謂、製剤）に未溶解の結晶及び結晶状の析出物の少なくとも一方が確認された場合には、経口医薬組成物（所謂、製剤）中に有効成分が完全に溶解していないと判断した。
　結果を表１３～表１６に示す。
　なお、表１３～表１６では、経口医薬組成物（所謂、製剤）中に有効成分が十分に溶解している場合を「良好」と表記した。 [Evaluation and measurement (6)]
1. Evaluation of Solubility The oral pharmaceutical composition (so-called formulation) obtained above was cooled to room temperature. Then, the oral pharmaceutical composition (so-called, preparation) after cooling was observed to visually confirm whether the active ingredient was dissolved.
Specifically, when neither undissolved crystals nor crystalline precipitates are confirmed in the oral pharmaceutical composition (so-called preparation), the active ingredient is contained in the oral pharmaceutical composition (so-called preparation). An oral pharmaceutical composition (so-called formulation) when it is judged that the composition is sufficiently dissolved and at least one of undissolved crystals and crystalline precipitates is confirmed in the oral pharmaceutical composition (so-called formulation) It was determined that the active ingredient was not completely dissolved therein.
The results are shown in Tables 13-16.
In Tables 13 to 16, the case where the active ingredient is sufficiently dissolved in the oral pharmaceutical composition (so-called preparation) is described as “good”.
２．分散粒子径の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて３０分間穏やかに撹拌し、分散した。
　得られた分散物１０質量部を、日本薬局方溶出試験第１液（所謂、胃液を模した液）３０質量部を用いて希釈し、分散物の希釈液を得た。
　得られた分散物の希釈液を用いて、動的光散乱法により、分散粒子径を測定した。具体的には、測定装置として、濃厚系粒径アナライザー　ＦＰＡＲ－１０００（製品名、大塚電子（株））を用い、雰囲気温度２５℃の条件下、散乱強度分布における中位径（ｄ５０）を求めた。
　結果を表１３～表１６に示す。
　ｄ５０は、３００ｎｍ以下が好ましく、２００ｎｍ以下がより好ましく、１００ｎｍ以下が更に好ましい。また、ｄ９０は、１０００ｎｍ以下が好ましく、６００ｎｍ以下がより好ましく、３００ｎｍ以下が更に好ましい。 2. Measurement of Dispersed Particle Size After contacting 10 parts by mass of an oral pharmaceutical composition (so-called preparation) with 90 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), addition to 37 ° C. The mixture was warmed, and gently stirred and dispersed for 30 minutes at 500 rpm using a hot stirrer.
Ten parts by mass of the obtained dispersion was diluted with 30 parts by mass of Japanese Pharmacopoeia Dissolution Test First Solution (so-called liquid simulating gastric juice) to obtain a diluted solution of the dispersion.
The dispersed particle diameter was measured by the dynamic light scattering method using the diluted solution of the obtained dispersion. Specifically, using a concentrated particle size analyzer FPAR-1000 (product name, Otsuka Electronics Co., Ltd.) as a measuring device, the median diameter (d50) in the scattering intensity distribution is determined under the condition of an atmosphere temperature of 25 ° C. The
The results are shown in Tables 13-16.
The d50 is preferably 300 nm or less, more preferably 200 nm or less, and still more preferably 100 nm or less. Moreover, 1000 nm or less is preferable, as for d90, 600 nm or less is more preferable, and 300 nm or less is still more preferable.
３．分散所要時間の測定
　日本薬局方溶出試験第１液（所謂、胃液を模した液）９０質量部に対し、経口医薬組成物（所謂、製剤）１０質量部を接触させた後、３７℃に加温し、ホットスターラーを用いて、５００ｒｐｍの条件にて穏やかに撹拌した。撹拌物を目視にて観察し、経口医薬組成物（所謂、製剤）に由来する１ｍｍ以上の大きさの固まりが確認されなくなるまでの時間を、分散に要する時間（即ち、分散所要時間）として計測した。
　結果を表１３～表１６に示す。 3. Measurement of the time required for dispersion After contacting 10 parts by weight of an oral pharmaceutical composition (so-called preparation) with 90 parts by weight of the Japanese Pharmacopoeia Dissolution Test First Solution (So-called liquid simulating gastric juice), add to 37 ° C. The mixture was warmed and gently stirred at 500 rpm using a hot stirrer. The substance to be stirred is visually observed, and the time taken for the lump having a size of 1 mm or more derived from the oral pharmaceutical composition (so-called preparation) not to be confirmed is measured as the time required for dispersion (that is, the time required for dispersion). did.
