WO2007142259A1 - Complexe contenant de la 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2h-pyridazin-3-one et procédé de production de celui-ci - Google Patents

Complexe contenant de la 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2h-pyridazin-3-one et procédé de production de celui-ci Download PDF

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Publication number
WO2007142259A1
WO2007142259A1 PCT/JP2007/061442 JP2007061442W WO2007142259A1 WO 2007142259 A1 WO2007142259 A1 WO 2007142259A1 JP 2007061442 W JP2007061442 W JP 2007061442W WO 2007142259 A1 WO2007142259 A1 WO 2007142259A1
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WO
WIPO (PCT)
Prior art keywords
silica
compound
benzyl
methylthio
sulfonic acid
Prior art date
Application number
PCT/JP2007/061442
Other languages
English (en)
Japanese (ja)
Inventor
Hiroshi Miura
Makoto Kanebako
Toshio Inagi
Original Assignee
Kowa Company, Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kowa Company, Ltd. filed Critical Kowa Company, Ltd.
Priority to JP2008520599A priority Critical patent/JPWO2007142259A1/ja
Publication of WO2007142259A1 publication Critical patent/WO2007142259A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to 2-benzyl-5- (4-chlorophenol) -6- [4- (methylthio) phenol] -2 ⁇ -pyridazin-3-one having excellent dissolution properties and adsorption efficiency
  • the present invention relates to a composite of silica and silica and a production method thereof.
  • Compound 1 2-Benzyl-5- (4-black mouth phenol) -6- [4- (methylthio) phenol] -2H-pyridazin-3-one (hereinafter referred to as Compound 1) is excellent It is a pharmaceutical compound having an inhibitory action on interleukin-118 production, and is useful as a preventive and therapeutic agent for immune system diseases, inflammatory diseases, ischemic diseases, etc. (Patent Document 1). However, since this compound has a low dissolution property from a preparation that is extremely difficult to dissolve in water, improvement of the dissolution property of Compound 1 was an important issue in designing a formulation containing the compound.
  • Patent Document 1 Japanese Patent No. 3335132
  • Patent Document 2 WO2004Z096280
  • An object of the present invention is to provide a preparation excellent in the dissolution property and adsorption efficiency of Compound 1 and a method for producing the same.
  • the present invention is capable of efficiently adsorbing Compound 1 which is a very poorly water-soluble drug on silica and providing a preparation excellent in the dissolution property of Compound 1 adsorbed on the silica. wear.
  • Compound 1 used in the present invention can be prepared, for example, according to the method described in Patent Document 1.
  • the silica having a sulfonic acid group used in the present invention is obtained by, for example, treating a silica having a silanol group with a silane coupling agent having a thiol group or a phenol group, followed by an oxidation reaction and a sulfonation reaction.
  • Those prepared by processing can be used.
  • a specific example is Nagel's Nucleosil 100-SA (registered trademark).
  • the average pore diameter of silica having a sulfonic acid group is preferably from 1 to 1000 nm. More preferred is nm. Particularly preferred is 2 to 200 nm. Note that the average pore diameter can be measured by, for example, a mercury injection method.
  • the specific surface area of the silica having a sulfonic acid group is preferably 1 to 2000 m 2 Zg.
  • 1800 m 2 Zg is particularly preferred more preferred instrument 50 ⁇ 1500m 2 Zg.
  • the specific surface area can be measured, for example, by a gas adsorption method.
  • the number of functional groups of the silica having a sulfonic acid group is from 0.01 to: LOO Znm 2 is preferable, 0.1 to 20 Znm 2 is more preferable 0.5 to 10 Znm 2 is particularly preferred.
  • the composite of Compound 1 of the present invention and silica having a sulfonic acid group is obtained by mixing Compound 1 and silica having a sulfonic acid group in the presence of a supercritical fluid or a subcritical fluid as described later. As such, compound 1 has a structure adsorbed on silica having a sulfonic acid group.
  • the weight average particle diameter of the composite of the present invention is 1 ⁇ m or more, preferably 1 to 2000 ⁇ m, and particularly preferably 3 to 500 / ⁇ ⁇ .
  • the weight average particle diameter can be measured by a laser diffraction method or the like.
  • the content of Compound 1 in the complex of the present invention is preferably 0.1 to 91% by mass, more preferably 1 to 67% by mass, and more preferably 2 to 50% by mass, based on the complex weight. preferable.
  • the present invention provides a method for producing a composite of the compound 1 described above and silica having a sulfonic acid group.
  • This method includes the steps of mixing Compound 1 and silica having sulfonic acid groups in the presence of a supercritical fluid or subcritical fluid, and removing the supercritical fluid or subcritical fluid from the mixture.
  • the supercritical fluid used in the present invention is a single phase having a gas diffusivity and a liquid solubility that exceeds the limit temperature (pressure) at which the gas and liquid can coexist. It is a fluid.
