WO2013147072A1 - Cocrystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one - Google Patents

Cocrystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one Download PDF

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WO2013147072A1
WO2013147072A1 PCT/JP2013/059357 JP2013059357W WO2013147072A1 WO 2013147072 A1 WO2013147072 A1 WO 2013147072A1 JP 2013059357 W JP2013059357 W JP 2013059357W WO 2013147072 A1 WO2013147072 A1 WO 2013147072A1
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crystal
acid
hydroxypentadecyl
trimethyl
cyclohexen
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PCT/JP2013/059357
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French (fr)
Japanese (ja)
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田中　大介
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大鵬薬品工業株式会社
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/713—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups a keto group being part of a six-membered ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/04—Drugs for disorders of the muscular or neuromuscular system for myasthenia gravis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C53/00—Saturated compounds having only one carboxyl group bound to an acyclic carbon atom or hydrogen
    • C07C53/126—Acids containing more than four carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to a novel co-crystal 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one useful as a pharmaceutical, a process for producing the same, and a pharmaceutical composition containing the same .
  • Patent Document 1 describes that a cyclohexenone long-chain alcohol containing a compound represented by the formula (1) exhibits a nerve growth promoting action and is useful as a medicament for the prevention / treatment of brain diseases such as dementia. Yes. Further, for example, in Patent Document 2, it is also known that it is useful as a therapeutic agent for dysuria represented by prostatic hypertrophy.
  • 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one itself is a waxy compound at room temperature and is easy to melt because of its low melting point (about 30 ° C). Since it is a compound, when it was developed as a pharmaceutical, there was a concern about difficulty in formulation.
  • a co-crystal is defined as a substance in which a host compound is crystallized with a substance (guest compound) that is solid at room temperature by some action, such as hydrogen bonding or intermolecular force, and crystallizes by ionic bonding. Is clearly distinguished (for example, Non-Patent Document 1).
  • the formation of a co-crystal enables functions and physical properties that cannot be obtained with a crystal composed of only a single compound.
  • a host compound and a guest compound to form a co-crystal, for example, one of them is acidic. It is known that it is difficult to selectively interact with different compounds such as having a site and the other having a basic site. That is, the combination of a host compound and a guest compound for obtaining a co-crystal is highly difficult to predict.
  • the present invention provides a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one that is useful as a pharmaceutical and has excellent oral absorption, and a pharmaceutical composition thereof The purpose is to do.
  • the present inventors obtain a novel crystal having excellent physical properties as a pharmaceutical, particularly a novel co-crystal, for 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one.
  • a co-crystal having a higher melting point was found in the combination of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a specific fatty acid.
  • the co-crystal of the present invention showed an improvement of about 2 to 23 times C max and about 2 to 14 times AUC 0-24hr , thus completing the present invention.
  • 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one represented by formula (I) and a fatty acid having 14 to 17 carbon atoms A co-crystal with is provided.
  • a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a linear fatty acid having 14 to 17 carbon atoms is provided.
  • a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid, palmitic acid, or myristic acid is provided. .
  • 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid, palmitic acid, or myristic acid are from 1: 0.5 to 1
  • a co-crystal composed of a constituent molar ratio of up to 2 is provided.
  • the constituent molar ratio of the co-crystal may be 1: 1.
  • a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid comprising 7.7, 12.5, 17.1, 18.8 , 22.0, 22.4, 24.2, any one, any two, any three, any four, or any five or more co-crystals.
  • a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid having peaks of 7.7, 18.8 and 22.4 A co-crystal characterized by is provided.
  • differential scanning calorimetry a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a fatty acid having 14 to 17 carbon atoms
  • a co-crystal is provided in which the peak top value of the endothermic peak measured by is between about 40 and about 55 ° C. when the rate of temperature increase during DSC measurement is between 2 and 10 ° C./min.
  • a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid measured by differential scanning calorimetry.
  • composition comprising any of the above-described co-crystals as an active ingredient is provided.
  • 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one co-crystal that is useful as a pharmaceutical and has excellent oral absorption, stability, and the like, And a pharmaceutical composition thereof.
  • the co-crystal and pharmaceutical composition of the present invention are easy to handle for formulation.
  • Reference Compound 1 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (hereinafter referred to as Reference Compound 1) represented by the formula (1) is the above-mentioned patent document. 1 can be produced by the production method described in 1.
  • the co-crystal of the present invention is a co-crystal of Reference Compound 1 and a fatty acid having 14 to 17 carbon atoms.
  • the co-crystal is composed of Reference Compound 1 and a fatty acid having 14 to 17 carbon atoms in a molar ratio of about 1: 0.5 to 1: 2, particularly about 1: 1.
  • the constituent molar ratio of the reference compound 1 and the fatty acid having 14 to 17 carbon atoms can be determined by the integral ratio of 1 H-NMR. That is, in 1 H-NMR of the cocrystal, the constituent molar ratio of the cocrystal can be calculated from the ratio of the integral ratio of the peak derived from the reference compound 1 and the integral ratio of the peak derived from the fatty acid. Since the range of errors in the integration ratio of 1 H-NMR can be the range of errors in the constituent molar ratio of the co-crystal, the range of “1: 1 constituent ratio” can occur in the integration ratio of 1 H-NMR. A range of errors is included. 9 to 11 show 1 H-NMR of Reference Compound 1, palmitic acid, and myristic acid, and the constituent molar ratio of the cocrystal is determined by comparing these charts with the chart of the cocrystal. be able to.
  • fatty acid having 14 to 17 carbon atoms examples include margaric acid, palmitic acid, pentadecanoic acid and myristic acid, preferably a linear fatty acid having 14 to 17 carbon atoms, more preferably margaric acid, palmitic acid and myristic acid. Which is an acid.
  • the co-crystal of the present invention can be obtained by mixing the reference compound 1 and a fatty acid having 14 to 17 carbon atoms in a specific composition ratio in a solvent as necessary to precipitate the co-crystal.
  • the composition ratio capable of forming a co-crystal between the reference compound 1 and the fatty acid having 14 to 17 carbon atoms is 1: 0.5 to 1: 2). Until the mixture is heated and cooled after heating (the melting method).
  • solvents include ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran (THF), diethyl ether and diisopropyl ether, lower alcohols such as methanol, ethanol, isopropanol and n-butanol, chloroform, dichloromethane and carbon tetrachloride.
  • solvents include ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran (THF), diethyl ether and diisopropyl ether, lower alcohols such as methanol, ethanol, isopropanol and n-butanol, chloroform, dichloromethane and carbon tetrachloride.
  • Examples include chlorinated hydrocarbons, esters such as ethyl acetate, hydrocarbons such as hexane and cyclohexane, aromatic hydrocarbons such as benzene and toluene, and dioxane.
  • Preferred solvents are THF and acetone.
  • a solvent may be used independently and may mix and use 2 or more types of solvents.
  • the co-crystal of the present invention has an endothermic peak peak value measured by differential scanning calorimetry (hereinafter referred to as DSC), approximately when the rate of temperature increase during DSC measurement is 2 to 10 ° C./min. Detected between 40 and about 55 ° C.
  • DSC differential scanning calorimetry
  • the term “about” means ⁇ 5 ° C.
  • the peak top value of the endothermic peak measured by DSC varies depending on the range of temperature rise per minute.
  • the peak top value of the endothermic peak of the 1: 1 co-crystal of Reference Compound 1 and palmitic acid is:
  • the heating rate is 55 ° C. (co-crystal solvent: acetone) or 53 ° C. (co-crystal solvent: THF) at 10 ° C./min, and the heating rate is 2 ° C./min. 45.9 ° C. (co-crystal solvent: THF).
  • the peak top value of the endothermic peak of the 1: 1 co-crystal of Reference Compound 1 and myristic acid is 42.1 ° C. (co-crystal solvent: THF) at a heating rate of 2 ° C./min.
  • the peak top value of the endothermic peak of the 1: 1 co-crystal of Reference Compound 1 and margaric acid is 48.1 ° C. (no co-crystal solvent: none) at a rate of temperature rise of 2 ° C./min.
  • a cocrystal having a peak top value in a range obtained by adding “about” to the peak top value of each of the above cocrystals is included in the “cocrystal” of the present invention.
  • the peak top value of the endothermic peak varies depending on the solvent (for example, acetone and THF) in which the cocrystal is precipitated, and the crystal form of the cocrystal may be slightly different. Is included.
  • the 2 ⁇ peak of powder X-ray diffraction is 13.5, 14.9, 16.3, 19.4, 21.0, 22.9, 24.0, and either 1, 2, or 2 It may be characterized by 3, any 4, or any 5 or more peaks.