The results are shown in Tables 13-16.
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000013
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000014
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000015
Figure JPOXMLDOC01-appb-T000016
Figure JPOXMLDOC01-appb-T000016
　表１３～表１６中、各成分の量を示す数値の単位は、質量部である。
　表１３～表１６中、各成分の量を示す欄に記載の「－」は、該当する成分を含まないことを意味する。
　表１４に記載の実施例４１、及び表１６に記載の実施例４９は、他の実施例及び比較例との対比のために記載したものであり、それぞれ既述の表に記載の実施例４１及び実施例４９と同じ経口医薬組成物である。 In Tables 13 to 16, the units of numerical values indicating the amount of each component are parts by mass.
In Tables 13 to 16, “-” described in the column indicating the amount of each component means that the corresponding component is not included.
Example 41 described in Table 14 and Example 49 described in Table 16 are described for comparison with other Examples and Comparative Examples, and Example 41 described in the above-mentioned Table. And the same oral pharmaceutical composition as Example 49.
　表１３～表１６に示すように、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリドの含有量（Ｃ）＝３：１～９：１であり、かつ、ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が１０質量部以上５０質量部以下である実施例３８～実施例５３の経口医薬組成物（所謂、製剤）は、有効成分の溶解性に優れていた。
　また、実施例３８～実施例５３の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、微細な分散粒子を形成することが確認された。
　さらに、実施例３８～実施例５３の経口医薬組成物（所謂、製剤）は、日本薬局方溶出試験第１液（所謂、胃液を模した液）中で、速やかに乳化し、分散することが確認された。 As shown in Tables 13 to 16, the mass ratio of the polyoxyethylene hydrogenated castor oil (B) content to the triglyceride (C) content is the polyoxyethylene hydrogenated castor oil (B) content: The content of triglyceride (C) is 3: 1 to 9: 1, and based on 100 parts by mass in total of polyoxyethylene hydrogenated castor oil (B), triglyceride (C), and hydrophilic solvent (D) The oral pharmaceutical compositions (so-called formulations) of Examples 38 to 53 in which the content of the hydrophilic solvent (D) is 10 parts by mass or more and 50 parts by mass or less were excellent in the solubility of the active ingredient.
In addition, the oral pharmaceutical compositions (so-called preparations) of Examples 38 to 53 can form fine dispersed particles in Japanese Pharmacopoeia dissolution test first liquid (so-called liquid simulating gastric juice). confirmed.
Furthermore, the oral pharmaceutical composition (so-called preparation) of Example 38 to Example 53 can be rapidly emulsified and dispersed in Japanese Pharmacopoeia Dissolution Test First Liquid (so-called liquid simulating gastric juice). confirmed.
　一方、トリグリセリド（Ｃ）の含有量に対するポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量が３倍未満である比較例５３及び比較例５８の経口医薬組成物（所謂、製剤）では、分散粒子径が大きくなることが確認された。
　親水性溶媒（Ｄ）を含まない比較例５５及び比較例６０の経口医薬組成物（所謂、製剤）では、分散所要時間が長くなることが確認された。
　ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が１０質量部未満である比較例５６及び比較例６１の経口医薬組成物（所謂、製剤）では、分散所要時間が長くなることが確認された。
　トリグリセリド（Ｃ）を含まない比較例５４及び比較例５９の経口医薬組成物（所謂、製剤）では、分散粒子径が大きくなることが確認された。
　ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が５０質量部を超える比較例５７の経口医薬組成物（所謂、製剤）では、分散粒子径が大きくなることが確認された。 On the other hand, in the oral pharmaceutical compositions (so-called formulations) of Comparative Example 53 and Comparative Example 58 in which the content of polyoxyethylene hydrogenated castor oil (B) is less than 3 times the content of triglyceride (C), the dispersed particle size Was confirmed to increase.
In the oral pharmaceutical compositions (so-called formulations) of Comparative Example 55 and Comparative Example 60 which do not contain a hydrophilic solvent (D), it was confirmed that the time required for dispersion becomes longer.
Comparative Example 56 in which the content of the hydrophilic solvent (D) is less than 10 parts by mass with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D). And in the oral pharmaceutical composition (so-called preparation) of Comparative Example 61, it was confirmed that the time required for dispersion becomes long.
