WO2012002539A1 - Novel noncrystalline bosentan and process for preparation thereof - Google Patents

Novel noncrystalline bosentan and process for preparation thereof Download PDF

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WO2012002539A1
WO2012002539A1 PCT/JP2011/065197 JP2011065197W WO2012002539A1 WO 2012002539 A1 WO2012002539 A1 WO 2012002539A1 JP 2011065197 W JP2011065197 W JP 2011065197W WO 2012002539 A1 WO2012002539 A1 WO 2012002539A1
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bosentan
amorphous
minutes
spray
solvent
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PCT/JP2011/065197
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French (fr)
Japanese (ja)
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洋介 平井
直任 尾塩
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 JP2012522716A priority Critical patent/JPWO2012002539A1/en
Publication of WO2012002539A1 publication Critical patent/WO2012002539A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/69—Benzenesulfonamido-pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a novel amorphous bosentan having high solubility and long-term stability, a process for producing the same, and a pharmaceutical composition containing the amorphous bosentan.
  • Bosentan is N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidin-4-yl] -4-tert-butyl having the structure: Benzenesulfonamide, known as an endothelin receptor antagonist.
  • the bosentan is useful for the treatment of cardiovascular diseases such as hypertension, ischemic heart disease, 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 the dissolution concentration is less than 0.03 mg / mL.
  • the solubility in water should be increased. Is required to maintain this solubility 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
  • porous carriers such as magnesium aluminate metasilicate
  • Patent Document 1 describes a method (solvent precipitation method) in which bosentan is dissolved in t-butyl methyl ether and dichloromethane while being heated and cooled, and the precipitated solid is collected by filtration and vacuum dried to obtain amorphous bosentan.
  • Patent Document 2 describes a method (solvent distillation method) in which bosentan is dissolved in methanol, acetonitrile, and methylene chloride under heating and then filtered, and the solvent is removed under vacuum to obtain amorphous bosentan.
  • Patent Document 3 discloses a method in which bosentan is dissolved in an organic solvent, and then the solvent is distilled off. A poor solvent such as heptane is added to the residue to precipitate a solid, which is collected by filtration and then heated to dry to produce amorphous bosentan. Is described.
  • an object of the present invention is to provide bosentan having both high solubility in water and long-term stability, and a simple method for producing the bosentan.
  • the present inventor has rapidly spray-dried the bosentan-containing solution to obtain an aqueous solution having a pH of 6.8, which is the pH in the intestinal tract, which is an absorption site in the digestive tract.
  • the present inventors have found that amorphous bosentan having a remarkably excellent dissolution concentration therein and whose solubility is stably maintained over time can be obtained.
  • a solution containing 0.1 to 80% by weight of bosentan in an air current of 0 to 300 ° C. has a time until the sprayed droplets are pulverized to 0.1 minutes to 2 minutes.
  • Amorphous bosentan having an average particle size of 0.1 to 500 ⁇ m obtained by spray drying under the above conditions is provided.
  • the present invention also provides a solution containing 0.1 to 80% by weight of bosentan in an air current of 0 to 300 ° C., and the time until the sprayed droplets are pulverized is 0.1 to 2 minutes.
  • the present invention provides a method for producing amorphous bosentan having an average particle size of 0.1 to 500 ⁇ m, characterized by spray drying under the following conditions.
  • the present invention also provides amorphous anhydrous bosentan.
  • a production method a production method is provided in which a solution containing bosentan is sprayed and dried.
  • the present invention provides a pharmaceutical composition containing 10 to 2000 parts by mass of a pharmaceutical additive with respect to 100 parts by mass of the amorphous bosentan.
  • a novel amorphous bosentan can be easily and industrially produced by the spraying method of the present invention, and further, amorphous bosentan which is substantially entirely amorphous can be produced. it can.
  • Amorphous bosentan by the production method of the present invention can improve bioavailability compared to conventional bosentan, shorten the action start time, and reduce drug dosage and side effects.
  • the long-term stability is improved, it is possible to simplify the production method and storage more suitable for production. Improving dissolution compared to crystalline bosentan not only improves bioavailability, but also improves compliance with patients and adherence to patients with intractable diseases in order to reduce individual differences and dietary effects. Can do.
  • Example 1 and Comparative Examples 1 to 5 It is a change in dissolved concentration of Example 1 and Comparative Examples 1 to 5 after production.
  • 6 is an X-RD chart of Example 1 and Comparative Examples 1 to 5 after manufacture.
  • 6 is a DSC chart of Example 1 and Comparative Examples 1 to 5 after manufacture. It is a dissolution concentration change of Example 1 and Comparative Examples 1, 2, 4, and 5 after the stability test.
  • 2 is an X-RD chart of Example 1 and Comparative Examples 1, 2, 4, and 5 after a stability test. It is a DSC chart of Example 1 and Comparative Examples 1, 2, 4, and 5 after the stability test. It is a chart of DTA and TG of Example 1 after manufacture.
  • 6 is a chart of DTA and TG of Comparative Example 1.
  • the amorphous bosentan of the present invention is rapidly spray-dried, that is, a solution containing 0.1 to 80% by weight of bosentan in an air stream at 0 to 300 ° C. until the sprayed droplets are pulverized. It can be obtained by spray drying under the condition that the time is 0.1 minute to 2 minutes.
  • Examples of the raw material bosentan used in the production of the amorphous bosentan of the present invention include bosentan anhydride, bosentan monohydrate, bosentan polyhydrate, bosentan solvate, and pharmaceutically acceptable bosentan salt.
  • Bosentan monohydrate currently used as a pharmaceutical is preferable.
  • bosentan used as a raw material is dissolved in a solvent and used, any form may be used. That is, either crystalline bosentan or non-crystalline bosentan may be used as a mixture, and any of known crystal polymorphs may be used as the crystal.
  • the raw material bosentan-containing solution is a solution in which bosentan is dissolved in a soluble solvent.
  • the solvent used here is preferably an organic solvent 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 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), dimethylsulfoxide (DMSO) and the like may be mentioned, and two or more of these may be used in combination.
  • a supercritical state may be used.
  • the conditions for dissolving bosentan in a solvent are preferably 0 to 100 ° C. under normal pressure from the viewpoint of preventing decomposition of bosentan.
  • the bosentan concentration in the bosentan-containing solution is preferably 0.1 to 80% by weight, more preferably 1 to 70% by weight, from the viewpoint of the solubility and sprayability of bosentan.