  • the co-crystal of Reference Compound 1 of the present invention and palmitic acid has 2 ⁇ peaks of powder X-ray diffraction of 7.7, 11.1, 11.8, 12.5, 13.3, 14.6, 17.1, 17.8, 18.8, 19.8, 20.5, 21.2, 22.0, 22.4, 24.2, 29.3 and may be characterized by any 1, any 2, any 3, any 4, or any 5 or more peaks. More preferably, the co-crystal of Reference Compound 1 and palmitic acid is any one of 7.7, 12.5, 17.1, 18.8, 22.0, 22.4, 24.2, any 2, any 3, any 4, or any 5 or Further peaks can be characterized. Particularly preferably, the co-crystal of Reference Compound 1 and palmitic acid can be characterized by peaks of 7.7, 18.8 and 22.4.
  • the 2 ⁇ peak of powder X-ray diffraction is 8.2, 12.1, 13.2, 14.3, 16.5, 18.7, 21.5, 22.0, 23.1, 23.6, 24.4, It may be characterized by 1, any 2, any 3, any 4, or any 5 or more peaks.
  • the peak value in the powder X-ray diffraction spectrum may cause some errors depending on the measurement equipment or the measurement conditions such as the peak reading condition.
  • the peak value may have a measurement error in the range of about ⁇ 0.2 ° 2 ⁇ .
  • FIGS. 1-3 Examples of powder X-ray diffraction patterns of co-crystals of Reference Compound 1 and margaric acid, palmitic acid, and myristic acid are shown in FIGS. 1-3, and examples of DSC charts are shown in FIGS. 4-6.
  • the present invention provides a pharmaceutical composition containing the co-crystal of the present invention.
  • the co-crystal of the present invention When used as a medicine, it can be combined with a pharmaceutical carrier, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of such forms include oral preparations, injections, and suppositories. Any of an agent, an ointment, a patch and the like may be used, and an oral agent is preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
  • a pharmaceutical carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.
  • excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid
  • a binder water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc.
  • the disintegrating agent include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose.
  • Phosphate, borax, polyethylene glycol and the like, as the colorant, titanium oxide, iron oxide, white as the flavoring agent sugar, orange peel, citric acid can be exemplified tartaric acid.
  • oral liquids, syrups, elixirs and the like can be produced by conventional methods by adding a corrigent, a buffer, a stabilizer, a corrigent and the like to the co-crystal of the present invention.
  • the flavoring and flavoring agents may be those listed above
  • examples of the buffer include sodium citrate
  • examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • pH adjusters When preparing injections, add pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, etc. to the co-crystal of the present invention, and then inject subcutaneously, intramuscularly and intravenously using conventional methods.
  • Agent can be produced.
  • examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate.
  • examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like.
  • local anesthetics include procaine hydrochloride and lidocaine hydrochloride.
  • isotonic agents include sodium chloride and glucose.
  • a pharmaceutical carrier known in the art such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc.
  • Tween registered trademark
  • bases, stabilizers, wetting agents, preservatives and the like that are usually used for the co-crystal of the present invention are blended as necessary, and mixed and formulated by conventional methods.
  • the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like.
  • the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
  • the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method.
  • a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane, or a film or foam sheet made of cotton, suf, or chemical fiber is suitable.
  • the amount of the co-crystal of the present invention to be incorporated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which it is applied, or its dosage form, but generally the reference compound per dosage unit form
  • the amount of 1 is preferably about 0.01 to 200 mg for oral preparations.
  • the daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 0.01 to 2000 mg / day, preferably 0.01
  • the dose may be ⁇ 200 mg and is preferably administered once a day or divided into 2 to 4 times.
  • the co-crystal of the present invention is used singly or in combination.
  • Diseases that can be treated by administering a drug containing the co-crystal of the present invention include dysuria, such as uninhibited neurogenic bladder, reflex neurogenic bladder, type 1 diabetic neurogenic bladder, 2 Type diabetic neurogenic bladder, diabetic neurogenic bladder, autonomic neurogenic bladder, flaccid neurogenic bladder, hypotonic bladder, other neurogenic bladder, postoperative bladder function decline, overactive bladder Non-neurogenic overactive bladder, detrusor sphincter dysfunction, bladder contraction failure, urethral insufficiency, bladder dysfunction, urethral dysfunction, stress urinary incontinence, overflow urinary incontinence, urge urinary incontinence, reflex Urinary incontinence, etc. and neurological disorders such as spinal cord injury, spinal canal stenosis, neuropathic pain, neuropathic sensory disorder, diabetic pain, diabetic sensory disorder, autonomic neuropathy, myasthenia gravis .
  • dysuria such as uninhibited neurogenic bladder, reflex neurogenic bladder, type 1
  • Examples 1 to 3 and Comparative Examples 1 to 11 Cocrystallization Screening by Melting Method Both compounds were mixed and heated to melt so that the reference compound 1 and the guest compound shown in Table 1 each had a molar ratio of 1: 1. Thereafter, it was confirmed whether or not a co-crystal was formed by cooling. When the product forms a solid compound and the differential scanning calorimetry (DSC) shows a decrease in the endothermic peak derived from the reference compound 1 and a new endothermic peak assumed to be derived from the co-crystal. It was judged that there was a possibility that a co-crystal was formed.
  • DSC differential scanning calorimetry
  • arachidic acid, stearic acid, palmitic acid ascorbic acid ester, 1-hexadecanol and 16-hydroxyhexadecanoic acid which are fatty acids having 20 and 18 carbon atoms, have an endothermic peak derived from Reference Compound 1 together with a new endothermic peak. It was detected and suggested the possibility of partial co-crystallization.
  • Co-crystallization was not observed for other fatty acids such as lauric acid having 12 or 10 carbon atoms, decanoic acid, or ester thereof.
  • Test Example 1 Screening of co-crystallization by solvent evaporation Palmitic acid, stearic acid, and ascorbyl palmitate suggested to form uniform co-crystals or partial co-crystals in Example 2 and Comparative Examples 2 and 5 The acid ester was examined for co-crystallization with Reference Compound 1 by solvent evaporation.
  • Reference compound 1 and guest compound (palmitic acid, stearic acid, palmitic ascorbic acid ester) are mixed and dissolved in a solvent at a molar ratio of 1: 0.5 to 1: 2.0, and then the solvent is volatilized naturally with stirring. The co-crystallization was examined.
  • a solvent ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, chloroform, and dichloromethane were used.
  • Test Example 2 Verification Test of Cocrystallization
  • Examples 2, 3, and Comparative Examples 2, 5 palmitic acid, myristic acid, stearic acid, and palmitic acid ascorbic acid ester, which were suggested to cocrystallize with reference compound 1, were guest.
  • Reference compound 1 100 mg, 0.274 mmol
  • guest compound 0.274 mmol
  • Measuring device JNM-EX270 (manufactured by JEOL Ltd.) Measuring solvent: DMSO-d6 The results are shown in Table 3.
  • the configuration molar ratio for example, in the case of palmitic acid co-crystal, the peak integration ratio of around 2.15 ppm ⁇ 2.20 ppm in 1 H -NMR chart of FIG. 7, the peak around 2.16 ppm in the 1 H-NMR chart of FIG. 9 And the integral ratio of the peak around 2.15 ppm to 2.20 ppm in the 1 H-NMR chart of FIG.
  • Powder X-ray measurement conditions Measuring device: X'Pert PRO MPD (manufactured by PANalytical) Scanning range (2 ⁇ ): 2 to 40 ° Scanning speed: 0.2 ° / s Tube voltage: 40 kV Tube current: 30 mA
  • Test Example 3 Pharmacokinetic study (rat) Reference compound 1 and the co-crystal of the present invention (co-crystal of reference compound 1 and palmitic acid, co-crystal of reference compound 1 and myristic acid, and co-crystal of reference compound 1 and margaric acid, the constituent moles of the co-crystal The ratio was 1: 1), and a drug suspension (3 mg / mL as the reference compound 1 equivalent concentration) was prepared with 0.5% HPMC. The number of rats in each group was 4 and each drug suspension was orally administered to rats (Wistar, female, 6 weeks old) using an oral sonde (30 mg / kg as the reference compound 1 equivalent). .
  • Blood was collected from the jugular vein using a heparinized syringe at each blood collection point (0.5, 1, 2, 4, 6, 8, 24 hr). The collected blood was centrifuged (13000 rpm, 2 min, 4 ° C.), and the concentration of Reference Compound 1 in plasma was measured by LC / MS / MS. Table 4 shows the measurement results.
  • the co-crystal of the present invention showed an improvement of about 2 to 23 times C max and about 2 to 14 times AUC 0-24hr as compared to Reference Compound 1. .