In the oral pharmaceutical compositions (so-called, preparations) of Comparative Example 54 and Comparative Example 59 which do not contain triglyceride (C), it was confirmed that the dispersed particle size became large.
The content of the hydrophilic solvent (D) exceeds 50 parts by mass with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D) In the case of oral pharmaceutical compositions (so-called preparations), it was confirmed that the dispersed particle size was increased.
　２０１７年１１月１日に出願された日本国特許出願２０１７－２１２１６６号の開示は、その全体が参照により本明細書に取り込まれる。
　本明細書に記載された全ての文献、特許出願、及び技術規格は、個々の文献、特許出願、及び技術規格が参照により取り込まれることが具体的に、かつ、個々に記された場合と同程度に、本明細書中に参照により取り込まれる。 The disclosure of Japanese Patent Application 2017-212166, filed November 1, 2017, is incorporated herein by reference in its entirety.
All documents, patent applications, and technical standards described herein are as if each individual document, patent application, and technical standard is specifically and individually incorporated by reference. To the extent, it is incorporated herein by reference.

Claims (11)

  1. 　炭素数が７以上１８以下の飽和炭化水素基を有し、かつ、オクタノール／水分配係数の常用対数であるｌｏｇＰが６以上９以下の有効成分（Ａ）と、
    　ポリオキシエチレン硬化ヒマシ油（Ｂ）と、
    　トリグリセリド（Ｃ）と、
    　親水性溶媒（Ｄ）と、を含み、
    　ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量と、トリグリセリド（Ｃ）の含有量との質量比が、ポリオキシエチレン硬化ヒマシ油（Ｂ）の含有量：トリグリセリドの含有量（Ｃ）＝３：１～９：１であり、
    　ポリオキシエチレン硬化ヒマシ油（Ｂ）、トリグリセリド（Ｃ）、及び親水性溶媒（Ｄ）の合計１００質量部に対して、親水性溶媒（Ｄ）の含有量が１０質量部以上５０質量部以下である経口医薬組成物。     An active ingredient (A) having a saturated hydrocarbon group having 7 to 18 carbon atoms and having log P of 6 to 9 which is a common logarithm of octanol / water distribution coefficient,
    Polyoxyethylene hydrogenated castor oil (B),
    Triglyceride (C),
    Containing a hydrophilic solvent (D),
    The mass ratio of the content of polyoxyethylene hydrogenated castor oil (B) to the content of triglyceride (C) is the content of polyoxyethylene hydrogenated castor oil (B): content of triglyceride (C) = 3: 1 to 9: 1,
    The content of the hydrophilic solvent (D) is 10 parts by mass to 50 parts by mass with respect to a total of 100 parts by mass of the polyoxyethylene hydrogenated castor oil (B), the triglyceride (C), and the hydrophilic solvent (D) An oral pharmaceutical composition.
  2. 　トリグリセリド（Ｃ）が、脂肪酸鎖の平均炭素数が１４以上２４以下の長鎖脂肪酸トリグリセリドである請求項１に記載の経口医薬組成物。 The oral pharmaceutical composition according to claim 1, wherein the triglyceride (C) is a long chain fatty acid triglyceride in which the average carbon number of the fatty acid chain is 14 or more and 24 or less.
  3. 　トリグリセリド（Ｃ）の含有率が、経口医薬組成物の全量に対し、４質量％以上２５質量％以下である請求項１又は請求項２に記載の経口医薬組成物。 The oral pharmaceutical composition according to claim 1 or 2, wherein the content of triglyceride (C) is 4% by mass or more and 25% by mass or less based on the total amount of the oral pharmaceutical composition.
  4. 　親水性溶媒（Ｄ）が、マクロゴール３００、マクロゴール４００、プロピレングリコール、エタノール、濃グリセリン、トリアセチン、クエン酸トリエチル、及びベンジルアルコールからなる群より選ばれる少なくとも１種である請求項１～請求項３のいずれか１項に記載の経口医薬組成物。 The hydrophilic solvent (D) is at least one selected from the group consisting of macrogol 300, macrogol 400, propylene glycol, ethanol, concentrated glycerin, triacetin, triethyl citrate, and benzyl alcohol. The oral pharmaceutical composition according to any one of 3.
  5. 　有効成分（Ａ）の融点が０℃以上１００℃以下である請求項１～請求項４のいずれか１項に記載の経口医薬組成物。 The oral pharmaceutical composition according to any one of claims 1 to 4, wherein the melting point of the active ingredient (A) is 0 ° C or more and 100 ° C or less.
