WO2012002547A1 - Dispersion solide de bosentan - Google Patents

Dispersion solide de bosentan Download PDF

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WO2012002547A1
WO2012002547A1 PCT/JP2011/065230 JP2011065230W WO2012002547A1 WO 2012002547 A1 WO2012002547 A1 WO 2012002547A1 JP 2011065230 W JP2011065230 W JP 2011065230W WO 2012002547 A1 WO2012002547 A1 WO 2012002547A1
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bosentan
solid dispersion
solvent
dispersion according
matrix component
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PCT/JP2011/065230
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English (en)
Japanese (ja)
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直任 尾塩
洋介 平井
仁 坂井
田中　伸和
邦雄 真田
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富士化学工業株式会社
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Priority to JP2012522721A priority Critical patent/JP5850576B2/ja
Publication of WO2012002547A1 publication Critical patent/WO2012002547A1/fr

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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
    • A61K31/33—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a bosentan solid dispersion having high solubility and long-term stability of bosentan without depending on pH, a process for producing the same, and a pharmaceutical composition containing the bosentan solid dispersion.
  • Bosentan is the chemical name N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidin-4-yl] -4-tert-butyl-benzenesulfonamide. And is known as an endothelin receptor antagonist.
  • the bosentan is useful for the treatment of cardiovascular diseases such as hypertension, ischemia, vasospasm and angina, and is used as a therapeutic agent for pulmonary arterial pulmonary hypertension. Methods for synthesizing bosentan are described in US Pat. No. 5,292,740 and US Pat. No. 6,136,971.
  • Bosentan and its derivatives are sparingly water-soluble, especially at a pH of 5 or less, and have a dissolution concentration of less than 0.03 mg / mL. To increase bioavailability, bosentan and its derivatives have increased solubility in water. It is required that properties such as solubility be maintained for 3 years or more.
  • the average particle size is pulverized to nano-size, the inclusion method with cyclodextrin, etc., to porous carriers such as magnesium aluminate metasilicate A method of making it adsorb, a method of making microspheres by emulsification, a method of non-crystallizing, and the like are known.
  • Patent Documents 1, 2, and 3 a method of changing the crystal structure of bosentan to a highly soluble crystal form or a non-crystallizing method
  • Patent Document 4 A method in which a synthetic polymer, dimethyl ether is dissolved at high temperature and high pressure and sprayed in an air stream to be finely dispersed in a matrix component (Patent Document 4).
  • An active substance is added to a mixed solution of a soluble solvent and an insoluble solvent.
  • Patent Document 5 A solid dispersion of a poorly soluble drug that is dissolved and spray-dried
  • an object of the present invention is to provide a bosentan-containing pharmaceutical composition that has good solubility of bosentan in water without depending on pH and that maintains the dissolution even after long-term storage.
  • the present inventor has mixed bosentan and various components to produce a solid dispersion and studied its elution, and mixed bosentan and a matrix component selected from a specific polymer at a certain ratio.
  • a bosentan solid dispersion By forming a solid dispersion, a bosentan solid dispersion can be obtained that exhibits good dissolution properties in both water and pH 6.8 intestinal pH aqueous solution and that maintains its dissolution properties even after long-term storage.
  • the present invention has been completed.
  • the present invention is a solid dispersion comprising (A) bosentan and (B) a matrix component selected from a cellulosic polymer, a synthetic homopolymer and a synthetic copolymer, wherein the mass ratio of (A) to (B) (A: B) is 1: 0.05 to 1:10, the concentration in water at 37 ° C. is 50 to 500 ⁇ g / mL, and the pH is 6.8 potassium dihydrogen phosphate-hydroxylated at 37 ° C.
  • a solid dispersion having a dissolution concentration in an aqueous sodium solution of 0.6 to 10 mg / mL is provided.
  • the present invention also provides a pharmaceutical composition containing 1 to 10,000 parts by weight of a pharmaceutical additive component per 100 parts by weight of the bosentan solid dispersion.