  • C max of co-crystal with palmitic acid increased more than 20 times and AUC 0-24hr increased more than 10 times
  • C max of co-crystal with myristic acid and AUC 0-24hr were also higher than reference compound 1.
  • the AUC 0-24hr of the co-crystal with margaric acid was also significantly increased with respect to the reference compound 1, and it was revealed that the co-crystal of the present invention significantly improved the pharmacokinetics.

Abstract

The present invention is a cocrystal of 3-(15-hydroxypentadecyl)-2,4,4-trimethyl-2-cyclohexen-1-one and a C14-17 fatty acid.

Description

3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンの共結晶Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one
（関連分野の相互参照）
　本願は、2012年3月29日に出願した特願2012-075604号明細書（その全体が参照により本明細書中に援用される）の優先権の利益を主張するものである。 (Cross-reference of related fields)
This application claims the benefit of priority of Japanese Patent Application No. 2012-075604 filed on Mar. 29, 2012, the entirety of which is incorporated herein by reference.
　本発明は、医薬として有用な、 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オン新規共結晶、その製造方法、それを含有する医薬組成物に関する。 The present invention relates to a novel co-crystal 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one useful as a pharmaceutical, a process for producing the same, and a pharmaceutical composition containing the same .
　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンは、構造が下記式（１）で表される化合物である。 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one is a compound having a structure represented by the following formula (1).
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　特許文献１において、式（１）で表される化合物を含むシクロヘキセノン長鎖アルコールが神経成長促進作用を示し、痴呆症等の脳疾患予防・治療用の医薬として有用であることが記載されている。また例えば特許文献２において、前立腺肥大症に代表される排尿障害治療剤として有用であることも知られている。 Patent Document 1 describes that a cyclohexenone long-chain alcohol containing a compound represented by the formula (1) exhibits a nerve growth promoting action and is useful as a medicament for the prevention / treatment of brain diseases such as dementia. Yes. Further, for example, in Patent Document 2, it is also known that it is useful as a therapeutic agent for dysuria represented by prostatic hypertrophy.
　しかしながら、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オン自体は常温においてロウ状の化合物であり、低融点（約30 ℃）のため融解しやすい化合物であることから、医薬品として開発する場合には、製剤化における困難性等に懸念があった。 However, 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one itself is a waxy compound at room temperature and is easy to melt because of its low melting point (about 30 ° C). Since it is a compound, when it was developed as a pharmaceutical, there was a concern about difficulty in formulation.
　一般的に共結晶とは、ホスト化合物が、室温で固体である物質（ゲスト化合物）と何らかの作用、例えば水素結合や分子間力等により結晶化したものと定義され、イオン結合により結晶化する塩とは明確に区別されている（例えば非特許文献１）。共結晶の形成は、単一化合物のみから構成される結晶では得られない機能や物性の発現を可能にするが、ホスト化合物とゲスト化合物とが共結晶を形成するためには、例えば一方が酸性部位を有し、他方が塩基性部位を有するなど、異なる化合物同士を選択的に相互作用させることが可能な場合でないと困難であることが知られている。すなわち、共結晶が得られるためのホスト化合物とゲスト化合物の組合せについては予測困難性が高い。 In general, a co-crystal is defined as a substance in which a host compound is crystallized with a substance (guest compound) that is solid at room temperature by some action, such as hydrogen bonding or intermolecular force, and crystallizes by ionic bonding. Is clearly distinguished (for example, Non-Patent Document 1). The formation of a co-crystal enables functions and physical properties that cannot be obtained with a crystal composed of only a single compound. However, in order for a host compound and a guest compound to form a co-crystal, for example, one of them is acidic. It is known that it is difficult to selectively interact with different compounds such as having a site and the other having a basic site. That is, the combination of a host compound and a guest compound for obtaining a co-crystal is highly difficult to predict.
　上記特許文献、及び非特許文献においては、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンの結晶多型に関する具体的な記載はなく、共結晶については全く示唆されてもいない。 In the above-mentioned patent documents and non-patent documents, there is no specific description regarding the crystal polymorphism of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one. There is no suggestion about.
国際公開WO1999/008987号公報International Publication WO1999 / 008987 Publication 国際公開WO2002/066024号公報International Publication WO2002 / 066024 Publication
　本発明は医薬品として有用で、経口吸収性に優れた3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンの共結晶、及びその医薬組成物を提供することを目的とする。 The present invention provides a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one that is useful as a pharmaceutical and has excellent oral absorption, and a pharmaceutical composition thereof The purpose is to do.
　本発明者らは、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンについて、医薬品として優れた物性を有する新規結晶、特に新規な共結晶を得ることを目的として検討した。その結果、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと特定の脂肪酸との組合せにおいて、より高融点の共結晶を見出した。しかも全く予想しなかったことに、後述するラットを用いた薬物動態試験（PK試験）において、公知の3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンに比較して、本発明の共結晶は約２倍～23倍のCmax、及び約２倍～14倍のAUC0-24hrの改善が認められ、本発明を完成した。 The present inventors obtain a novel crystal having excellent physical properties as a pharmaceutical, particularly a novel co-crystal, for 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one. We examined for the purpose. As a result, a co-crystal having a higher melting point was found in the combination of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a specific fatty acid. Moreover, in the pharmacokinetic test (PK test) using rats described later, the known 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexene-1- Compared to ON, the co-crystal of the present invention showed an improvement of about 2 to 23 times C max and about 2 to 14 times AUC 0-24hr , thus completing the present invention.
　本発明の一態様によれば、式（I）で表される3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと炭素数14～17の脂肪酸との共結晶が提供される。 According to one embodiment of the present invention, 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one represented by formula (I) and a fatty acid having 14 to 17 carbon atoms A co-crystal with is provided.
Figure JPOXMLDOC01-appb-C000002
Figure JPOXMLDOC01-appb-C000002
　一実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと炭素数14～17の直鎖脂肪酸との共結晶が提供される。 In one embodiment, a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a linear fatty acid having 14 to 17 carbon atoms is provided.
　別の実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、マルガリン酸、パルミチン酸、又はミリスチン酸との共結晶が提供される。 In another embodiment, a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid, palmitic acid, or myristic acid is provided. .
　別の実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、マルガリン酸、パルミチン酸、又はミリスチン酸とが、１：0.5から１：２までの構成モル比で構成される共結晶が提供される。 In another embodiment, 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid, palmitic acid, or myristic acid are from 1: 0.5 to 1 A co-crystal composed of a constituent molar ratio of up to 2 is provided.
　別の実施形態において、上記共結晶の構成モル比は、１：１であってよい。 In another embodiment, the constituent molar ratio of the co-crystal may be 1: 1.
　別の実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、パルミチン酸との共結晶であって、7.7、12.5、17.1、18.8、22.0、22.4、24.2のいずれか１、いずれか２、いずれか３、いずれか４、若しくはいずれか５またはそれ以上のピークを特徴とする共結晶。 In another embodiment, a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid comprising 7.7, 12.5, 17.1, 18.8 , 22.0, 22.4, 24.2, any one, any two, any three, any four, or any five or more co-crystals.
　別の実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、パルミチン酸との共結晶であって、7.7、18.8及び22.4のピークを特徴とする共結晶が提供される。 In another embodiment, a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid having peaks of 7.7, 18.8 and 22.4 A co-crystal characterized by is provided.
　別の実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと炭素数14～17の脂肪酸との共結晶であって示差走査熱量測定により測定される吸熱ピークのピークトップ値が、DSC測定時の昇温速度が2～10 ℃/minの場合に、約40～約55 ℃の間である共結晶が提供される。
別の実施形態において、3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、パルミチン酸との共結晶であって、示差走査熱量測定により測定される吸熱ピークのピークトップ値が、DSC測定時の昇温速度が2 ℃/minの場合に、約45.9 ℃である共結晶。 In another embodiment, differential scanning calorimetry, a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a fatty acid having 14 to 17 carbon atoms A co-crystal is provided in which the peak top value of the endothermic peak measured by is between about 40 and about 55 ° C. when the rate of temperature increase during DSC measurement is between 2 and 10 ° C./min.
In another embodiment, a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid, measured by differential scanning calorimetry. A co-crystal with a peak top value of approximately 45.9 ° C when the temperature rise rate during DSC measurement is 2 ° C / min.
　別の実施形態において、上記のいずれかに記載の共結晶を有効成分として含む医薬組成物が提供される。 In another embodiment, a pharmaceutical composition comprising any of the above-described co-crystals as an active ingredient is provided.