  • Spray drying is performed in an air stream with an inlet temperature of 0 to 300 ° C. under the condition that the time until the sprayed droplets are pulverized is 0.1 to 2 minutes in order to improve solubility and stability. It is important in obtaining the combined amorphous bosentan. In other words, pulverization in less than 0.1 minutes is difficult in actual production, and when pulverization takes 2 minutes or more, uniform amorphous bosentan cannot be obtained. More preferably, the time until the droplets are pulverized is 0.1 to 1.8 minutes, and more preferably 0.2 to 1.6 minutes. Here, the time until the droplets are pulverized can be adjusted by the spray drying capacity, the air volume, the temperature, and the like. Further, the temperature in the air stream to be sprayed is preferably 20 to 200 ° C., more preferably 30 to 180 ° C.
  • the stability of the amorphous state of amorphous bosentan by the spraying method of the present invention is high after spraying bosentan dissolved in a solvent into an air stream to form fine droplets (1000 ⁇ m or less). This is because the solvent is removed in a short time of 1 to 2 minutes to obtain a powder. In order to remove the solvent in a short time, the molecules are gathered as they are in a molecular state in which bosentan is dissolved in the solvent and randomly dispersed, and is obtained as a powder. Furthermore, the proportion of the amorphous state in which the bosentan molecules are arranged randomly is substantially 100%. On the other hand, in other manufacturing methods, it is not only difficult but also industrially impossible to produce such a completely amorphous state.
  • a very long time is required to completely crystallize crystalline bosentan.
  • the molecules are completely dispersed at the time of preparing the solution.
  • fine crystals are formed in part, and an amorphous state including them in part is obtained.
  • the solvent evaporation method in order to obtain a solid of bosentan, it takes time to evaporate the solvent. For example, since it takes 10 minutes or more, a non-crystal that cannot be measured by X-ray is partially included. It is in a crystalline state.
  • crystal growth occurs due to the seed effect of the crystals, which is a factor that inhibits the stability of amorphous bosentan. This crystal growth is observed by X-rays and causes a decrease in elution.
  • the amorphous material contains a small amount of crystal, not only the solubility in water decreases, but also the fine crystals dispersed in the solution or on the particle surface cause a seed crystal effect. It is known to cause a decrease in dissolved concentration in order to promote the precipitation of substances from
  • a disk-type or nozzle-type (for example, pressure nozzle, 2 fluid nozzle, 4 fluid nozzle) spray dryer is used as the spray device.
  • the inlet temperature is preferably about 0 to 300 ° C
  • the outlet temperature is preferably about 0 to 100 ° C.
  • the spray drying of the present invention is a method of spraying a solution from a nozzle, and includes a spray drying method, a fluidized bed method, a rolling bed method, a stirring method, and the like.
  • Nozzle type is used as in
  • the temperature is preferably about 0 to 300 ° C. at the inlet temperature and about 0 to 100 ° C. at the outlet temperature.
  • the blowing condition and the dynamic condition of the carrier are arbitrarily set according to the characteristics of the solvent and carrier used according to the apparatus used.
  • a carrier an additive that can be used for a pharmaceutical used in these production methods is usually used.
  • the average particle diameter of the obtained amorphous bosentan is preferably from 0.1 to 500 ⁇ m, more preferably from 1 to 300 ⁇ m, and even more preferably from 2 to 150 ⁇ m, from the viewpoints of blendability and solubility in the pharmaceutical composition.
  • the particle size can be adjusted by spray drying conditions.
  • an average particle diameter is the value of D50 of the integrated diameter by laser measurement.
  • the amorphous bosentan of the present invention is amorphous bosentan substantially free of crystalline bosentan.
  • crystals are not substantially confirmed by powder X-ray structural analysis described later.
  • the endothermic peak near 113 ° C. peculiar to bosentan crystals is not confirmed by thermal analysis, but a small endothermic peak is confirmed around 85 ° C.
  • the amorphous bosentan of the present invention has a chemical composition of anhydrous bosentan, bosentan monohydrate, bosentan polyhydrate, bosentan sodium, bosentan potassium, bosentan calcium, bosentan barium and other pharmaceutically acceptable bosentan salts. is there. Two or more of these can be combined. Preferred are anhydrous bosentan and bosentan monohydrate, and more preferred is anhydrous bosentan (amorphous anhydrous bosentan).
  • Amorphous anhydrous bosentan is amorphous bosentan and does not contain water molecules in the amorphous structure. It can be confirmed by thermogravimetry that the weight does not decrease due to the separation of water molecules at a temperature of 40 to 70 ° C.
  • Amorphous anhydrous bosentan is produced by dissolving crystalline bosentan monohydrate in a solvent and removing the solvent in a short time, or heating and melting and kneading the crystalline bosentan monohydrate under pressure. It is preferable.
  • the amorphous bosentan of the present invention has improved solubility in water, and in particular, the solubility of the intestinal tract that is the absorption site after oral administration, that is, the aqueous solution having a pH of 6.8, has been significantly improved.
  • the dissolution concentration in an aqueous solution of potassium dihydrogen phosphate-sodium hydroxide having a pH of 6.8 at 37 ° C. is 0.6 to 10 mg / mL, preferably 0.8 to 10 mg / mL.
  • pH 6.8 potassium dihydrogen phosphate-sodium hydroxide aqueous solution is the second disintegration test liquid used in the Japanese Pharmacopoeia to test the dissolution of medicinal ingredients from pharmaceutical preparations in the intestine.
  • This dissolution concentration is expressed as a dissolution concentration 60 to 120 minutes after adding amorphous bosentan to the aqueous solution, more preferably a dissolution concentration after 120 minutes.
  • the above-mentioned dissolution concentration of the amorphous bosentan of the present invention is 1.5 times or more, further 4 times or more, particularly 8 times or more higher than that of crystalline bosentan. Therefore, the amorphous bosentan of the present invention has higher solubility in water than the conventional crystalline bosentan, extremely high solubility in the intestinal tract as the absorption site, and it is absorbed over a long period from the stomach to the small intestine.
  • the amorphous bosentan of the present invention maintains excellent solubility even after long-term storage. More specifically, after standing for 7 days at a temperature of 40 ° C. and a relative humidity of 75%, the dissolution concentration in an aqueous solution of potassium dihydrogen phosphate-sodium hydroxide having a pH of 6.8 at 37 ° C. is 0.6 to 10 mg / mL, Preferably, it is 0.8 to 10 mg / mL.
  • This dissolution concentration is also a dissolution concentration 60 to 120 minutes after adding amorphous bosentan to the aqueous solution, more preferably a dissolution concentration after 120 minutes.
  • the dissolution concentration of the amorphous bosentan of the present invention after standing for 7 days at a temperature of 40 ° C. and a relative humidity of 75% is 1.5 times or more, further 4 times or more, particularly 8 times or more higher than that of crystalline bosentan. Therefore, the amorphous bosentan of the present invention maintains high solubility even after long-term storage and is useful as a pharmaceutical product.