  • the present invention also provides a process for producing the above bosentan solid dispersion.
  • the bosentan solid dispersion of the present invention can improve the bioavailability of bosentan independent of pH, shortening the action time, reducing drug dosage and side effects, and improving long-term stability Therefore, the manufacturing method and storage suitable for production can be simplified. Improving the dissolution of bosentan compared to crystals at any pH range not only improves bioavailability, but also reduces individual differences and dietary effects, improving patient compliance and improving patient compliance with intractable diseases. It is possible to improve adherence.
  • FIG. 2 is an X-RD chart of a bosentan solid dispersion of Example 15 and Comparative Example 1 before and after an acceleration test.
  • 6 is an amorphous bosentan of Comparative Example 3 and an X-DR chart of Comparative Example 1 before and after the acceleration test. It is a DSC chart of the bosentan solid dispersion of Example 15 and Comparative Example 1 before and after the acceleration test. It is the DSC chart of the amorphous bosentan of the comparative example 3 before and behind an acceleration test, and the comparative example 1.
  • the solid dispersion of the present invention is a solid dispersion comprising (A) bosentan and (B) a matrix component selected from a cellulose polymer, a synthetic homopolymer and a synthetic copolymer.
  • bosentan used in the solid dispersion (A) of the present invention examples include bosentan anhydride, bosentan monohydrate, bosentan polyhydrate, bosentan solvate, bosentan salt acceptable for pharmaceuticals, and the like.
  • Bosentan used as a raw material may be in any form because it is dispersed in the size of a single molecule or nanoparticle in production. Either a crystal or an amorphous material or a mixture may be used, and any of known crystal polymorphs may be used as the crystal.
  • the matrix component is selected from cellulosic polymers, synthetic homopolymers and synthetic copolymers.
  • the solid dispersion of the present invention is a solid dispersion comprising (A) bosentan and (B) a matrix selected from the three types of polymers
  • the solid dispersion has excellent elution properties without depending on pH. It becomes a solid dispersion.
  • bosentan is used as a solid dispersion using fats and oils, surfactants, natural polymers, starch, saccharides and amino acids, a solid dispersion with good elution cannot be obtained.
  • the mass ratio (A: B) of (A) bosentan to (B) matrix component can be arbitrarily selected depending on the characteristics of the matrix component and the physical properties to be imparted, but it has good dissolution and stability independent of pH. Is from 1: 0.05 to 1:10, more preferably from 1: 0.1 to 1: 5, still more preferably from 1: 0.1 to 1: 3, most preferably 1: 0.1 to 1: 2.
  • the crystals of bosentan were not substantially confirmed by X-RD (X'Pert-MPD type, manufactured by Philips) (see FIG. 1 of Example 15), and DSC (Thermo) plus DSC8230 (manufactured by Rigaku Corporation) does not confirm the endothermic peak of bosentan at about 115 ° C. (see FIG. 3 of Example 15). From these, it is assumed that the bosentan solid dispersion is dispersed in the matrix component with a particle size that does not exhibit physical properties as a single molecule and / or crystal.
  • Cellulose polymers include nonionic cellulose polymers and ionic cellulose polymers.
  • nonionic cellulose polymers include hypromellose (manufactured by Shin-Etsu Chemical Co., Ltd .: TC-5E, TC-5R, Metroze 60SH, etc.), hydroxypropyl cellulose (Nippon Soda Co., Ltd .: NISSO HPC-L, HPC-SSL, etc.), methylcellulose (Shin-Etsu Chemical Co., Ltd .: Metroze SM-4, SM-15, etc.), hydroxyethyl methylcellulose, Examples thereof include hydroxypropyl methylcellulose acetate and hydroxyethylcellulose acetate.