  • the critical point is, for example, JW Tom and PG Debenedetti's “Particle Formation with supercritical Fluids—A ReviewJ, N. Page 1991, which is described in detail in Fig.l in 1991.
  • the pressure and temperature at the critical point are the critical pressure (Pc) and critical temperature (Tc)
  • the subcritical fluid means that either the temperature or the pressure is the critical pressure (Pc) or the critical temperature (T c) Fluid that is in a state beyond Uh.
  • Supercritical fluids include water, carbon dioxide (CO), nitrogen (N), nitrous oxide (N 0),
  • the carbon dioxide may be liquid carbon dioxide, gaseous carbon dioxide, or dry ice.
  • the critical point of carbon dioxide is a pressure of about 7.38 MPa and a temperature of about 31.0 ° C.
  • Supercritical fluid CO above this critical point has a density close to that of liquid, such as oil.
  • non-polar substances are highly soluble, they have low viscosity like gas and excellent diffusivity, and mass transfer is easy.
  • the production method of the present invention includes a step of mixing Compound 1 and silica having a sulfonic acid group in the presence of a supercritical fluid or a subcritical fluid.
  • the compounding weight ratio of the compound 1 and the silica having a sulfonic acid group in the intensive process is preferably 1: 0.1 to L000, more preferably 1: 0.5 to L00, and 1: 1. ⁇ 50 is particularly preferred.
  • the weight ratio of compound 1 to supercritical fluid or subcritical fluid is preferably 1: 1 to L000000, 1:10 to L00000 force is more preferable, 1: 50 to 50,000 is particularly preferable, .
  • the mixing time of Compound 1 and silica having a sulfonic acid group in the presence of a supercritical fluid or subcritical fluid is preferably 1 minute to 24 hours, and more preferably 0.5 to 12 hours 1 ⁇ 8 hours is particularly preferred.
  • the temperature of the supercritical fluid or subcritical fluid at the time of mixing is ⁇ 40 to: L0 0 ° C is preferable, 0 to 80 ° C is more preferable, and 10 to 60 ° C is particularly preferable.
  • the processing pressure of the supercritical fluid or subcritical fluid during mixing is preferably 1 to 50 MPa, more preferably 1 to 40 MPa, and particularly preferably 6 to 30 MPa.
  • Mixing of Compound 1 and silica having a sulfonic acid group in the presence of a supercritical fluid or a subcritical fluid is performed by, for example, (1) placing Compound 1 and silica having a sulfonic acid group in a pressure-resistant container. After filling the substance to be used as a supercritical fluid or subcritical fluid here, the temperature and pressure in the container are maintained at the temperature and pressure at which the substance becomes a supercritical state or subcritical state. (2) Compound 1 and silica having a sulfonic acid group are placed in a pressure-resistant container, and the temperature in the container is such that the substance used as a supercritical fluid or subcritical fluid is in a supercritical state or a subcritical state.
  • the complex of the present invention can be recovered by removing the supercritical fluid or subcritical fluid from the reaction system by an appropriate method. Removal of supercritical fluid or subcritical fluid from the reaction system can be achieved by, for example, reducing the temperature and pressure at which the powerful fluid can be discharged from the reaction vessel to lower than the critical temperature and critical pressure of the fluid. The presence of the supercritical fluid and subcritical fluid may be removed by eliminating the state or subcritical state.
  • an appropriate solvent, a polymer compound, a surfactant, and various other components acceptable as pharmaceutical additives may be used as desired. Is possible.
  • Examples of the solvent include water; aromatic hydrocarbons such as benzene, toluene and xylene; ethers such as dimethyl ether, jetyl ether, dixanthane, diethoxyethane, tetrahydrofuran and 1,2-dimethoxyethane; Organochlorine organic solvents such as dichloromethane, chloroform, carbon tetrachloride and 1,2-dichloroethane; alkyl-tolyls such as acetonitrile and propio-tolyl; -troalkanes such as nitromethane and nitroethane; N, N-dimethyl Amides such as formamide and N, N-dimethylacetamide; Ketones such as acetone; Fatty acids such as acetic acid and oleic acid; Alcohols such as methanol, ethanol and isopropanol; Sulfoxides such as dimethyl sulfoxide; or These mixed solvents are
  • polymer compound examples include pullulan, sodium carboxymethylcellulose, sodium alginate, xanthan gum, polybulur pyrrolidone, carboxybutyl polymer, methylcellulose, agar, gelatin and the like.
  • Surfactants include polyoxyethylene polyoxypropylene glycol, polyoxyethylene hydrogenated castor oil, polyoxyethylene alkyl ethers such as polyoxyethylene lauryl ether, polyoxyethylene sorbitan fatty acid ester (polysorbate), sorbitan monostearate, etc.
  • Nonionic surfactants such as sorbitan fatty acid esters of cation, cationic surfactants such as salt benzalcoum, salt benzennium, salt cetyl pyridinium, calcium stearate, stearic acid
  • anionic surfactants such as magnesium and sodium lauryl sulfate.