  • amorphous bosentan of the present invention is more excellent in solubility after long-term storage than amorphous bosentan obtained by other methods.
  • amorphous bosentan obtained by a solvent distillation method may be in an amorphous state immediately after production and has high elution properties.
  • the amorphous state cannot be maintained over a long period of time, resulting in a decrease in elution.
  • crystals are formed after one week, resulting in a decrease in the dissolution concentration.
  • the dissolution concentration of the amorphous bosentan of the present invention is 1.5 times or more that of amorphous bosentan by the solvent distillation method, Preferably it is 2 times or more.
  • the amorphous bosentan of the present invention is useful as a pharmaceutical composition because it maintains an amorphous form even after long-term storage and has good absorbability in the intestinal tract.
  • the amorphous bosentan thus obtained can be used for dry granulation and wet granulation using additives that can be used in pharmaceuticals for tablet mixing, dissolution, sustained release, and bitterness masking.
  • Amorphous bosentan-containing particles can be obtained.
  • the particle size and bulk density can be increased by thickening with a roller compactor or the like.
  • a pharmaceutical additive is mixed with amorphous bosentan and / or amorphous bosentan-containing particles to obtain an oral pharmaceutical composition such as a tablet, capsule, powder, solution, emulsion or suspension.
  • an oral pharmaceutical composition such as a tablet, capsule, powder, solution, emulsion or suspension.
  • pharmaceutical compositions such as injections, suppositories, eye drops, nasal cavities, and inhalants can be obtained as parenterals. As these production methods, known methods can be used.
  • Pharmaceutical additives include binders (eg, carmellose, hydroxypropyl cellulose, alginic acid, gelatin, partially pregelatinized starch, povidone, 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, etc.), lubricants (eg, Sucrose fatty acid ester, magnesium stearate, talc, sodium
  • edible blue No. 2 edible yellow 5 No., edible lake pigment, iron sesquioxide, astaxanthin), stabilizers (for example, sodium edetate, tocopherol, tocotrienol, cyclodextrin, etc.), flavoring agents, flavoring agents and the like.
  • These pharmaceutical additives are contained in an amount of 10 to 2000 parts by mass, preferably 20 to 1500 parts by mass, more preferably 20 to 900 parts by mass with respect to 100 parts by mass of amorphous bosentan.
  • the pharmaceutical composition containing the amorphous bosentan of the present invention can be expected to have an area under the blood concentration time curve equivalent to that of the conventional crystalline bosentan even if the dosage is reduced by improving 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, IV), but pulmonary arterial hypertension (WHO functional class) I), other pulmonary hypertension, acute and / or chronic renal failure, fingertip ulcer associated with scleroderma, arteriosclerosis, pulmonary hypertension associated with chronic pulmonary thromboembolism, idiopathic pulmonary fibrosis, sleep apnea syndrome It is also promising as a therapeutic, prophylactic or management agent for vascular thickening (restenosis), angina pectoris, myocardial infarction, chronic heart failure, cerebral vasospasm after subarachnoid hemorrhage, etc.
  • the amorphous bosentan of the present invention is used in combination with the following drugs to treat, prevent or manage pulmonary hypertension including pulmonary arterial hypertension and the like, for example, Rho-kinase inhibitor, prostacyclin Agonist, 5-HT 2A antagonist, anticoagulant, antiplatelet agent, diuretic, cardiac glycoside, calcium channel blocker, lipid lowering agent, vasodilator, endothelial antagonist, phosphodiesterase inhibitor, endopeptidase inhibitor, It can be combined with selective serotonin reuptake inhibitors, thromboxane inhibitors, vascular remodeling regulators, endothelin receptor antagonists and other therapeutic agents known to lower pulmonary artery pressure.
  • drugs for example, Rho-kinase inhibitor, prostacyclin Agonist, 5-HT 2A antagonist, anticoagulant, antiplatelet agent, diuretic, cardiac glycoside, calcium channel blocker, lipid lowering agent, vasodilator, endothelial antagonist, phosphodiesterase inhibitor,
  • 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 Impact Method 1 g of crystalline bosentan monohydrate powder was ground in a mortar for 2.5 hours to obtain amorphous bosentan powder.
  • Comparative Example 4 is crystalline bosentan monohydrate.
  • 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.
  • X-ray measurement was performed by X'Pert-MPD type (manufactured by Philips), and DSC (thermal analysis) measurement was performed by Thermo plus DSC8230 (manufactured by Rigaku).
  • the results of X-RD and DSC of Example 1 and Comparative Examples 1 to 4 are shown in FIGS. 2 and 3, respectively.
  • Example 1 and Comparative Example 3 have no crystal peak and are in an amorphous state.
  • Comparative Example 1 and Comparative Example 2 are similar to the crystal pattern of Comparative Example 4 (crystalline bosentan monohydrate), but have a low-intensity crystal peak, indicating that crystals remain.
  • the characteristic endothermic peak does not appear in Example 1 and Comparative Examples 1 to 4.
  • Example 4 The differential heat and thermogravimetric measurements were performed on the powders of Example 1 and Comparative Example 4 using a differential thermothermogravimetric simultaneous measurement apparatus (Seiko Instruments Inc., SSC / 5200). The results are shown in FIGS. In Comparative Example 4, there is a change in weight in the vicinity of 40 to 70 ° C., but not in Example 1, and it can be seen that the amorphous bosentan of Example 1 is an anhydride.
  • the dissolution concentration of the amorphous bosentan of Example 1 was 1.07 mg / mL, which was 8% relative to the amorphous bosentan of Comparative Examples 1 and 2 and the crystalline bosentan of Comparative Example 4. It shows that the dissolution concentration is twice or more and the improvement in solubility is extremely excellent.
  • the amorphous bosentan by the spraying method of Example 1 had a dissolution concentration of 0.92 mg / mL, and the amorphous bosentan of Comparative Examples 1 and 3 and the crystals of Comparative Example 4 produced by a method other than the spraying method. Dissolving concentration is twice or more higher than bosentan. Further, the amorphous bosentan of Comparative Example 3 has a decrease in dissolution concentration after 60 minutes, whereas the amorphous bosentan by the spray method of Example 1 maintains a high dissolution concentration.
  • Comparative Example 3 Depending on the acceleration conditions, in the X-RD pattern, although Comparative Example 3 is slight, a crystal pattern appears. In Comparative Example 1, the crystal pattern has grown. The DSC pattern is almost the same as in Example 1 and Comparative Example 3. From these, it is shown in Comparative Example 3 that the endothermic peak does not appear in DSC, and a minute amount of crystal precipitation occurs so that a slight crystal pattern appears in X-RD. These microcrystals are a cause of a decrease in solubility in dissolution.