　本発明によれば、医薬品として有用で、経口吸収性、安定性等に優れた3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンの共結晶、及びその医薬組成物を提供できる。本発明の共結晶及び医薬組成物は製剤化のハンドリングが容易である。 According to the present invention, 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one co-crystal that is useful as a pharmaceutical and has excellent oral absorption, stability, and the like, And a pharmaceutical composition thereof. The co-crystal and pharmaceutical composition of the present invention are easy to handle for formulation.
3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとマルガリン酸の共結晶の粉末Ｘ線回折チャートPowder X-ray diffraction chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとパルミチン酸の共結晶の粉末Ｘ線回折チャートX-ray powder diffraction chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとミリスチン酸の共結晶の粉末Ｘ線回折チャートX-ray powder diffraction chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and myristic acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとマルガリン酸の共結晶のDSCチャートDSC chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとパルミチン酸の共結晶のDSCチャートDSC chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとミリスチン酸の共結晶のDSCチャートDSC chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and myristic acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとパルミチン酸の共結晶の1H -NMRチャート 1 H-NMR chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンとミリスチン酸の共結晶の1H -NMRチャート 1 H-NMR chart of co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and myristic acid 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンの1H -NMRチャート 1 H-NMR chart of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one パルミチン酸の1H -NMRチャート 1 H-NMR chart of palmitic acid ミリスチン酸の1H -NMRチャート 1 H-NMR chart of myristic acid
　本発明において、式（１）で表される3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オン（以下、参考化合物１）は、前述の特許文献１に記載された製造方法によって製造できる。 In the present invention, 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one (hereinafter referred to as Reference Compound 1) represented by the formula (1) is the above-mentioned patent document. 1 can be produced by the production method described in 1.
　本発明の共結晶は、参考化合物１と炭素数14～17の脂肪酸との共結晶である。 The co-crystal of the present invention is a co-crystal of Reference Compound 1 and a fatty acid having 14 to 17 carbon atoms.
　共結晶は、参考化合物１と炭素数14～17の脂肪酸とが、１：0.5から１：２までの範囲程度、特に１：１程度の構成モル比で構成される。 The co-crystal is composed of Reference Compound 1 and a fatty acid having 14 to 17 carbon atoms in a molar ratio of about 1: 0.5 to 1: 2, particularly about 1: 1.
　なお参考化合物１と炭素数14～17の脂肪酸の構成モル比は、1H -NMRの積分比で定めることができる。すなわち共結晶の1H -NMRにおいて、参考化合物１に由来するピークの積分比と、脂肪酸に由来するピークの積分比との比より、共結晶の構成モル比を算出することができる。1H -NMRの積分比の誤差の範囲が、共結晶の構成モル比の誤差の範囲となり得るため、「１：１の構成比」の範囲には、1H -NMRの積分比において生じうる誤差の範囲が包含される。図９～図１１には、参考化合物１、パルミチン酸、ミリスチン酸の1H -NMRが示されており、これらのチャートと共結晶のチャートを比較することで、共結晶の構成モル比を定めることができる。 The constituent molar ratio of the reference compound 1 and the fatty acid having 14 to 17 carbon atoms can be determined by the integral ratio of 1 H-NMR. That is, in 1 H-NMR of the cocrystal, the constituent molar ratio of the cocrystal can be calculated from the ratio of the integral ratio of the peak derived from the reference compound 1 and the integral ratio of the peak derived from the fatty acid. Since the range of errors in the integration ratio of 1 H-NMR can be the range of errors in the constituent molar ratio of the co-crystal, the range of “1: 1 constituent ratio” can occur in the integration ratio of 1 H-NMR. A range of errors is included. 9 to 11 show 1 H-NMR of Reference Compound 1, palmitic acid, and myristic acid, and the constituent molar ratio of the cocrystal is determined by comparing these charts with the chart of the cocrystal. be able to.
　炭素数14～17の脂肪酸としては、マルガリン酸、パルミチン酸、ペンタデカン酸、ミリスチン酸が挙げられ、好ましくは炭素数14～17の直鎖脂肪酸であり、より好ましくはマルガリン酸、パルミチン酸、及びミリスチン酸が挙げられる 。 Examples of the fatty acid having 14 to 17 carbon atoms include margaric acid, palmitic acid, pentadecanoic acid and myristic acid, preferably a linear fatty acid having 14 to 17 carbon atoms, more preferably margaric acid, palmitic acid and myristic acid. Which is an acid.
　本発明の共結晶は、参考化合物１と炭素数14～17の脂肪酸を特定の構成比で、必要に応じて溶媒中で混合し、共結晶を析出させることで得ることができる。溶媒を使用しない場合には、参考化合物１と炭素数14～17の脂肪酸を、共結晶を形成できる構成比(例えば参考化合物１と炭素数14～17の脂肪酸が、１：0.5から１：２までの範囲程度)で混合し、加熱後に冷却することで共結晶を析出させる（融解法）。溶媒を使用する場合には、参考化合物１と炭素数14～17の脂肪酸を適切な比率で、必要に応じて加熱しながら溶媒に溶解し、溶媒を蒸発させるか、参考化合物１の溶解度を低下させる溶媒(貧溶媒)を徐々に加えるなどの方法で、共結晶を析出させることができる。溶媒としては、アセトン、メチルエチルケトンなどのケトン類、テトラヒドロフラン（THF）、ジエチルエーテル、ジイソプロピルエーテルなどのエーテル類、メタノール、エタノール、イソプロパノール、n-ブタノールなどの低級アルコール、クロロホルム、ジクロロメタン、四塩化炭素などの塩素化炭化水素、酢酸エチルなどのエステル類、ヘキサン、シクロヘキサンなどの炭化水素、ベンゼン、トルエンなどの芳香族炭化水素、ジオキサンなどが挙げられ、好ましい溶媒はTHF、アセトンである。溶媒は単独で使用してもよく、２種以上の溶媒を混合して使用してもよい。 The co-crystal of the present invention can be obtained by mixing the reference compound 1 and a fatty acid having 14 to 17 carbon atoms in a specific composition ratio in a solvent as necessary to precipitate the co-crystal. In the case where no solvent is used, the composition ratio capable of forming a co-crystal between the reference compound 1 and the fatty acid having 14 to 17 carbon atoms (for example, the reference compound 1 and the fatty acid having 14 to 17 carbon atoms is 1: 0.5 to 1: 2). Until the mixture is heated and cooled after heating (the melting method). When using a solvent, dissolve Reference Compound 1 and a fatty acid having 14 to 17 carbon atoms in an appropriate ratio in the solvent while heating, if necessary, and evaporate the solvent or reduce the solubility of Reference Compound 1 The co-crystal can be precipitated by a method such as gradually adding a solvent (poor solvent) to be added. Solvents include ketones such as acetone and methyl ethyl ketone, ethers such as tetrahydrofuran (THF), diethyl ether and diisopropyl ether, lower alcohols such as methanol, ethanol, isopropanol and n-butanol, chloroform, dichloromethane and carbon tetrachloride. Examples include chlorinated hydrocarbons, esters such as ethyl acetate, hydrocarbons such as hexane and cyclohexane, aromatic hydrocarbons such as benzene and toluene, and dioxane. Preferred solvents are THF and acetone. A solvent may be used independently and may mix and use 2 or more types of solvents.
　本発明の共結晶は、示差走査熱量測定（Differential scanning calorimetry、以下DSC）により測定される吸熱ピークのピークトップ値が、DSC測定時の昇温速度が2～10 ℃/minの場合に、約40～約55 ℃の間に検出される。 The co-crystal of the present invention has an endothermic peak peak value measured by differential scanning calorimetry (hereinafter referred to as DSC), approximately when the rate of temperature increase during DSC measurement is 2 to 10 ° C./min. Detected between 40 and about 55 ° C.