  • ammo mucanoreboxy Examples thereof include surfactants having a fluorine group such as rate perfluoroether.
  • the complex of the present invention can be used as a pharmaceutical preparation as it is, but it can be made into an oral preparation and a parenteral preparation by adding an additive usually used in a pharmaceutical preparation.
  • lactose As an additive for oral preparations, lactose, crystalline cellulose, sucrose, mannitol, light anhydrous carboxylic acid, calcium hydrogen phosphate and other excipients; methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, gelatin, Binding agents such as polyvinylpyrrolidone and pullulan; disintegrants such as croscarmellose sodium, carmellose calcium, crospovidone, low-substituted hydroxypropylcellulose; lubricants such as magnesium stearate and talc; tar dyes and tridioic acid Illustrative examples include coloring agents such as pig iron; corrigents such as stevia, aspartame, and fragrances.
  • additives for parenteral preparations include monohydric alcohols such as benzyl alcohol, polyhydric alcohols such as concentrated dariserine and 1,3-butylene glycol, esters such as diisopropyl adipate and triacetin, crotamiton, and the like Ketones, oils such as oleic acid, castor oil, etc .; celluloses such as hydroxyethyl cellulose and hydroxypropyl cellulose; polysaccharides such as sucrose and ⁇ -cyclodextrin; sugar solvents such as sorbitol and mantol Water-soluble polymers such as synthetic polymers such as alcohols, polybulal alcohol, polybulurpyrrolidone, polyacrylic acid; anionic surfactants such as calcium stearate, magnesium stearate, sodium lauryl sulfate, and salt benzalco Um, benzethonium chloride, salt cetyl pyridinium, etc.
  • monohydric alcohols such as benzy
  • Surfactants such as cationic surfactants, glyceryl monostearate, sucrose fatty acid ester, polyoxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, etc .; myristate pill Such as L-menthol, terpenes such as dL-camphor, higher fatty acids such as oleic acid; phenolic substances such as methyl parabenzoate and poxybenzoic acid pills, chlorobutanol, phenol -Neutral substances such as ruethyl alcohol, reverse soaps such as salt benzalcoum, salt benzentonium, antioxidants such as vitamin E, butyhydroxyanisole, ascorbic acid, sodium bisulfite, thio Reducing agents such as sodium sulfate, citrate or tartaric acid and salts thereof, lecithin, ethyl Di Stabilizers such as chelating agents such as amine tetraacetic acid (edetic acid); pH adjusters such as phospho
  • the form of the preparation of the present invention includes, for example, oral preparations such as tablets, capsules, granules, fine granules, injections, suppositories, vaginal preparations, sublingual preparations, implants, eye drops, and sprays.
  • oral preparations such as tablets, capsules, granules, fine granules, injections, suppositories, vaginal preparations, sublingual preparations, implants, eye drops, and sprays.
  • parenteral preparations such as drugs.
  • FIG. 1 is a graph showing the number of adsorbed drugs per unit functional group in the composite of Example 1, the composite of Comparative Examples 1 to 4 and the physical mixture of Comparative Example 5.
  • 0.3 g of compound 1 and 4 g of silica having silanol groups (specific surface area 160 m 2 Zg, number of functional groups per unit surface area 5.0 / nm 2 ) were put in a pressure-resistant container (volume 500 mL). Furthermore, liquefied carbon dioxide was introduced into the pressure resistant container from a liquefied carbon dioxide cylinder so that the pressure inside the pressure resistant container was 18 MPa when the temperature inside the pressure resistant container was 60 ° C. The pressure-resistant container was stirred under the conditions of 60 ° C. and 18 MPa, and this was maintained for 5 hours. Then, the composite of Comparative Example 1 was obtained by leaving still and discharging carbon dioxide.
  • [Comparative Example 2] (methyl group) 0.15 g of Compound 1 and 4 g of silica having a methyl group (specific surface area 80 m 2 Zg, number of functional groups per unit surface area 8.5 / nm 2 ) were put in a pressure-resistant container (volume 500 mL). Further, liquefied carbon dioxide was introduced from the liquefied carbon dioxide cylinder into the pressure resistant container so that the pressure inside the pressure resistant container was 18 MPa when the temperature inside the pressure resistant container was 60 ° C. The pressure-resistant container was stirred under the conditions of 60 ° C. and 18 MPa, and this was maintained for 5 hours. Then, the composite of Comparative Example 2 was obtained by leaving still and discharging carbon dioxide.
  • the amount of drug adsorption was measured for the complex and physical mixture obtained in Example 1, Comparative Examples 1 to 4 and Comparative Example 5, and the number of drug adsorption (efficiency) per unit functional group was calculated.
  • the number of drug adsorption per unit functional group is the number of drug molecules adsorbed per functional group, and was calculated from the following formula. Number of drug adsorptions per unit functional group (1 unit / functional group)
  • the compound 1 having a complex strength according to the present invention has good elution properties.