  • the amorphous bosentan produced by the spraying method of the present invention can maintain an amorphous state longer than the amorphous bosentan produced by other methods even in spray drying in a wide temperature range of 40 to 110 ° C. And when dissolved in water, the dissolution concentration can be maintained over a long period of time.
  • Amorphous bosentan was produced in the same manner as in [Example 1]. 1 g of crystalline bosentan-hydrate powder was dissolved in 50 m of the solvent shown in Table 5. Subsequently, spray drying was performed at a heat input temperature of 80 ° C., a waste heat temperature of 50 ° C., and a spray rate of 6 mL / min, and the resulting powder was further dried overnight at 40 ° C. under reduced pressure (5 Torr or less). Bosentan powder was obtained.
  • Amorphous bosentan by spray drying of the present invention can maintain an amorphous state longer than amorphous bosentan by other production methods, regardless of whether the highly hydrophilic ethanol or the highly lipophilic methylene chloride is used. It has high stability and can maintain the dissolved concentration for a long period when dissolved in water.

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Abstract

Provided are: a bosentan which combines high solubility in water and long-term stability; and an easy and simple process for the preparation of the bosentan. A noncrystalline bosentan having a mean particle diameter of 0.1 to 500μm, which is obtained by spray-drying a 0.1 to 80wt% bosentan solution in an air stream at 0 to 300°C under such conditions that the time elapsed until the sprayed droplets are converted into powder falls within a range of 0.1 to 2 minutes.

Description

新規な非晶質ボセンタン及びその製造方法Novel amorphous bosentan and method for producing the same
　本発明は、溶解性及び長期安定性が高い新規な非晶質ボセンタン及びその製法、並びにその非晶質ボセンタンを含む医薬組成物に関する。 The present invention relates to a novel amorphous bosentan having high solubility and long-term stability, a process for producing the same, and a pharmaceutical composition containing the amorphous bosentan.
　ボセンタンは、下式の構造を有するＮ－［６－（２－ヒドロキシエトキシ）－５－（２－メトキシフェノキシ）－２－（２－ピリミジニル）－ピリミジン－４－イル］－４－ｔｅｒｔ－ブチルベンゼンスルホンアミドであり、エンドセリン受容体拮抗薬として知られている。該ボセンタンは高血圧症、虚血性心疾患、血管攣縮及び狭心症などの心血管疾患の治療に有用であり、肺動脈性肺高血圧症の治療薬として使用されている。ボセンタンの合成方法は、米国特許５，２９２，７４０号公報、米国特許６，１３６，９７１号公報に記載されている。 Bosentan is N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (2-pyrimidinyl) -pyrimidin-4-yl] -4-tert-butyl having the structure: Benzenesulfonamide, known as an endothelin receptor antagonist. The bosentan is useful for the treatment of cardiovascular diseases such as hypertension, ischemic heart disease, 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.
Figure JPOXMLDOC01-appb-C000001
Figure JPOXMLDOC01-appb-C000001
　ボセンタン及びその誘導体は、難水溶性であり、特にｐＨ５以下では溶解濃度が０．０３ｍｇ／ｍＬ未満であり、経口投与におけるバイオアベイラビリティーを高めるためには、水への溶解性を高めること、さらにはこの溶解性が３年以上維持されることが求められている。 Bosentan and its derivatives are sparingly water-soluble, especially at a pH of 5 or less, and the dissolution concentration is less than 0.03 mg / mL. In order to increase the bioavailability in oral administration, the solubility in water should be increased. Is required to maintain this solubility for 3 years or more.
　一般に、難溶性の薬物の水への溶解濃度を向上させるには、平均粒子径をナノサイズまで粉砕する方法、シクロデキストリンなどで包接化する方法、メタケイ酸アルミン酸マグネシウムなどの多孔性担体に吸着させる方法、乳化などによりマイクロスフェアにする方法、及び非結晶化する方法などが知られている。 In general, in order to improve the dissolution concentration of poorly soluble drugs in water, 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 adsorbing, a method of forming microspheres by emulsification, a method of non-crystallizing, and the like are known.
　これまで、ボセンタンの水への溶解性を向上させる方法としては、ボセンタンを溶解性の高い結晶系に結晶構造を変えることや非結晶化する方法が知られている。特許文献１には、ボセンタンをｔ―ブチルメチルエーテルとジクロロメタンに熱時溶解後冷却し、析出した固体を濾取し、真空乾燥により非晶質ボセンタンを得る方法（溶媒析出法）が記載されている。特許文献２には、ボセンタンをメタノール、アセトニトリル、塩化メチレンに熱時溶解後に濾過し、溶媒を真空下に除去して非晶質ボセンタンを得る方法（溶媒留去法）が記載されている。特許文献３には、ボセンタンを有機溶媒に溶解後に溶媒を留去し、残渣にヘプタンなどの貧溶媒を加えて固体を析出させて濾取し、熱時乾燥により非晶質ボセンタンを製造する方法が記載されている。 Conventionally, as a method for improving the solubility of bosentan in water, a method of changing the crystal structure of bosentan to a highly soluble crystal system or making it non-crystallized is known. Patent Document 1 describes a method (solvent precipitation method) in which bosentan is dissolved in t-butyl methyl ether and dichloromethane while being heated and cooled, and the precipitated solid is collected by filtration and vacuum dried to obtain amorphous bosentan. Yes. Patent Document 2 describes a method (solvent distillation method) in which bosentan is dissolved in methanol, acetonitrile, and methylene chloride under heating and then filtered, and the solvent is removed under vacuum to obtain amorphous bosentan. Patent Document 3 discloses a method in which bosentan is dissolved in an organic solvent, and then the solvent is distilled off. A poor solvent such as heptane is added to the residue to precipitate a solid, which is collected by filtration and then heated to dry to produce amorphous bosentan. Is described.
国際公開ＷＯ２００８／１３５７９５号パンフレットInternational Publication WO2008 / 135595 Pamphlet 国際公開ＷＯ２００９／０４７６３７号パンフレットInternational Publication WO2009 / 047637 Pamphlet 国際公開ＷＯ２００９／０８３７３９号パンフレットInternational Publication WO2009 / 083739 Pamphlet
　薬物が非晶質状態から結晶状態に転移すると溶解濃度が極端に低下し、医薬品としての効用は極めて低下する。従って、薬物の非結晶体は、投与まで非晶質状態を維持することが必要である。そのため、非晶質ボセンタンにおいてもボセンタンの非晶質状態を長期間に渡って維持することが必要とされる。また、溶解濃度は消化管から吸収されるまでの間の時間は持続する必要がある。これまでの先行技術では、ボセンタンの非晶質状態の安定性や水への溶解濃度の維持が充分ではなかった。
　従って、本発明の課題は、水への高い溶解性及びその長期の安定性を兼ね備えたボセンタン、並びにそのボセンタンの簡便な製造方法を提供することにある。 When the drug transitions from the amorphous state to the crystalline state, the dissolved concentration is extremely lowered, and the utility as a pharmaceutical is extremely lowered. Therefore, it is necessary for the amorphous form of the drug to remain in an amorphous state until administration. Therefore, it is necessary for amorphous bosentan to maintain the amorphous state of bosentan for a long period of time. Also, the dissolution concentration needs to last for a period of time before it is absorbed from the digestive tract. In the prior art so far, the stability of bosentan in the amorphous state and the maintenance of the concentration in water have not been sufficient.