　これに関して、「約」という用語は±5 ℃を意味する。DSCにより測定される吸熱ピークのピークトップ値は、１分あたりの昇温の幅により測定温度が変化し、例えば参考化合物１とパルミチン酸の１：１共結晶の吸熱ピークのピークトップ値は、後述の試験例で示されるように、昇温速度:10 ℃/minで55 ℃（共結晶溶媒：アセトン）または53 ℃(共結晶溶媒：THF)であり、昇温速度:2 ℃/minで45.9 ℃（共結晶溶媒：THF)である。参考化合物１とミリスチン酸の１：１共結晶の吸熱ピークのピークトップ値は、昇温速度:2 ℃/minで42.1 ℃（共結晶溶媒：THF)である。参考化合物１とマルガリン酸の１：１共結晶の吸熱ピークのピークトップ値は、昇温速度:2 ℃/minで48.1 ℃（共結晶溶媒：なし)である。上記の各共結晶のピークトップ値に「約」を付けた範囲のピークトップ値を有する共結晶は、本発明の「共結晶」に包含される。また、吸熱ピークのピークトップ値は、共結晶を析出させる溶媒（例えば、アセトンとTHF）によって異なり、共結晶の結晶形が多少異なる可能性があるが、これらはいずれも本発明の「共結晶」に包含される。 In this regard, the term “about” means ± 5 ° C. The peak top value of the endothermic peak measured by DSC varies depending on the range of temperature rise per minute. For example, the peak top value of the endothermic peak of the 1: 1 co-crystal of Reference Compound 1 and palmitic acid is: As shown in the test examples described later, the heating rate is 55 ° C. (co-crystal solvent: acetone) or 53 ° C. (co-crystal solvent: THF) at 10 ° C./min, and the heating rate is 2 ° C./min. 45.9 ° C. (co-crystal solvent: THF). The peak top value of the endothermic peak of the 1: 1 co-crystal of Reference Compound 1 and myristic acid is 42.1 ° C. (co-crystal solvent: THF) at a heating rate of 2 ° C./min. The peak top value of the endothermic peak of the 1: 1 co-crystal of Reference Compound 1 and margaric acid is 48.1 ° C. (no co-crystal solvent: none) at a rate of temperature rise of 2 ° C./min. A cocrystal having a peak top value in a range obtained by adding “about” to the peak top value of each of the above cocrystals is included in the “cocrystal” of the present invention. Moreover, the peak top value of the endothermic peak varies depending on the solvent (for example, acetone and THF) in which the cocrystal is precipitated, and the crystal form of the cocrystal may be slightly different. Is included.
　本発明の参考化合物１とマルガリン酸の共結晶は、粉末Ｘ線回折の２θのピークが、13.5、14.9、16.3、19.4、21.0、22.9、24.0であり、いずれか１、いずれか２、いずれか３、いずれか４、若しくはいずれか５またはそれ以上のピークを特徴とし得る。 In the co-crystal of Reference Compound 1 of the present invention and margaric acid, the 2θ peak of powder X-ray diffraction is 13.5, 14.9, 16.3, 19.4, 21.0, 22.9, 24.0, and either 1, 2, or 2 It may be characterized by 3, any 4, or any 5 or more peaks.
　本発明の参考化合物１とパルミチン酸の共結晶は、粉末Ｘ線回折の２θのピークが、7.7、11.1、11.8、12.5、13.3、14.6、17.1、17.8、18.8、19.8、20.5、21.2、22.0、22.4、24.2、29.3であり、いずれか１、いずれか２、いずれか３、いずれか４、若しくはいずれか５またはそれ以上のピークを特徴とし得る。より好ましくは、参考化合物１とパルミチン酸の共結晶は、7.7、12.5、17.1、18.8、22.0、22.4、24.2のいずれか１、いずれか２、いずれか３、いずれか４、若しくはいずれか５またはそれ以上のピークを特徴とし得る。特に好ましくは、参考化合物１とパルミチン酸の共結晶は、7.7、18.8及び22.4のピークを特徴とし得る。 The co-crystal of Reference Compound 1 of the present invention and palmitic acid has 2θ peaks of powder X-ray diffraction of 7.7, 11.1, 11.8, 12.5, 13.3, 14.6, 17.1, 17.8, 18.8, 19.8, 20.5, 21.2, 22.0, 22.4, 24.2, 29.3 and may be characterized by any 1, any 2, any 3, any 4, or any 5 or more peaks. More preferably, the co-crystal of Reference Compound 1 and palmitic acid is any one of 7.7, 12.5, 17.1, 18.8, 22.0, 22.4, 24.2, any 2, any 3, any 4, or any 5 or Further peaks can be characterized. Particularly preferably, the co-crystal of Reference Compound 1 and palmitic acid can be characterized by peaks of 7.7, 18.8 and 22.4.
　本発明の参考化合物１とミリスチン酸の共結晶は、粉末Ｘ線回折の２θのピークが、8.2、12.1、13.2、14.3、16.5、18.7、21.5、22.0、23.1、23.6、24.4であり、いずれか１、いずれか２、いずれか３、いずれか４、若しくはいずれか５またはそれ以上のピークを特徴とし得る。  In the co-crystal of Reference Compound 1 of the present invention and myristic acid, the 2θ peak of powder X-ray diffraction is 8.2, 12.1, 13.2, 14.3, 16.5, 18.7, 21.5, 22.0, 23.1, 23.6, 24.4, It may be characterized by 1, any 2, any 3, any 4, or any 5 or more peaks.
　なお粉末Ｘ線回折スペクトルにおけるピーク値は、測定機器により、もしくはピークの読み取り条件等の測定条件により、多少の誤差を生じることがある。本明細書においてピーク値は、±0.2°２θ程度の範囲で測定誤差を有し得る。 Note that the peak value in the powder X-ray diffraction spectrum may cause some errors depending on the measurement equipment or the measurement conditions such as the peak reading condition. In this specification, the peak value may have a measurement error in the range of about ± 0.2 ° 2θ.
　参考化合物１とマルガリン酸、パルミチン酸、ミリスチン酸との共結晶の粉末Ｘ線回折パターンの一例を図１～３に、DSCチャートの一例を図４～６に示す。 Examples of powder X-ray diffraction patterns of co-crystals of Reference Compound 1 and margaric acid, palmitic acid, and myristic acid are shown in FIGS. 1-3, and examples of DSC charts are shown in FIGS. 4-6.
　本発明は、本発明の共結晶を含有する医薬組成物を提供するものである。 The present invention provides a pharmaceutical composition containing the co-crystal of the present invention.
　本発明の共結晶を医薬として用いるにあたっては、薬学的担体と配合し、予防又は治療目的に応じて各種の投与形態を採用可能であり、該形態としては、例えば、経口剤、注射剤、坐剤、軟膏剤、貼付剤等のいずれでもよく、好ましくは、経口剤が採用される。これらの投与形態は、各々当業者に公知慣用の製剤方法により製造できる。 When the co-crystal of the present invention is used as a medicine, it can be combined with a pharmaceutical carrier, and various administration forms can be adopted depending on the purpose of prevention or treatment. Examples of such forms include oral preparations, injections, and suppositories. Any of an agent, an ointment, a patch and the like may be used, and an oral agent is preferably employed. Each of these dosage forms can be produced by a conventional formulation method known to those skilled in the art.
　薬学的担体としては、製剤素材として慣用の各種有機あるいは無機担体物質が用いられ、固形製剤における賦形剤、滑沢剤、結合剤、崩壊剤、液状製剤における溶剤、溶解補助剤、懸濁化剤、等張化剤、緩衝剤、無痛化剤等として配合される。また、必要に応じて防腐剤、抗酸化剤、着色剤、甘味剤などの製剤添加物を用いることもできる。 As a pharmaceutical carrier, various organic or inorganic carrier substances commonly used as pharmaceutical materials are used. Excipients, lubricants, binders, disintegrants in solid preparations, solvents in liquid preparations, solubilizers, suspensions It is blended as an agent, isotonic agent, buffer, soothing agent and the like. In addition, formulation additives such as preservatives, antioxidants, colorants, sweeteners and the like can be used as necessary.
　経口用固形製剤を調製する場合は、本発明の共結晶に賦形剤、必要に応じて結合剤、崩壊剤、滑沢剤、着色剤、矯味・矯臭剤等を加えた後、常法により錠剤、被覆錠剤、顆粒剤、散剤、カプセル剤等を製造することができる。そのような添加剤としては、当該分野で一般的に使用されるものでよく、例えば、賦形剤としては、乳糖、白糖、塩化ナトリウム、ブドウ糖、デンプン、炭酸カルシウム、カオリン、微結晶セルロース、珪酸等を、結合剤としては、水、エタノール、プロパノール、単シロップ、ブドウ糖液、デンプン液、ゼラチン液、カルボキシメチルセルロース、ヒドロキシプロピルセルロース、ヒドロキシプロピルスターチ、メチルセルロース、エチルセルロース、シェラック、リン酸カルシウム、ポリビニルピロリドン等が用いられ、崩壊剤としては、乾燥デンプン、アルギン酸ナトリウム、カンテン末、炭酸水素ナトリウム、炭酸カルシウム、ラウリル硫酸ナトリウム、ステアリン酸モノグリセリド、乳糖等を、滑沢剤としては、精製タルク、ステアリン酸塩、ホウ砂、ポリエチレングリコール等を、着色剤としては、酸化チタン、酸化鉄等を、矯味・矯臭剤としては白糖、橙皮、クエン酸、酒石酸等を例示できる。 When preparing an oral solid preparation, after adding an excipient, a binder, a disintegrant, a lubricant, a coloring agent, a flavoring / flavoring agent, etc. to the co-crystal of the present invention, if necessary, by a conventional method Tablets, coated tablets, granules, powders, capsules and the like can be produced. Such additives may be those commonly used in the art. For example, excipients include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, silicic acid As a binder, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. are used. Examples of the disintegrating agent include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium lauryl sulfate, stearic acid monoglyceride, and lactose. Phosphate, borax, polyethylene glycol and the like, as the colorant, titanium oxide, iron oxide, white as the flavoring agent sugar, orange peel, citric acid, can be exemplified tartaric acid.