  • Examples of the ionic cellulose polymer include hydroxypropyl methylcellulose acetate succinate (manufactured by Shin-Etsu Chemical Co., Ltd .: Shin-Etsu AQOAT-AS-LF, AS-MF, AS-HG, etc.), hydroxypropyl methylcellulose succinate, hydroxypropyl Cellulose acetate succinate, hydroxyethylmethylcellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate (manufactured by Shin-Etsu Chemical Co., Ltd .: HP-50, HP-55, etc.), hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose Acetate phthalate, carboxyethyl cellulose, ethyl carboxymethyl cellulose, carboxymethyl Cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose
  • Examples of the synthetic homopolymer include polyvinyl pyrrolidone (manufactured by BASF: Kollidon K30, K90, K17, etc.), cross-linked polyvinyl pyrrolidone, polyethylene glycol (manufactured by Sanyo Chemical Industries, Ltd .: Macrogol 4000, 6000, 20000, etc.). , Polyvinyl alcohol, polyvinyl acetate phthalate, polyvinyl acetal diethylaminoacetate, carboxyvinyl polymer, and the like.
  • Synthetic copolymers include, for example, methacrylic acid copolymers (Rohm: Eudragit L100, L100-55, S100, L30D-55, etc.), aminoalkyl methacrylate copolymers (Rohm: Eudragit E100, RS100, etc.), polyvinyl alcohol polyvinyl Examples thereof include acetate copolymer, polyethylene glycol polypropylene glycol copolymer, polyethylene polyvinyl alcohol copolymer, polyvinyl pyrrolidone copolymer (BASF Corporation: Kollidon VA64, SR, etc.).
  • hypromellose hydroxypropylcellulose, methylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose acetate, hydroxyethylcellulose acetate, hydroxypropylmethylcellulose acetate succinate, hydroxypropylmethylcellulose succinate, hydroxypropylcellulose acetate succinate, hydroxyethyl Methylcellulose succinate, hydroxyethylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, hydroxyethylmethylcellulose acetate succinate, hydroxyethylmethylcellulose acetate phthalate, carboxyethylcellulose, carboxymethyl Cellulose, carboxymethyl ethyl cellulose, cellulose acetate phthalate, methyl cellulose acetate phthalate, ethyl cellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxypropyl methylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate, hydroxy
  • At least one selected from hypromellose, hydroxypropylcellulose, methylcellulose, hydroxypropylmethylcellulose acetate succinate, cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, polyvinylpyrrolidone, polyethylene glycol, polyvinylpyrrolidone copolymer and methacrylic acid copolymer is preferred.
  • the bosentan solid dispersion of the present invention has higher elution performance in water than crystalline bosentan in an aqueous solution.
  • the solubility is better than that of crystalline bosentan or amorphous bosentan.
  • the dissolution concentration in water (distilled water) at 37 ° C. is 50 to 500 ⁇ g / mL.
  • the dissolution concentration in an aqueous solution at pH 6.8 at 37 ° C., particularly in an aqueous potassium dihydrogen phosphate-sodium hydroxide solution at pH 6.8 at 37 ° C. is 0.6 to 10 mg / mL.
  • a high dissolution concentration in an aqueous solution having a pH of 6.8 means that the dissolution property in the intestinal tract, which is the absorption site of bosentan, is good.
  • the dissolved concentration of bosentan here is determined by the method described in the examples described later. That is, after adding to a solution, a density
  • the dissolved concentration of bosentan after 10 to 120 minutes, preferably after 60 minutes, and most preferably after 120 minutes. Therefore, the bosentan solid dispersion of the present invention can maintain the dissolution concentration when bosentan is dissolved in water for a long time.
  • Some solid dispersions of sparingly soluble drugs are in an over-dissolved state even if the dissolution concentration temporarily increases, so that some drug crystals reprecipitate and the dissolution concentration decreases over time.
  • amorphous bosentan There is a similar tendency in amorphous bosentan.
  • the dissolution concentration does not decrease within 120 minutes after elution. Since bosentan is absorbed over a long period from the stomach to the small intestine, it is preferable that the retention time of the dissolved concentration is long.