Accordingly, an object of the present invention is to provide bosentan having both high solubility in water and long-term stability, and a simple method for producing the bosentan.
　そこで本発明者は、新たなボセンタン非晶体を得るべく種々検討した結果、ボセンタン含有溶液を急速に噴霧乾燥することにより、消化管内での吸収部位である腸管内のｐＨであるｐＨ６．８の水溶液中での溶解濃度が格段に優れ、かつその溶解性が経時的に安定に維持された非晶質ボセンタンが得られることを見出し、本発明を完成した。 Therefore, as a result of various studies to obtain a new bosentan amorphous material, the present inventor has rapidly spray-dried the bosentan-containing solution to obtain an aqueous solution having a pH of 6.8, which is the pH in the intestinal tract, which is an absorption site in the digestive tract. The present inventors have found that amorphous bosentan having a remarkably excellent dissolution concentration therein and whose solubility is stably maintained over time can be obtained.
　すなわち、本発明は、ボセンタンを０．１～８０重量％含有する溶液を、０～３００℃の気流中に、噴霧された液滴が粉末化するまでの時間が０．１分～２分となる条件で噴霧乾燥することにより得られる、平均粒子径０．１～５００μｍの非晶質ボセンタンを提供するものである。
　また、本発明は、ボセンタンを０．１～８０重量％含有する溶液を、０～３００℃の気流中に、噴霧された液滴が粉末化するまでの時間が０．１分～２分となる条件で噴霧乾燥することを特徴とする、平均粒子径０．１～５００μｍの非晶質ボセンタンの製造法を提供するものである。
　また、本発明は、非晶質無水ボセンタンを提供するものである。その製造方法として、ボセンタンを含有する溶液を噴霧して乾燥する製造方法を提供する。
　さらに、本発明は、上記の非晶質ボセンタン１００質量部に対して、医薬添加物１０～２０００質量部を含有する医薬組成物を提供するものである。 That is, according to the present invention, a solution containing 0.1 to 80% by weight of bosentan in an air current of 0 to 300 ° C. has a time until the sprayed droplets are pulverized to 0.1 minutes to 2 minutes. Amorphous bosentan having an average particle size of 0.1 to 500 μm obtained by spray drying under the above conditions is provided.
The present invention also provides a solution containing 0.1 to 80% by weight of bosentan in an air current of 0 to 300 ° C., and the time until the sprayed droplets are pulverized is 0.1 to 2 minutes. The present invention provides a method for producing amorphous bosentan having an average particle size of 0.1 to 500 μm, characterized by spray drying under the following conditions.
The present invention also provides amorphous anhydrous bosentan. As the production method, a production method is provided in which a solution containing bosentan is sprayed and dried.
Furthermore, the present invention provides a pharmaceutical composition containing 10 to 2000 parts by mass of a pharmaceutical additive with respect to 100 parts by mass of the amorphous bosentan.
　本発明の噴霧法によって新規な非晶質ボセンタン、特に非晶質無水ボセンタンを簡便に工業的に製造し、さらには実質的に全てを非晶質状態とした非晶質ボセンタンを製造することができる。本発明の製法による非晶質ボセンタンは従来のボセンタンよりもバイオアベイラビリティーを向上させ、作用開始時間の短縮、薬剤投与量と副作用を減少させることができる。また、長期安定性が向上しているためより生産に適した製造方法や保存を簡便にすることができる。結晶ボセンタンに比べて溶出改善する事はバイオアベイラビリティーの向上のみならず、固体差変動・食事の影響などを減少させるため、患者への服薬コンプライアンス向上並びに難治性疾患に対する患者のアドヒアランス向上を行うことができる。 A novel amorphous bosentan, particularly amorphous anhydrous bosentan, can be easily and industrially produced by the spraying method of the present invention, and further, amorphous bosentan which is substantially entirely amorphous can be produced. it can. Amorphous bosentan by the production method of the present invention can improve bioavailability compared to conventional bosentan, shorten the action start time, and reduce drug dosage and side effects. Moreover, since the long-term stability is improved, it is possible to simplify the production method and storage more suitable for production. Improving dissolution compared to crystalline bosentan not only improves bioavailability, but also improves compliance with patients and adherence to patients with intractable diseases in order to reduce individual differences and dietary effects. Can do.
製造後の実施例１及び比較例１～５の溶解濃度変化である。It is a change in dissolved concentration of Example 1 and Comparative Examples 1 to 5 after production. 製造後の実施例１及び比較例１～５のＸ－ＲＤチャートである。6 is an X-RD chart of Example 1 and Comparative Examples 1 to 5 after manufacture. 製造後の実施例１及び比較例１～５のＤＳＣチャートである。6 is a DSC chart of Example 1 and Comparative Examples 1 to 5 after manufacture. 安定性試験後の実施例１及び比較例１、２、４、５の溶解濃度変化である。It is a dissolution concentration change of Example 1 and Comparative Examples 1, 2, 4, and 5 after the stability test. 安定性試験後の実施例１及び比較例１、２、４、５のＸ－ＲＤチャートである。2 is an X-RD chart of Example 1 and Comparative Examples 1, 2, 4, and 5 after a stability test. 安定性試験後の実施例１及び比較例１、２、４、５のＤＳＣチャートである。It is a DSC chart of Example 1 and Comparative Examples 1, 2, 4, and 5 after the stability test. 製造後の実施例１のＤＴＡとＴＧのチャートである。It is a chart of DTA and TG of Example 1 after manufacture. 比較例１のＤＴＡとＴＧのチャートである。6 is a chart of DTA and TG of Comparative Example 1.
　本発明の非晶質ボセンタンは、急速な噴霧乾燥、すなわち、ボセンタンを０．１～８０重量％含有する溶液を、０～３００℃の気流中に、噴霧された液滴が粉末化するまでの時間が０．１分～２分となる条件で噴霧乾燥することにより得られる。 The amorphous bosentan of the present invention is rapidly spray-dried, that is, a solution containing 0.1 to 80% by weight of bosentan in an air stream at 0 to 300 ° C. until the sprayed droplets are pulverized. It can be obtained by spray drying under the condition that the time is 0.1 minute to 2 minutes.