　経口用液体製剤を調製する場合は、本発明の共結晶に矯味剤、緩衝剤、安定化剤、矯臭剤等を加えて常法により内服液剤、シロップ剤、エリキシル剤等を製造することができる。この場合矯味・矯臭剤としては、上記に挙げられたものでよく、緩衝剤としては、クエン酸ナトリウム等が、安定剤としては、トラガント、アラビアゴム、ゼラチン等が挙げられる。 When an oral liquid preparation is prepared, oral liquids, syrups, elixirs and the like can be produced by conventional methods by adding a corrigent, a buffer, a stabilizer, a corrigent and the like to the co-crystal of the present invention. . In this case, the flavoring and flavoring agents may be those listed above, examples of the buffer include sodium citrate, and examples of the stabilizer include tragacanth, gum arabic, and gelatin.
　注射剤を調製する場合は、本発明の共結晶にｐＨ調節剤、緩衝剤、安定化剤、等張化剤、局所麻酔剤等を添加し、常法により皮下、筋肉内及び静脈内用注射剤を製造することができる。この場合のｐＨ調節剤及び緩衝剤としては、クエン酸ナトリウム、酢酸ナトリウム、リン酸ナトリウム等が挙げられる。安定化剤としては、ピロ亜硫酸ナトリウム、ＥＤＴＡ、チオグリコール酸、チオ乳酸等が挙げられる。局所麻酔剤としては、塩酸プロカイン、塩酸リドカイン等が挙げられる。等張化剤としては、塩化ナトリウム、ブドウ糖等が例示できる。 When preparing injections, add pH adjusters, buffers, stabilizers, tonicity agents, local anesthetics, etc. to the co-crystal of the present invention, and then inject subcutaneously, intramuscularly and intravenously using conventional methods. Agent can be produced. In this case, examples of the pH adjuster and buffer include sodium citrate, sodium acetate, and sodium phosphate. Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid and the like. Examples of local anesthetics include procaine hydrochloride and lidocaine hydrochloride. Examples of isotonic agents include sodium chloride and glucose.
　坐剤を調製する場合は、本発明の共結晶に当業界において公知の製剤用担体、例えば、ポリエチレングリコール、ラノリン、カカオ脂、脂肪酸トリグリセリド等を、さらに必要に応じてツイーン（登録商標）のような界面活性剤等を加えた後、常法により製造することができる。 When preparing a suppository, a pharmaceutical carrier known in the art, such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, etc., is added to the co-crystal of the present invention, if necessary, such as Tween (registered trademark). After adding a surfactant or the like, it can be produced by a conventional method.
　軟膏剤を調製する場合は、本発明の共結晶に通常使用される基剤、安定剤、湿潤剤、保存剤等が必要に応じて配合され、常法により混合、製剤化される。基剤としては、流動パラフィン、白色ワセリン、サラシミツロウ、オクチルドデシルアルコール、パラフィン等が挙げられる。保存剤としては、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル等が挙げられる。 When preparing an ointment, bases, stabilizers, wetting agents, preservatives and the like that are usually used for the co-crystal of the present invention are blended as necessary, and mixed and formulated by conventional methods. Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyldodecyl alcohol, paraffin and the like. Examples of the preservative include methyl paraoxybenzoate, ethyl paraoxybenzoate, and propyl paraoxybenzoate.
　貼付剤を調製する場合は、通常の支持体に前記軟膏、クリーム、ゲル、ペースト等を常法により塗布すればよい。支持体としては、綿、スフ、化学繊維からなる織布、不織布や軟質塩化ビニル、ポリエチレン、ポリウレタン等のフィルムあるいは発泡体シートが適当である。 When preparing a patch, the ointment, cream, gel, paste or the like may be applied to a normal support by a conventional method. As the support, a woven fabric, nonwoven fabric, soft vinyl chloride, polyethylene, polyurethane, or a film or foam sheet made of cotton, suf, or chemical fiber is suitable.
　上記の各投与単位形態中に配合されるべき本発明の共結晶の量は、これを適用すべき患者の症状により、あるいはその剤形等により一定ではないが、一般に投与単位形態あたり、参考化合物１の量として経口剤では約0.01～200 mgとするのが望ましい。また、上記投与形態を有する薬剤の１日あたりの投与量は、患者の症状、体重、年齢、性別等によって異なり一概には決定できないが、通常成人１日あたり約0.01～2000 mg、好ましくは0.01～200 mgとすればよく、これを１日１回又は２～４回程度に分けて投与するのが好ましい。尚、本発明において、本発明の共結晶は、一種単独または複数種を組み合わせて用いられる。 The amount of the co-crystal of the present invention to be incorporated in each of the above dosage unit forms is not constant depending on the symptoms of the patient to which it is applied, or its dosage form, but generally the reference compound per dosage unit form The amount of 1 is preferably about 0.01 to 200 mg for oral preparations. The daily dose of the drug having the above dosage form varies depending on the patient's symptoms, body weight, age, sex, etc., and cannot be determined unconditionally, but is usually about 0.01 to 2000 mg / day, preferably 0.01 The dose may be ˜200 mg and is preferably administered once a day or divided into 2 to 4 times. In the present invention, the co-crystal of the present invention is used singly or in combination.
　本発明の共結晶を含有する薬剤を投与することにより治療できる疾病としては、排尿障害、例えば、無抑制性神経因性膀胱、反射性神経因性膀胱、１型糖尿病性神経因性膀胱、２型糖尿病性神経因性膀胱、糖尿病性神経因性膀胱、自律性神経因性膀胱、弛緩性神経因性膀胱、低緊張性膀胱、その他の神経因性膀胱、術後膀胱機能低下、過活動膀胱、非神経因性過活動膀胱、排尿筋尿道括約筋協調不全、膀胱収縮不全、尿道弛緩不全、膀胱機能障害、尿道機能障害、腹圧性尿失禁、溢流性尿失禁、切迫性尿失禁、反射性尿失禁等、及び神経障害、例えば、脊髄損傷、脊柱管狭窄症、神経因性疼痛、神経因性感覚障害、糖尿病性疼痛、糖尿病性感覚障害、自律神経障害、重症筋無力症等が挙げられる。 Diseases that can be treated by administering a drug containing the co-crystal of the present invention include dysuria, such as uninhibited neurogenic bladder, reflex neurogenic bladder, type 1 diabetic neurogenic bladder, 2 Type diabetic neurogenic bladder, diabetic neurogenic bladder, autonomic neurogenic bladder, flaccid neurogenic bladder, hypotonic bladder, other neurogenic bladder, postoperative bladder function decline, overactive bladder Non-neurogenic overactive bladder, detrusor sphincter dysfunction, bladder contraction failure, urethral insufficiency, bladder dysfunction, urethral dysfunction, stress urinary incontinence, overflow urinary incontinence, urge urinary incontinence, reflex Urinary incontinence, etc. and neurological disorders such as spinal cord injury, spinal canal stenosis, neuropathic pain, neuropathic sensory disorder, diabetic pain, diabetic sensory disorder, autonomic neuropathy, myasthenia gravis .
　以下、本発明を実施例及び比較例に基づきより詳細に説明する。
実施例１～３、比較例１～11　融解法による共結晶化スクリーニング
　参考化合物１と、表１に示すゲスト化合物がそれぞれ１：１のモル比となるように両化合物を混合し、加熱融解した後、放冷することにより共結晶を形成するか確認した。生成物が固形化合物を形成し、且つ示差走査熱量測定（Differential scanning calorimetry、以下DSC）において参考化合物１由来の吸熱ピークの減少、及び共結晶由来と想定される新規吸熱ピークが確認された場合に、共結晶を形成している可能性があると判断した。 Hereinafter, the present invention will be described in more detail based on examples and comparative examples.
Examples 1 to 3 and Comparative Examples 1 to 11 Cocrystallization Screening by Melting Method Both compounds were mixed and heated to melt so that the reference compound 1 and the guest compound shown in Table 1 each had a molar ratio of 1: 1. Thereafter, it was confirmed whether or not a co-crystal was formed by cooling. When the product forms a solid compound and the differential scanning calorimetry (DSC) shows a decrease in the endothermic peak derived from the reference compound 1 and a new endothermic peak assumed to be derived from the co-crystal. It was judged that there was a possibility that a co-crystal was formed.