  • the bosentan solid dispersion of the present invention has a dissolution concentration of 1.5 times or more in distilled water, preferably 2 times or more, more preferably 5 times or more, with respect to crystalline bosentan, and has a pH of 1 to 5
  • the bosentan solid dispersion has a dissolution concentration of 2 times or more, preferably 5 times or more, more preferably 10 times or more of the crystalline bosentan, and at pH 6.8, the bosentan solid dispersion is a crystalline substance.
  • the dissolution concentration is 2 times or more, preferably 5 times or more, more preferably 10 times or more.
  • the solid dispersion of the present invention has a dissolution concentration of 1.5 times or more, preferably 2 times or more, respectively, with respect to amorphous bonsentan.
  • the solid dispersion of the present invention maintains excellent dissolution properties after long-term storage. Specifically, after standing for 7 days at a temperature of 40 ° C. and a relative humidity of 75%, the dissolution concentration in water at 37 ° C. is 50 to 500 ⁇ g / mL, and the pH is 6.8 potassium dihydrogen phosphate-water at 37 ° C. The dissolution concentration in an aqueous sodium oxide solution is 0.6 to 10 mg / mL. Here, the dissolution concentration is the dissolution concentration 120 minutes after the addition of the solid dispersion.
  • the dissolution concentration after standing for 7 days at a temperature of 40 ° C. and a relative humidity of 75% is such that the solid dispersion of the present invention is 1.5 times or more, preferably 2 times or more, more preferably 2 times or more in distilled water with respect to amorphous bosentan. Is more than three times. In an aqueous solution of pH 6.8, it is 1.5 times or more, preferably 3 times or more, more preferably 4 times or more.
  • the bosentan solid dispersion of the present invention is described below.
  • the bosentan solid dispersion of the present invention has a structure in which bosentan is dispersed as monomolecules and / or fine particles in a matrix component.
  • the average particle size is 400 nm or less, preferably 200 nm or less, more preferably 50 nm, and most preferably 20 nm or less.
  • the structure of the bosentan solid dispersion can be identified from the fact that crystals are not substantially confirmed by powder X-ray structural analysis described later, and the endothermic peak peculiar to bosentan crystals is not confirmed by thermal analysis.
  • the bosentan solid dispersion of the present invention can be generally produced by a method for producing a solid dispersion of a drug. Examples thereof include a solvent method, a melting method, and a mechanochemical method.
  • bosentan, a matrix component, and optionally a pharmaceutical additive component are suspended or dissolved in an organic solvent. It is then produced by removing or precipitating the solvent.
  • the method for removing the solvent include an evaporation method, a spray method, a filtration method, and a freeze-drying method.
  • Spray methods include fluidized bed method, spray drying method, rolling bed method, stirring method, supercritical method, etc. Since the solvent can be removed in a short time, bosentan and matrix components are in the same molecular dispersion state as in the solvent.
  • a spray method is preferred because a solid dispersion of the above can be obtained.
  • the solvent is instantaneously removed, and the spray drying method is preferable because it can be continuously produced in large quantities.
  • the time required for removing the solvent is preferably shorter, preferably within 120 minutes, preferably within 60 minutes, more preferably within 10 minutes, even more preferably within 5 minutes, and most preferably within 2 minutes.
  • the time required for the removal of the solvent is a time for obtaining the solid material of the bosentan solid dispersion of the present invention, and a part of the solvent may remain. The remaining solvent can be removed by secondary drying described later.
  • the solvent to be used may be any pharmaceutically acceptable solvent, for example, a solvent in which bosentan is dissolved, such as ethanol, methanol, 2-propanol, acetone, 2-butanone, methyl isobutyl ketone, tetrahydrofuran (THF), tetrahydropyran, 1,4-dioxane, diethyl ether, diisopropyl ether, t-butyl methyl ether, hexane, heptane, toluene, acetonitrile, methylene chloride, chloroform, carbon tetrachloride, methyl acetate, ethyl acetate, butyl acetate, acetic acid, formic acid, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMAc), dimethyl sulfoxide (DMSO) and the like can be mentioned.