  6. 　有効成分（Ａ）が、炭素数が３以上７以下の環構造を更に有する請求項１～請求項５のいずれか１項に記載の経口医薬組成物。 The oral pharmaceutical composition according to any one of claims 1 to 5, wherein the active ingredient (A) further has a ring structure having 3 to 7 carbon atoms.
  7. 　有効成分（Ａ）が、ステロイド骨格を有する化合物、フェノチアジン骨格を有する化合物、チオキサンテン骨格を有する化合物、ブチロフェノン骨格を有する化合物、及びクロラムフェニコール脂肪酸エステル化合物からなる群より選ばれる少なくとも１種の化合物である請求項１～請求項６のいずれか１項に記載の経口医薬組成物。 At least one selected from the group consisting of a compound having a steroid skeleton, a compound having a phenothiazine skeleton, a compound having a thioxanthene skeleton, a compound having a butyrophenone skeleton, and a chloramphenicol fatty acid ester compound as the active ingredient (A). The oral pharmaceutical composition according to any one of claims 1 to 6, which is a compound.
  8. 　ステロイド骨格を有する化合物が、メテノロンエナント酸エステル、テストステロンエナント酸エステル、テストステロンデカノアート、ウンデカン酸テストステロン、ナンドロロンデカン酸エステル、及びデキサメタゾンパルミチン酸エステルからなる群より選ばれる少なくとも１種であり、
    　フェノチアジン骨格を有する化合物が、フルフェナジンエナント酸エステル、フルフェナジンデカン酸エステル、パルミチン酸ピポチアジン、及びペルフェナジンデカノアートからなる群より選ばれる少なくとも１種であり、
    　チオキサンテン骨格を有する化合物が、フルペンチキソールデカノアート及びズクロペンチキソールデカノアートから選ばれる少なくとも１種であり、
    　ブチロフェノン骨格を有する化合物が、ハロペリドールデカン酸エステル及びデカン酸ブロムペリドールから選ばれる少なくとも１種であり、
    　クロラムフェニコール脂肪酸エステル化合物が、クロラムフェニコールパルミチン酸エステル及びクロラムフェニコールステアリン酸エステルから選ばれる少なくとも１種である請求項７に記載の経口医薬組成物。     The compound having a steroid skeleton is at least one selected from the group consisting of methenolone enanthate, testosterone enanthate, testosterone decanoate, testosterone undecanoate, nandrolone decanoate, and dexamethasone palmitate.
    The compound having a phenothiazine skeleton is at least one selected from the group consisting of fluphenazine enanthate, fluphenazine decanoate, pipothiazine palmitate, and perphenazine decanoate,
    The compound having a thioxanthene skeleton is at least one selected from flupenthixol decanoate and zuclopenthixol decanoate,
    The compound having a butyrophenone skeleton is at least one selected from haloperidol decanoic acid ester and bromperidol decanoate,
    The oral pharmaceutical composition according to claim 7, wherein the chloramphenicol fatty acid ester compound is at least one selected from chloramphenicol palmitic acid ester and chloramphenicol stearic acid ester.
  9. 　有効成分（Ａ）が、ステロイド骨格を有する化合物及びクロラムフェニコール脂肪酸エステル化合物からなる群より選ばれる少なくとも１種の化合物である請求項１～請求項８のいずれか１項に記載の経口医薬組成物。 The oral medicine according to any one of claims 1 to 8, wherein the active ingredient (A) is at least one compound selected from the group consisting of a compound having a steroid skeleton and a chloramphenicol fatty acid ester compound. Composition.
  10. 　有効成分（Ａ）が、ウンデカン酸テストステロン及びクロラムフェニコールパルミチン酸エステルから選ばれる少なくとも１種である請求項１～請求項９のいずれか１項に記載の経口医薬組成物。 The oral pharmaceutical composition according to any one of claims 1 to 9, wherein the active ingredient (A) is at least one selected from testosterone undecanoate and chloramphenicol palmitate.
  11. 　剤形が、カプセル剤である請求項１～請求項１０のいずれか１項に記載の経口医薬組成物。 The oral pharmaceutical composition according to any one of claims 1 to 10, wherein the dosage form is a capsule.
PCT/JP2018/037478 2017-11-01 2018-10-05 Oral pharmaceutical composition WO2019087696A1 (en)

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