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Abstract

La présente invention concerne une préparation présentant d'excellentes propriétés d'élution et d'adsorption de 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2H-pyridazin-3-one, ainsi qu'un procédé pour la production de celle-ci. L'invention concerne un complexe de 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2H-pyridazin-3-one et un oxyde de silicium ayant un groupe acide sulfonique dans lequel le 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2H-pyridazin-3-one est adsorbé sur l'oxyde de silicium ayant un groupe acide sulfonique, ainsi qu'un procédé de production dudit complexe comprenant les étapes consistant à : mélanger le 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2H-pyridazin-3-one et un oxyde de silicium ayant un groupe acide sulfonique en présence d'un fluide surcritique ou sous-critique ; puis à retirer le fluide surcritique ou sous-critique du mélange. L'invention permet l'adsorption efficace d'un composé 1, lequel est un médicament très peu soluble dans l'eau, sur un oxyde de silicium et permet l'obtention d'une préparation excellente en matière d'élution du composé 1 adsorbé sur l'oxyde de silicium.
PCT/JP2007/061442 2006-06-06 2007-06-06 Complexe contenant de la 2-benzyl-5-(4-chlorophényl)-6-[4-(méthylthio)phényl]-2h-pyridazin-3-one et procédé de production de celui-ci WO2007142259A1 (fr)

Priority Applications (1)

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JP2008520599A JPWO2007142259A1 (ja) 2006-06-06 2007-06-06 ２‐ベンジル‐５‐（４‐クロロフェニル）‐６‐［４‐（メチルチオ）フェニル］‐２ｈ‐ピリダジン‐３‐オン含有複合体及びその製造法

Applications Claiming Priority (2)

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JP2006156857 2006-06-06
JP2006-156857 2006-06-06

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WO2007142259A1 true WO2007142259A1 (fr) 2007-12-13

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096281A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau presentant une excellente propriete d'elution, procedes de preparation de cette derniere
WO2004096280A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau et procede de preparation de cette derniere

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004096281A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau presentant une excellente propriete d'elution, procedes de preparation de cette derniere
WO2004096280A1 (fr) * 2003-04-29 2004-11-11 Kowa Co., Ltd. Composition contenant un medicament extremement faiblement soluble dans l'eau et procede de preparation de cette derniere

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