　以下の表１において、用いたゲスト化合物及びその融点を示し、参考化合物１と共結晶化していると判断された場合に○と、固形化合物が得られなかった場合に×、部分的に共結晶化している可能性が示唆された場合に△を記した。 In Table 1 below, the guest compound used and its melting point are shown. When it is determined that the compound is co-crystallized with Reference Compound 1, it is indicated as ◯, when a solid compound is not obtained, x, partially co-crystallized. A △ mark is given when it is suggested that there is a possibility of conversion.
　DSC測定方法
　　装置：DSC8230（リガク社製）
　　化合物量：5～20 mg
　　昇温速度：2もしくは10 ℃/min
　　測定温度範囲：20 ℃からゲスト化合物の融点＋10 ℃まで
　　リファレンス：アルミナ DSC measuring method Equipment: DSC8230 (Rigaku)
Compound amount: 5-20 mg
Temperature increase rate: 2 or 10 ° C / min
Measurement temperature range: 20 ° C to the melting point of the guest compound + 10 ° C Reference: Alumina
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表１に示されるように、炭素数14～17の直鎖脂肪酸であるマルガリン酸、パルミチン酸及びミリスチン酸においてのみ参考化合物１由来の吸熱ピークを一切検出せず、均一な共結晶化している可能性が示唆された。マルガリン酸共結晶の粉末Ｘ線チャートを図１に、DSCチャートを図４に示す。 As shown in Table 1, no endothermic peak derived from Reference Compound 1 is detected only in margaric acid, palmitic acid and myristic acid, which are linear fatty acids having 14 to 17 carbon atoms, and uniform co-crystallization is possible. Sex was suggested. A powder X-ray chart of the margaric acid co-crystal is shown in FIG. 1, and a DSC chart is shown in FIG.
　一方、炭素数20、18の脂肪酸であるアラキジン酸、ステアリン酸、或いはパルミチン酸アスコルビン酸エステル、1-ヘキサデカノール及び16-ヒドロキシヘキサデカン酸においては、新規吸熱ピークと共に参考化合物１由来の吸熱ピークを検出し、部分的に共結晶化している可能性が示唆された。 On the other hand, arachidic acid, stearic acid, palmitic acid ascorbic acid ester, 1-hexadecanol and 16-hydroxyhexadecanoic acid, which are fatty acids having 20 and 18 carbon atoms, have an endothermic peak derived from Reference Compound 1 together with a new endothermic peak. It was detected and suggested the possibility of partial co-crystallization.
　炭素数12、10のラウリン酸、デカン酸等その他の脂肪酸、又はそのエステル体については、共結晶化が認められなかった。 Co-crystallization was not observed for other fatty acids such as lauric acid having 12 or 10 carbon atoms, decanoic acid, or ester thereof.
試験例１　溶媒蒸発による共結晶化のスクリーニング
　実施例２、比較例２、５において、均一な共結晶あるいは部分的に共結晶を形成することが示唆されたパルミチン酸、ステアリン酸、及びパルミチン酸アスコルビン酸エステルについて、溶媒蒸発による参考化合物１との共結晶化を検討した。 Test Example 1 Screening of co-crystallization by solvent evaporation Palmitic acid, stearic acid, and ascorbyl palmitate suggested to form uniform co-crystals or partial co-crystals in Example 2 and Comparative Examples 2 and 5 The acid ester was examined for co-crystallization with Reference Compound 1 by solvent evaporation.
　参考化合物１およびゲスト化合物（パルミチン酸、ステアリン酸、パルミチン酸アスコルビン酸エステル）を、１：0.5～１：2.0のモル比で溶媒中に混合溶解した後、攪拌しながら自然に溶媒を揮発させることにより共結晶化を検討した。溶媒としては、エタノール、イソプロパノール、アセトン、酢酸エチル、アセトニトリル、テトラヒドロフラン（THF）、イソプロピルエーテル、クロロホルム、及びジクロロメタンを用いた。 Reference compound 1 and guest compound (palmitic acid, stearic acid, palmitic ascorbic acid ester) are mixed and dissolved in a solvent at a molar ratio of 1: 0.5 to 1: 2.0, and then the solvent is volatilized naturally with stirring. The co-crystallization was examined. As the solvent, ethanol, isopropanol, acetone, ethyl acetate, acetonitrile, tetrahydrofuran (THF), isopropyl ether, chloroform, and dichloromethane were used.
　その結果、参考化合物１およびパルミチン酸（構成モル比　１：１）と、THF又はアセトン溶媒の組み合わせのとき固化した。固化した生成物のDSC測定において参考化合物１由来のピークが検出されず、新規吸熱ピークが検出されたことから、均一に共結晶化する組み合わせであることが示唆された。一方、その他のゲスト化合物との組合せや溶媒条件下では、均一な共結晶は得られなかった。 As a result, it was solidified when the reference compound 1 and palmitic acid (constitutive molar ratio 1: 1) were combined with THF or an acetone solvent. In DSC measurement of the solidified product, the peak derived from Reference Compound 1 was not detected, and a new endothermic peak was detected, suggesting that the combination was uniformly co-crystallized. On the other hand, uniform co-crystals were not obtained under combination with other guest compounds or under solvent conditions.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
試験例２　共結晶化の検証試験
　実施例２、３、比較例２、５において、参考化合物１と共結晶化が示唆されたパルミチン酸、ミリスチン酸、ステアリン酸、及びパルミチン酸アスコルビン酸エステルをゲスト化合物として、試験例１の溶媒を用いた共結晶化をより詳細に検討した。 Test Example 2 Verification Test of Cocrystallization In Examples 2, 3, and Comparative Examples 2, 5, palmitic acid, myristic acid, stearic acid, and palmitic acid ascorbic acid ester, which were suggested to cocrystallize with reference compound 1, were guest. As a compound, co-crystallization using the solvent of Test Example 1 was examined in more detail.
　参考化合物１ (100 mg、0.274 mmol) と、 ゲスト化合物(0.274 mmol)を１：１のモル比でTHFに溶解させ、撹拌下にて精製水を徐々に滴下することにより共結晶を得た。 Reference compound 1 (100 mg, 0.274 mmol) and guest compound (0.274 mmol) were dissolved in THF at a molar ratio of 1: 1, and purified water was gradually added dropwise with stirring to obtain a co-crystal.
　得られた共結晶については粉末Ｘ線、DSCをそれぞれ測定し、参考化合物１とゲスト化合物とのモル比については1H -NMRのプロトン比より算出し、表３に示した。パルミチン酸共結晶、ミリスチン酸共結晶の粉末Ｘ線チャートを図２～図３に、パルミチン酸共結晶、ミリスチン酸共結晶のDSCチャートを図５～図６に、パルミチン酸共結晶、ミリスチン酸共結晶、参考化合物１、パルミチン酸及びミリスチン酸の1H -NMRチャートをそれぞれ図７～図11に示す。 For the obtained co-crystal, powder X-ray and DSC were measured, respectively, and the molar ratio of Reference Compound 1 to the guest compound was calculated from the proton ratio of 1 H-NMR and shown in Table 3. The powder X-ray charts of palmitic acid co-crystal and myristic acid co-crystal are shown in FIGS. 2 to 3, and DSC charts of palmitic acid co-crystal and myristic acid co-crystal are shown in FIGS. 5 to 6, and palmitic acid co-crystal and myristic acid co-crystal are shown. 7 to 11 show 1 H-NMR charts of the crystal, reference compound 1, palmitic acid, and myristic acid, respectively.
　　　測定装置：JNM-EX270（日本電子（株）社製）　
　　　測定溶媒：DMSO-d6
　結果を表３に示す。 Measuring device: JNM-EX270 (manufactured by JEOL Ltd.)
Measuring solvent: DMSO-d6
The results are shown in Table 3.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表３に示すように、パルミチン酸又はミリスチン酸をゲスト化合物としたときに、構成モル比１：１の均一な共結晶が得られた。本明細書において、「均一な共結晶」とは、図面に示されるようなDSC、粉末Ｘ線回折のチャートにおいて、参考化合物1及びにゲスト化合物に由来するピークが肉眼的に検出できず、共結晶に由来するピークが肉眼的に検出でき、且つ1H -NMRのチャートにおいて、参考化合物１に由来するピークとゲスト化合物に由来するピークの積分比が１：１であることを意味する。 As shown in Table 3, when palmitic acid or myristic acid was used as the guest compound, a uniform co-crystal with a constitutional molar ratio of 1: 1 was obtained. In the present specification, “homogeneous co-crystal” means that in the DSC and powder X-ray diffraction charts as shown in the drawings, the peak derived from the reference compound 1 and the guest compound cannot be detected macroscopically. It means that the peak derived from the crystal can be detected with the naked eye, and in the 1 H-NMR chart, the integration ratio of the peak derived from the reference compound 1 and the peak derived from the guest compound is 1: 1.