  • the precipitation method is preferably a coprecipitation method.
  • the bosentan and the matrix component are dissolved or suspended in a solvent, and the dissolved bosentan and / or the matrix component is precipitated by adding a solvent insoluble or lowering the dissolution concentration by decreasing the temperature.
  • Bosentan and matrix components are dissolved or suspended in a solvent.
  • the concentration at this time is 0.2 to 40% by weight of the solid content, and preferably 1 to 20% by weight.
  • the solvent is then removed under reduced pressure or normal pressure.
  • the temperature at this time is a temperature at which the solvent can be distilled off, and can be appropriately selected from the distillation time, and is ⁇ 10 to 120 ° C., preferably 0 to 100 ° C.
  • Bosentan and matrix components are dissolved or suspended in an organic solvent.
  • the concentration at this time may be any concentration that allows spray drying, and the solid content is 0.1 to 80% by weight, preferably 0.5 to 50% by weight.
  • the solvent is then removed and granulated simultaneously by spray drying.
  • a disc-type or nozzle-type for example, pressure nozzle, two-fluid nozzle, four-fluid nozzle
  • the inlet temperature is preferably about 20 to 150 ° C.
  • the outlet temperature is preferably about 0 to 85 ° C.
  • a bosentan solid dispersion is obtained by a solvent method such as an evaporation method or a spray drying method, and further removal of the residual solvent is necessary, secondary drying can be performed.
  • the secondary drying can be performed by a drying method usually used in the manufacture of pharmaceuticals as long as the method can stably maintain the bosentan solid dispersion.
  • the melting method is a method for producing a bosentan solid dispersion by heating bosentan and a matrix component, and if necessary, other pharmaceutical additive components to a temperature at which any of the components melts, and then cooling after melting. is there. It can be arbitrarily selected according to the machine used, the temperature, and the conventional method. Extruders are examples of machines. At this time, a solvent may be added to lower the melting point, and the solvent is removed after melting.
  • the mechanochemical method is a method for producing a bosentan solid dispersion by simultaneously pulverizing and impacting bosentan and a matrix component, and if necessary, other pharmaceutical additive components.
  • the machine to be used, the temperature, and the pulverization conditions can be arbitrarily selected according to a conventional method.
  • the bosentan solid dispersion obtained in this way is subjected to dry granulation and wet granulation using additives that can be used in pharmaceuticals for mixing into tablets, dissolution, sustained release, and bitterness masking. It can be carried out.
  • additives that can be used in pharmaceuticals for mixing into tablets, dissolution, sustained release, and bitterness masking. It can be carried out.
  • the particle size and bulk density can be increased by thickening with a roller compactor or the like.
  • a pharmaceutical additive is mixed with bosentan solid dispersion and / or particles containing bosentan solid dispersion to obtain an oral type pharmaceutical composition such as a tablet, capsule, powder, liquid, emulsion or suspension.
  • an oral type pharmaceutical composition such as a tablet, capsule, powder, liquid, emulsion or suspension.
  • pharmaceutical compositions such as injections, suppositories, eye drops, inhalants, and external preparations for skin can also be obtained as parenteral agents.
  • known methods can be used.
  • Pharmaceutical additives include binders (eg, carmellose, hydroxypropyl cellulose, alginic acid, gelatin, partially pregelatinized starch, popidone, gum arabic, pullulan, dextrin, etc.), excipients (eg, starch, D-mannitol, lactose , Trehalose, crystalline cellulose, magnesium aluminate metasilicate, calcium hydrogen phosphate, hydrotalcite, anhydrous silicic acid, etc.), disintegrant (eg, crospovidone, croscarmellose sodium, low substituted hydroxypropyl cellulose, etc.), interface Activators (eg polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, sorbitan fatty acid ester, polysorbate, fatty acid glycerin ester, sodium lauryl sulfate), lubricant (sucrose Acid esters, magnesium stearate, talc, sodium stearyl fumarate
  • These pharmaceutical additives can be used in an amount of 1 to 10000 parts by mass with respect to 100 parts by mass of the bosentan solid dispersion.