　本発明の非晶質ボセンタンの製造に用いる原料のボセンタンとしては、ボセンタン無水物、ボセンタン一水和物、ボセンタン多水和物、ボセンタン溶媒和物、医薬品に許容されるボセンタン塩が挙げられる。好ましくは、現在医薬品として用いられているボセンタン一水和物である。 Examples of the raw material bosentan used in the production of the amorphous bosentan of the present invention include bosentan anhydride, bosentan monohydrate, bosentan polyhydrate, bosentan solvate, and pharmaceutically acceptable bosentan salt. Bosentan monohydrate currently used as a pharmaceutical is preferable.
　原料として用いるボセンタンは、溶媒に溶解させて用いるため、いずれの形態のものを用いてもよい。すなわち、結晶ボセンタン、非結晶ボセンタンのいずれでも混合物でもよく、結晶としては公知の結晶多形のうち、いずれを用いてもよい。 Since bosentan used as a raw material is dissolved in a solvent and used, any form may be used. That is, either crystalline bosentan or non-crystalline bosentan may be used as a mixture, and any of known crystal polymorphs may be used as the crystal.
　原料ボセンタン含有溶液は、ボセンタンを溶解可能な溶媒に溶解した溶液である。ここで用いる溶媒としては、有機溶媒が好ましく、例えばエタノール、メタノール、２－プロパノール、アセトン、２－ブタノン、メチルイソブチルケトン、テトラヒドロフラン（ＴＨＦ）、テトラヒドロピラン、１，４－ジオキサン、ジエチルエーテル、ジイソプロピルエーテル、ｔ－ブチルメチルエーテル、ヘキサン、ヘプタン、トルエン、アセトニトリル、塩化メチレン、クロロホルム、四塩化炭素、酢酸メチル、酢酸エチル、酢酸ブチル、酢酸、蟻酸、Ｎ，Ｎ－ジメチルホルムアミド（ＤＭＦ）、Ｎ，Ｎ－ジメチルアセトアミド（ＤＭＡｃ）、ジメチルスルホキシド（ＤＭＳＯ）などが挙げられ、これらの２種以上を組み合わせて用いてもよい。超臨界状態を用いてもよい。ボセンタンを溶媒に溶解させる場合の条件は、ボセンタンの分解を防止する点から、常圧下、０～１００℃の条件で行うのが好ましい。 The raw material bosentan-containing solution is a solution in which bosentan is dissolved in a soluble solvent. The solvent used here is preferably an organic solvent 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), dimethylsulfoxide (DMSO) and the like may be mentioned, and two or more of these may be used in combination. A supercritical state may be used. The conditions for dissolving bosentan in a solvent are preferably 0 to 100 ° C. under normal pressure from the viewpoint of preventing decomposition of bosentan.
　ボセンタン含有溶液中のボセンタン濃度は、ボセンタンの溶解性及び噴霧性の点から、０．１～８０重量％が好ましく、さらに１～７０重量％が好ましい。 The bosentan concentration in the bosentan-containing solution is preferably 0.1 to 80% by weight, more preferably 1 to 70% by weight, from the viewpoint of the solubility and sprayability of bosentan.
　噴霧乾燥は、入口温度が０～３００℃の気流中に、噴霧された液滴が粉末化するまでの時間が０．１分～２分となる条件で行うのが、溶解性と安定性を兼ね備えた非晶質ボセンタンを得るうえで重要である。すなわち、０．１分未満での粉末化は実生産上困難であり、粉末化に２分以上を要する場合は、均一な非晶質ボセンタンが得られない。より好ましい液滴が粉末化するまでの時間は、０．１分～１．８分であり、さらに好ましくは０．２分～１．６分である。ここで、液滴が粉末化するまでの時間は、噴霧乾燥の容量、風量、温度などにより調節することができる。また、噴霧する気流中の温度は、さらに２０～２００℃が好ましく、特に３０～１８０℃が好ましい。 Spray drying is performed in an air stream with an inlet temperature of 0 to 300 ° C. under the condition that the time until the sprayed droplets are pulverized is 0.1 to 2 minutes in order to improve solubility and stability. It is important in obtaining the combined amorphous bosentan. In other words, pulverization in less than 0.1 minutes is difficult in actual production, and when pulverization takes 2 minutes or more, uniform amorphous bosentan cannot be obtained. More preferably, the time until the droplets are pulverized is 0.1 to 1.8 minutes, and more preferably 0.2 to 1.6 minutes. Here, the time until the droplets are pulverized can be adjusted by the spray drying capacity, the air volume, the temperature, and the like. Further, the temperature in the air stream to be sprayed is preferably 20 to 200 ° C., more preferably 30 to 180 ° C.
　本発明の噴霧法による非晶質ボセンタンの非晶質状態の安定性が高いのは、溶媒に溶解中のボセンタンを気流中に噴霧し、微少な液滴（１０００μｍ以下）を形成させた後０．１分～２分という短時間で溶媒を取り除き粉末を得るからである。短時間で溶媒を取り除くため、ボセンタンが溶媒中に溶解しランダムに分散している分子状態でそのまま分子が集合し粉末として得られる。さらには、ボセンタン分子のランダムに並んだ非晶質状態の割合が実質的に１００％である。これに対して、他の製法では、このような完全な非晶質状態を製造することは、困難のみならず、工業的には不可能である。 The stability of the amorphous state of amorphous bosentan by the spraying method of the present invention is high after spraying bosentan dissolved in a solvent into an air stream to form fine droplets (1000 μm or less). This is because the solvent is removed in a short time of 1 to 2 minutes to obtain a powder. In order to remove the solvent in a short time, the molecules are gathered as they are in a molecular state in which bosentan is dissolved in the solvent and randomly dispersed, and is obtained as a powder. Furthermore, the proportion of the amorphous state in which the bosentan molecules are arranged randomly is substantially 100%. On the other hand, in other manufacturing methods, it is not only difficult but also industrially impossible to produce such a completely amorphous state.