　なお構成モル比については、例えばパルミチン酸共結晶の場合、図７の1H -NMRチャートにおける2.15 ppm～2.20 ppm付近のピークの積分比、図９の1H-NMRチャートにおける2.16 ppm付近のピークの積分比、及び図10の1H -NMRチャートにおける2.15 ppm～2.20 ppm付近のピークの積分比をそれぞれ比較することにより、算出した。 Note The configuration molar ratio, for example, in the case of palmitic acid co-crystal, the peak integration ratio of around 2.15 ppm ~ 2.20 ppm in 1 H -NMR chart of FIG. 7, the peak around 2.16 ppm in the 1 H-NMR chart of FIG. 9 And the integral ratio of the peak around 2.15 ppm to 2.20 ppm in the 1 H-NMR chart of FIG.
　一方、ステアリン酸、パルミチン酸、アスコルビン酸エステルについては、DSCチャートにおいて複雑な吸熱ピークを示し、均一な共結晶を形成しなかった。 On the other hand, stearic acid, palmitic acid, and ascorbic acid ester showed complicated endothermic peaks in the DSC chart and did not form a uniform co-crystal.
　粉末Ｘ線測定条件
　　測定装置　　　：X’Pert PRO MPD（PANalytical社製）
　　走査範囲（2θ)： 2～40°
　　走査速度　　　： 0.2°/ s
　　管電圧　　　　： 40 kV
　　管電流　　　　： 30 mA Powder X-ray measurement conditions Measuring device: X'Pert PRO MPD (manufactured by PANalytical)
Scanning range (2θ): 2 to 40 °
Scanning speed: 0.2 ° / s
Tube voltage: 40 kV
Tube current: 30 mA
試験例３　薬物動態試験（ラット）
　参考化合物１、及び本発明の共結晶（参考化合物１とパルミチン酸との共結晶、参考化合物１とミリスチン酸との共結晶、及び参考化合物１とマルガリン酸との共結晶、共結晶の構成モル比はそれぞれ１：１）を秤量し、0.5% HPMCにて薬剤懸濁液（参考化合物１換算濃度として3 mg/mL）を調製した。各群のラットの数を４匹とし、それぞれの薬剤懸濁液を、経口ゾンデを用いてラット（Wistar、雌性、6週齢）に経口投与した（参考化合物１換算量として30 mg/kg）。各採血ポイント（0.5、1、2、4、6、8、24 hr）にてヘパリン処置したシリンジを用い頸静脈より採血した。採取した血液を遠心（13000 rpm、2 min、 4 ℃）後、血漿中の参考化合物１濃度をLC/MS/MSにて測定した。測定結果を表４に示す。 Test Example 3 Pharmacokinetic study (rat)
Reference compound 1 and the co-crystal of the present invention (co-crystal of reference compound 1 and palmitic acid, co-crystal of reference compound 1 and myristic acid, and co-crystal of reference compound 1 and margaric acid, the constituent moles of the co-crystal The ratio was 1: 1), and a drug suspension (3 mg / mL as the reference compound 1 equivalent concentration) was prepared with 0.5% HPMC. The number of rats in each group was 4 and each drug suspension was orally administered to rats (Wistar, female, 6 weeks old) using an oral sonde (30 mg / kg as the reference compound 1 equivalent). . Blood was collected from the jugular vein using a heparinized syringe at each blood collection point (0.5, 1, 2, 4, 6, 8, 24 hr). The collected blood was centrifuged (13000 rpm, 2 min, 4 ° C.), and the concentration of Reference Compound 1 in plasma was measured by LC / MS / MS. Table 4 shows the measurement results.
　表４で示されるように、本発明の共結晶は、参考化合物１に比較して約２倍～23倍のCmax、及び約２倍～14倍のAUC0-24hrの改善が認められた。特にパルミチン酸との共結晶のCmaxは20倍以上、及びAUC0-24hrは10倍以上と有意に増大し、ミリスチン酸との共結晶のCmax及びAUC0-24hrも参考化合物１に対して有意に増大し、マルガリン酸との共結晶のAUC0-24hrも参考化合物１に対して有意に増大し、本発明の共結晶は大幅に薬物動態を改善することが明らかとなった。 As shown in Table 4, the co-crystal of the present invention showed an improvement of about 2 to 23 times C max and about 2 to 14 times AUC 0-24hr as compared to Reference Compound 1. . In particular, C max of co-crystal with palmitic acid increased more than 20 times and AUC 0-24hr increased more than 10 times, and C max of co-crystal with myristic acid and AUC 0-24hr were also higher than reference compound 1. The AUC 0-24hr of the co-crystal with margaric acid was also significantly increased with respect to the reference compound 1, and it was revealed that the co-crystal of the present invention significantly improved the pharmacokinetics.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006

Claims (10)

  1. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと炭素数14～17の脂肪酸との共結晶。 Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and fatty acid having 14 to 17 carbon atoms.
  2. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと炭素数14～17の直鎖脂肪酸との共結晶。 Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a linear fatty acid having 14 to 17 carbon atoms.
  3. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、マルガリン酸、パルミチン酸、又はミリスチン酸との共結晶。 Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid, palmitic acid or myristic acid.
  4. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、マルガリン酸、パルミチン酸、又はミリスチン酸とが、１：0.5から１：２までの構成モル比で構成される共結晶。 3- (15-Hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and margaric acid, palmitic acid, or myristic acid in a constituent mole of 1: 0.5 to 1: 2. A co-crystal composed of a ratio.
  5. 　請求項４に記載の構成モル比が、１：１である共結晶。 A co-crystal having a constitutional molar ratio according to claim 4 of 1: 1.
  6. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、パルミチン酸との共結晶であって、7.7、12.5、17.1、18.8、22.0、22.4、24.2のいずれか１、いずれか２、いずれか３、いずれか４、若しくはいずれか５またはそれ以上のピークを特徴とする共結晶。 Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid, 7.7, 12.5, 17.1, 18.8, 22.0, 22.4, 24.2 A co-crystal characterized by any one, any 2, any 3, any 4, or any 5 or more peaks.
  7. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、パルミチン酸との共結晶であって、7.7、18.8及び22.4のピークを特徴とする共結晶。 Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid characterized by peaks at 7.7, 18.8 and 22.4 .
  8. 　3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと炭素数14～17の脂肪酸との共結晶であって示差走査熱量測定により測定される吸熱ピークのピークトップ値が、DSC測定時の昇温速度が2～10 ℃/minの場合に、約40～約55 ℃の間である共結晶。 An endothermic peak measured by differential scanning calorimetry, which is a co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and a fatty acid having 14 to 17 carbon atoms A co-crystal whose peak top value is between about 40 and about 55 ° C when the rate of temperature rise during DSC measurement is 2 to 10 ° C / min.
  9. 3-(15-ヒドロキシペンタデシル)-2,4,4-トリメチル-2-シクロヘキセン-1-オンと、パルミチン酸との共結晶であって、示差走査熱量測定により測定される吸熱ピークのピークトップ値が、DSC測定時の昇温速度が2 ℃/minの場合に、約45.9 ℃である共結晶。 Co-crystal of 3- (15-hydroxypentadecyl) -2,4,4-trimethyl-2-cyclohexen-1-one and palmitic acid, the top of the endothermic peak measured by differential scanning calorimetry A co-crystal whose value is about 45.9 ° C when the heating rate during DSC measurement is 2 ° C / min.
  10. 　請求項１～９のいずれかに記載の共結晶を有効成分として含む医薬組成物。 A pharmaceutical composition comprising the co-crystal according to any one of claims 1 to 9 as an active ingredient.
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US10226426B2 (en) 2015-03-02 2019-03-12 Takeda Pharmaceutical Company Limited Suspension containing nano-cocrystal and manufacturing method
JP2019504079A (en) * 2016-01-22 2019-02-14 大鵬薬品工業株式会社 Method for preparing high purity cyclohexenone long chain alcohol
US11485696B2 (en) 2016-01-22 2022-11-01 Taiho Pharmaceutical Co., Ltd. Manufacturing method for high-purity cyclohexenone long-chain alcohol
WO2023153422A1 (en) * 2022-02-09 2023-08-17 大鵬薬品工業株式会社 Crystal form of cyclohexenone compound

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