  • the pharmaceutical composition containing the bosentan solid dispersion of the present invention can be expected to have an AUC equivalent to that of conventional crystalline bosentan even if the dosage is reduced due to the improvement of the dissolved concentration of bosentan.
  • Bosentan has endothelin receptor antagonism and is currently used only as a treatment for pulmonary arterial hypertension (WHO functional class II, III or IV).
  • the bosentan solid dispersion of the present invention can be combined with the following drugs to further treat agents such as, but not limited to, Rho-kinase for treating, preventing or managing pulmonary hypertension including pulmonary arterial hypertension.
  • agents such as, but not limited to, Rho-kinase for treating, preventing or managing pulmonary hypertension including pulmonary arterial hypertension.
  • Rho-kinase inhibitors examples include fasudil, Y-27632, and H-1152P.
  • prostacyclin agonists examples include iloprost, treprostinil, epoprostenol, beraprost, and ilomedin.
  • Examples of 5-HT 2A antagonists include sarpogrelate.
  • An example of the anticoagulant is warfarin.
  • Examples of the antiplatelet drug include aspirin.
  • diuretic examples include furosemide, trichloromethiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, bentlehydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, polythiazide, mefurside, ximapide, metrazone, spironolactone and triamterene.
  • cardiac glycosides include digoxin.
  • calcium channel blockers include diltiazem, nifedipine, amlodipine, nisoldipine, azelnidipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine and verapamil.
  • lipid lowering agent examples include HMG-CoA reductase inhibitors such as atorvastatin, fluvastatin, pravastatin, pitavastatin, simvastatin, itavastatin, cerivastatin, rosuvastatin, ZD-4522 and lovastatin.
  • HMG-CoA reductase inhibitors such as atorvastatin, fluvastatin, pravastatin, pitavastatin, simvastatin, itavastatin, cerivastatin, rosuvastatin, ZD-4522 and lovastatin.
  • vasodilator examples include prostacyclin and nitric oxide.
  • Examples of the phosphodiesterase inhibitor include amrinone, milrinone, and olprinone.
  • Phosphodiesterase IV inhibitors such as sildenafil, tadalafil and vardenafil.
  • Examples of the selective serotonin reuptake inhibitor include fluoxetine, serturlein, paroxetine, and venlafaxine.
  • Examples of the blood vessel remodeling regulator include Gleeveg.
  • Examples of the endothelin receptor antagonist include, besides bosentan, sitaxsentan, ambrisentan, crazosentan, and macitentan.
  • ACE inhibitors such as enalapril, ramipril, captopril, cilazapril, trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril, losartan, candesartan, irbesartan, embsartan, valsartan And AT-II inhibitors (ARB agents) such as olmesartan and telmisartan, iloprost, betaprost, L-arginine, adenosine, omapatrilato, oxygen, digoxin and the like.
  • ACE inhibitors such as enalapril, ramipril, captopril, cilazapril, trandolapril, fosinopril, quinapril, moexipril, lisinopril and perindopril, losartan, candesartan, ir
  • Comparative Example 1 is bosentan monohydrate crystal powder.
  • the disintegration test liquid 2 was prepared by adding 118 mL of 0.2N sodium hydroxide reagent and water to 250 mL of 0.2 M potassium dihydrogen phosphate test solution to make 1000 mL.
  • the solution is clear and colorless and has a pH of about 6.8.