　例えば、メカノケミカル法では、結晶ボセンタンを完全に非結晶化するには極めて長い時間が必要である。溶媒析出法では、溶液調製時には完全に分子で分散しているが、析出過程に一部に微少な結晶を形成し、それらを一部に含む非晶質状態となっている。溶媒留去法では、ボセンタンの固形物を得るために、溶媒を留去するのに時間がかかり、例えば１０分以上の時間を要するため、Ｘ線では測定できない微小の結晶を一部に含む非晶質状態となっている。これらの微少結晶は長期間保持すると、結晶の種効果により結晶の成長を生じ、非晶質ボセンタンの安定性を阻害する要因となっている。この結晶成長はＸ線で観察され、溶出性低下の原因となっている。一般に、非晶体に一部微少な結晶体が含まれていると、水への溶解度が低下するのみならず、溶液中に分散し又は粒子表面上の微細な結晶が種晶効果を起こし、溶液からの物質の析出を促進するため溶解濃度の低下を起こすことが知られている。 For example, in the mechanochemical method, a very long time is required to completely crystallize crystalline bosentan. In the solvent precipitation method, the molecules are completely dispersed at the time of preparing the solution. However, in the precipitation process, fine crystals are formed in part, and an amorphous state including them in part is obtained. In the solvent evaporation method, in order to obtain a solid of bosentan, it takes time to evaporate the solvent. For example, since it takes 10 minutes or more, a non-crystal that cannot be measured by X-ray is partially included. It is in a crystalline state. When these microcrystals are held for a long time, crystal growth occurs due to the seed effect of the crystals, which is a factor that inhibits the stability of amorphous bosentan. This crystal growth is observed by X-rays and causes a decrease in elution. In general, if the amorphous material contains a small amount of crystal, not only the solubility in water decreases, but also the fine crystals dispersed in the solution or on the particle surface cause a seed crystal effect. It is known to cause a decrease in dissolved concentration in order to promote the precipitation of substances from
　噴霧乾燥の場合、噴霧装置としては円盤式又はノズル式（例えば、加圧ノズル、２流体ノズル、４流体ノズル）の噴霧乾燥機を用いる。噴霧乾燥の際の温度としては、入口温度が約０～３００℃であり、出口温度が約０～１００℃が好ましい。 In the case of spray drying, a disk-type or nozzle-type (for example, pressure nozzle, 2 fluid nozzle, 4 fluid nozzle) spray dryer is used as the spray device. As the temperature at the time of spray drying, the inlet temperature is preferably about 0 to 300 ° C, and the outlet temperature is preferably about 0 to 100 ° C.
　本発明の噴霧乾燥は、ノズルから溶液を噴霧する方法であり、噴霧乾燥法、流動層法、転動層法、攪拌法などが含まれ、これらの方法において、担体に噴霧する場合は、前述と同様ノズル式を用いる。温度としては、入口温度が約０～３００℃であり、出口温度が約０～１００℃が好ましい。送風条件や担体の動的条件は、用いる装置に従って、用いる溶媒や担体の特性により任意に設定する。担体としては、通常、これらの製法で用いられる医薬品に使用可能な添加物を用いる。 The spray drying of the present invention is a method of spraying a solution from a nozzle, and includes a spray drying method, a fluidized bed method, a rolling bed method, a stirring method, and the like. Nozzle type is used as in The temperature is preferably about 0 to 300 ° C. at the inlet temperature and about 0 to 100 ° C. at the outlet temperature. The blowing condition and the dynamic condition of the carrier are arbitrarily set according to the characteristics of the solvent and carrier used according to the apparatus used. As a carrier, an additive that can be used for a pharmaceutical used in these production methods is usually used.
　得られる非晶質ボセンタンの平均粒子径は、医薬組成物への配合性及び溶解性の点から、０．１～５００μｍが好ましく、１～３００μｍがより好ましく、２～１５０μｍがさらに好ましい。なお、この粒子径は、噴霧乾燥条件により調節できる。なお、平均粒子径はレーザー測定による積算径のＤ５０の値である。 The average particle diameter of the obtained amorphous bosentan is preferably from 0.1 to 500 μm, more preferably from 1 to 300 μm, and even more preferably from 2 to 150 μm, from the viewpoints of blendability and solubility in the pharmaceutical composition. The particle size can be adjusted by spray drying conditions. In addition, an average particle diameter is the value of D50 of the integrated diameter by laser measurement.
　本発明の非晶質ボセンタンは、実質的に結晶ボセンタンを含んでいない非晶質ボセンタンである。本発明の非晶質ボセンタンは、後述の粉末Ｘ線構造解析によって結晶が実質的に確認されない。本発明の非晶質ボセンタンは、熱分析によってボセンタン結晶特有の１１３℃付近の吸熱ピークが確認されず、８５℃付近に小さな吸熱ピークが確認される。 The amorphous bosentan of the present invention is amorphous bosentan substantially free of crystalline bosentan. In the amorphous bosentan of the present invention, crystals are not substantially confirmed by powder X-ray structural analysis described later. In the amorphous bosentan of the present invention, the endothermic peak near 113 ° C. peculiar to bosentan crystals is not confirmed by thermal analysis, but a small endothermic peak is confirmed around 85 ° C.
　本発明の非晶質ボセンタンは、化学組成としては、無水ボセンタン、ボセンタン一水和物、ボセンタン多水和物、ボセンタンナトリウム、ボセンタンカリウム、ボセンタンカルシウム、ボセンタンバリウム及びその他医薬品に許容されるボセンタン塩である。これらを２種以上組み合わせることができる。好ましくは、無水ボセンタン、ボセンタン一水和物であり、より好ましくは無水ボセンタン（非晶質無水ボセンタン）である。 The amorphous bosentan of the present invention has a chemical composition of anhydrous bosentan, bosentan monohydrate, bosentan polyhydrate, bosentan sodium, bosentan potassium, bosentan calcium, bosentan barium and other pharmaceutically acceptable bosentan salts. is there. Two or more of these can be combined. Preferred are anhydrous bosentan and bosentan monohydrate, and more preferred is anhydrous bosentan (amorphous anhydrous bosentan).
　非晶質の無水ボセンタンは、非晶質ボセンタンであって、非晶質構造中に水分子を含んでいない。熱重量測定で温度４０～７０℃付近の水分子の離脱による重量の低下を生じないことで確認できる。非晶質の無水ボセンタンは、結晶ボセンタン一水和物を溶媒に溶かし、短時間で溶媒を除去する方法や、結晶ボセンタン一水和物を加圧しながら加熱し、溶融・混練する方法で製造することが好ましい。 Amorphous anhydrous bosentan is amorphous bosentan and does not contain water molecules in the amorphous structure. It can be confirmed by thermogravimetry that the weight does not decrease due to the separation of water molecules at a temperature of 40 to 70 ° C. Amorphous anhydrous bosentan is produced by dissolving crystalline bosentan monohydrate in a solvent and removing the solvent in a short time, or heating and melting and kneading the crystalline bosentan monohydrate under pressure. It is preferable.