  • the dissolution concentrations of the bosentan solid dispersions of Examples 1 to 12 showed a dissolution concentration of 10 times or more with respect to the crystalline bosentan of Comparative Example 1 at any time after 10 to 120 minutes. It shows that the dissolution concentration is twice or more, and the improvement in solubility is extremely excellent. It turns out that the stearic acid of fats and oils, the surfactant polyoxyethylene hydrogenated castor oil 60, polyoxyethylene lauryl ether, and the natural polymer xanthan gum are not suitable as a matrix for the solid dispersion of bosentan.
  • the dissolution concentration of the bosentan solid dispersions of Examples 1, 2, 7, and 10 was 10 times that of the crystalline bosentan of Comparative Example 1 after 10 to 120 minutes, and the dissolution concentration was extremely high. It turns out that it is excellent. That is, it is understood that even if the pharmaceutical is kept under conditions of a temperature of 40 ° C. and a relative humidity of 75%, the dissolution concentration does not change and the stability is extremely high.
  • the bosentan solid dispersions of Examples 13 to 14 of the present invention exhibited a dissolution concentration more than twice that of crystalline bosentan after 120 minutes of the dissolution test.
  • Amorphous bosentan temporarily showed an increase in dissolution concentration, but the dissolution concentration decreased with time.
  • the bosentan solid dispersion of the present invention had a high initial dissolution concentration, and the dissolution concentration was maintained high over time. Further, after leaving the dissolution test solution for one day, the concentration of the bosentan solid dispersion of the present invention hardly decreases. In Comparative Examples 1 and 6, the concentration is reduced to 1/5 compared to 120 minutes after the dissolution test.
  • the bosentan solid dispersion of the present invention maintains the concentration even in an aqueous solution, hardly precipitates bosentan crystals, and has excellent solubility.
  • Example 15 (Accelerated test) Example 15, Comparative Example 7, and Comparative Example 1 (crystalline bosentan monohydrate) were opened and maintained for 2 weeks under conditions of a temperature of 40 ° C. and a relative humidity of 75%.
  • Dissolution test 4 Take the accelerated test sample in a 30 mL screw tube, add 37 ° C test solution (distilled water or second solution (pH 6.8)), shake for 1 minute, soak in a 37 ° C warm bath, 150 times / min.
  • the dissolution concentration of bosentan was measured in the same manner as in the dissolution test 1 with the concentration at any time while shaking.
  • the amount of the sample added was equivalent to bosentan and was 15 mg for distilled water and 30 mg for 2 liquids.
  • Table 7 shows the results of distilled water
  • Table 8 shows the results of the second liquid.
  • the solid dispersion of the present invention has a dissolution concentration of 10 times or more with respect to crystalline bosentan and 3 times or more with respect to amorphous bosentan. ing.
  • the solid dispersion of the present invention does not show a decrease in dissolution concentration over time, and it can be seen that the supersaturated state of bosentan is extremely stable in an aqueous solution.
  • the bosentan solid dispersion of the present invention does not crystallize even under warming and humidification, so that the solubility remains high, whereas the amorphous bosentan crystallizes, so the solubility decreases. .

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  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne une composition pharmaceutique contenant du bosentan, présentant une bonne solubilité du bosentan dans l'eau, quel que soit le pH, et conservant cette solubilité même en cas de stockage de longue durée. Une telle dispersion solide est constituée (A) de bosentan et (B) d'un composant matrice choisi dans le groupe des polymères de la cellulose, des homopolymères de synthèse de la cellulose, et des copolymères de synthèse de la cellulose. Le rapport de masses (A:B) entre (A) et (B) se situe entre 1:0,05 et 1:10. La concentration en solution dans l'eau à 37°C se situe entre 50 et 500 µg/l. Enfin, la concentration en solution dans une solution aqueuse d'hydroxyde d'orthophosphate monosodique de potassium au pH de 6.8 à 37°C est comprise entre 0,6 et 10 mg/l.
PCT/JP2011/065230 2010-07-02 2011-07-01 Dispersion solide de bosentan WO2012002547A1 (fr)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014003677A1 (fr) * 2012-06-28 2014-01-03 Xspray Microparticles Ab Compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil
WO2014157603A1 (fr) * 2013-03-29 2014-10-02 アステラス製薬株式会社 Composition pharmaceutique pour administration orale
EP2848245A4 (fr) * 2012-05-11 2016-01-27 Hanall Biopharma Co Ltd Préparation orale à libération contrôlée de bosentan
JP2016537332A (ja) * 2013-11-22 2016-12-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 非ヌクレオシド逆転写酵素阻害剤の組成物
JP2018538325A (ja) * 2015-12-18 2018-12-27 ナトコ ファーマ リミテッド フェニルアミノピリミジン誘導体を含む医薬組成物
CN114533738A (zh) * 2022-02-19 2022-05-27 苏州海景医药科技有限公司 一种波生坦固体药物组合物及其制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007501219A (ja) * 2003-08-04 2007-01-25 ファイザー・プロダクツ・インク 薬物及び重合体の固体無定形分散を形成するための噴霧乾燥（スプレードライ）方法
WO2009053748A2 (fr) * 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines
WO2009083739A1 (fr) * 2008-01-01 2009-07-09 Cipla Limited Procédé de synthèse du bosentan, de ses formes polymorphiques et de ses sels
JP2010516781A (ja) * 2007-01-26 2010-05-20 アイエスピー インヴェストメンツ インコーポレイテッド 噴霧乾燥製品を製造するための調剤処理方法
JP2010132605A (ja) * 2008-12-04 2010-06-17 Ils Inc 活性成分の溶解性が高められた医薬組成物

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007501219A (ja) * 2003-08-04 2007-01-25 ファイザー・プロダクツ・インク 薬物及び重合体の固体無定形分散を形成するための噴霧乾燥（スプレードライ）方法
JP2010516781A (ja) * 2007-01-26 2010-05-20 アイエスピー インヴェストメンツ インコーポレイテッド 噴霧乾燥製品を製造するための調剤処理方法
WO2009053748A2 (fr) * 2007-10-24 2009-04-30 Generics [Uk] Limited Nouvelles formes cristallines
WO2009083739A1 (fr) * 2008-01-01 2009-07-09 Cipla Limited Procédé de synthèse du bosentan, de ses formes polymorphiques et de ses sels
JP2010132605A (ja) * 2008-12-04 2010-06-17 Ils Inc 活性成分の溶解性が高められた医薬組成物

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2848245A4 (fr) * 2012-05-11 2016-01-27 Hanall Biopharma Co Ltd Préparation orale à libération contrôlée de bosentan
WO2014003677A1 (fr) * 2012-06-28 2014-01-03 Xspray Microparticles Ab Compositions pharmaceutiques comprenant des particules de dispersion solide contenant du tadalafil
WO2014157603A1 (fr) * 2013-03-29 2014-10-02 アステラス製薬株式会社 Composition pharmaceutique pour administration orale
JP5900702B2 (ja) * 2013-03-29 2016-04-06 アステラス製薬株式会社 経口投与用医薬組成物
US9408835B2 (en) 2013-03-29 2016-08-09 Astellas Pharma Inc. Pharmaceutical composition for oral administration
JP2016537332A (ja) * 2013-11-22 2016-12-01 メルク・シャープ・アンド・ドーム・コーポレーションＭｅｒｃｋ Ｓｈａｒｐ ＆ Ｄｏｈｍｅ Ｃｏｒｐ． 非ヌクレオシド逆転写酵素阻害剤の組成物
JP2018538325A (ja) * 2015-12-18 2018-12-27 ナトコ ファーマ リミテッド フェニルアミノピリミジン誘導体を含む医薬組成物
CN114533738A (zh) * 2022-02-19 2022-05-27 苏州海景医药科技有限公司 一种波生坦固体药物组合物及其制备方法

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