　本発明の非晶質ボセンタンは、水に対する溶解性が向上しており、特に経口投与された後の吸収部位である腸管のｐＨ、すなわちｐＨ６．８の水性溶液に対する溶解性が顕著に向上している。より詳細には、３７℃のｐＨ６．８のリン酸二水素カリウム－水酸化ナトリウム水溶液への溶解濃度が０．６～１０ｍｇ／ｍＬ、好ましくは０．８～１０ｍｇ／ｍＬである。ここで、ｐＨ６．８のリン酸二水素カリウム－水酸化ナトリウム水溶液は、日本薬局方において、腸管における医薬製剤から薬効成分の溶出性を試験するために用いられる崩壊試験第２液である。なお、この溶解濃度は、非晶質ボセンタンを前記水性溶液に添加後６０～１２０分後の溶解濃度、より好ましくは１２０分後の溶解濃度で表す。
　本発明の非晶質ボセンタンの上記溶解濃度は、結晶ボセンタンよりも１．５倍以上、さらには４倍以上、特に８倍以上高い。
　従って、本発明の非晶質ボセンタンは、従来の結晶ボセンタンに比べて水に対する溶解性が高く、吸収部位である腸管での溶解性が極めて高く、胃から小腸までの長い時間に渡って吸収される。 The amorphous bosentan of the present invention has improved solubility in water, and in particular, the solubility of the intestinal tract that is the absorption site after oral administration, that is, the aqueous solution having a pH of 6.8, has been significantly improved. Yes. More specifically, the dissolution concentration in an aqueous solution of potassium dihydrogen phosphate-sodium hydroxide having a pH of 6.8 at 37 ° C. is 0.6 to 10 mg / mL, preferably 0.8 to 10 mg / mL. Here, pH 6.8 potassium dihydrogen phosphate-sodium hydroxide aqueous solution is the second disintegration test liquid used in the Japanese Pharmacopoeia to test the dissolution of medicinal ingredients from pharmaceutical preparations in the intestine. This dissolution concentration is expressed as a dissolution concentration 60 to 120 minutes after adding amorphous bosentan to the aqueous solution, more preferably a dissolution concentration after 120 minutes.
The above-mentioned dissolution concentration of the amorphous bosentan of the present invention is 1.5 times or more, further 4 times or more, particularly 8 times or more higher than that of crystalline bosentan.
Therefore, the amorphous bosentan of the present invention has higher solubility in water than the conventional crystalline bosentan, extremely high solubility in the intestinal tract as the absorption site, and it is absorbed over a long period from the stomach to the small intestine. The
　また、本発明の非晶質ボセンタンは、長期間保存後も優れた溶解性を維持する。より詳細には、温度４０℃、相対湿度７５％で７日間放置後における、３７℃のｐＨ６．８のリン酸二水素カリウム－水酸化ナトリウム水溶液への溶解濃度が０．６～１０ｍｇ／ｍＬ、好ましくは０．８～１０ｍｇ／ｍＬである。
　なお、この溶解濃度も非晶性ボセンタンを前記水性溶液に添加後６０～１２０分後の溶解濃度、より好ましくは１２０分後の溶解濃度である。
　本発明非晶質ボセンタンの温度４０℃、相対湿度７５％で７日間放置後における溶解濃度は、結晶ボセンタンよりも１．５倍以上、さらには４倍以上、特に８倍以上高い。
　従って、本発明の非晶質ボセンタンは、長期保存後も高い溶解性を維持しており、医薬品として有用である。 Further, the amorphous bosentan of the present invention maintains excellent solubility even after long-term storage. More specifically, after standing for 7 days at a temperature of 40 ° C. and a relative humidity of 75%, the dissolution concentration in an aqueous solution of potassium dihydrogen phosphate-sodium hydroxide having a pH of 6.8 at 37 ° C. is 0.6 to 10 mg / mL, Preferably, it is 0.8 to 10 mg / mL.
This dissolution concentration is also a dissolution concentration 60 to 120 minutes after adding amorphous bosentan to the aqueous solution, more preferably a dissolution concentration after 120 minutes.
The dissolution concentration of the amorphous bosentan of the present invention after standing for 7 days at a temperature of 40 ° C. and a relative humidity of 75% is 1.5 times or more, further 4 times or more, particularly 8 times or more higher than that of crystalline bosentan.
Therefore, the amorphous bosentan of the present invention maintains high solubility even after long-term storage and is useful as a pharmaceutical product.
　また、本発明の非晶質ボセンタンは、他の方法により得られた非晶質ボセンタンよりも、長期保存後の溶解性が優れている。例えば、溶媒留去法による非晶質ボセンタンは、製造直後は非晶質状態であり溶出性が高い場合がある。しかし、長期間にわたっては非晶質状態を維持することができず、溶出性の低下を起こす。加速安定性試験の温度４０℃相対湿度７５％の条件下では、１週間後に結晶を形成し、溶解濃度の低下を生じる。この加速試験後、前記のｐＨ６．８水性溶液に添加後１２０分で、本発明の非晶質ボセンタンの溶解濃度は、溶媒留去法による非晶質ボセンタンに対して、１．５倍以上、好ましくは２倍以上である。 In addition, the amorphous bosentan of the present invention is more excellent in solubility after long-term storage than amorphous bosentan obtained by other methods. For example, amorphous bosentan obtained by a solvent distillation method may be in an amorphous state immediately after production and has high elution properties. However, the amorphous state cannot be maintained over a long period of time, resulting in a decrease in elution. Under the accelerated stability test at a temperature of 40 ° C. and a relative humidity of 75%, crystals are formed after one week, resulting in a decrease in the dissolution concentration. After this acceleration test, 120 minutes after the addition to the pH 6.8 aqueous solution, the dissolution concentration of the amorphous bosentan of the present invention is 1.5 times or more that of amorphous bosentan by the solvent distillation method, Preferably it is 2 times or more.
　本発明の非晶質ボセンタンは、長期保存後も非晶質の形態を維持しており、腸管での吸収性が良好であるため、医薬組成物として有用である。 The amorphous bosentan of the present invention is useful as a pharmaceutical composition because it maintains an amorphous form even after long-term storage and has good absorbability in the intestinal tract.
　このようにして得られた非晶質ボセンタンは、錠剤への混合性や溶出性、徐放性、苦味マスキングのために医薬品に使用可能な添加剤を用いて、乾式造粒や湿式造粒を行い非晶質ボセンタン含有粒子とすることができる。非晶質ボセンタンの粒子径や嵩密度の違いで医薬添加物との混合性が劣る場合は、ローラーコンパクターなどで厚密化を行い、粒子径や嵩密度を大きくすることができる。 The amorphous bosentan thus obtained can be used for dry granulation and wet granulation using additives that can be used in pharmaceuticals for tablet mixing, dissolution, sustained release, and bitterness masking. Amorphous bosentan-containing particles can be obtained. When mixing with a pharmaceutical additive is inferior due to the difference in the particle size and bulk density of amorphous bosentan, the particle size and bulk density can be increased by thickening with a roller compactor or the like.
　非晶質ボセンタン及び／又は非晶質ボセンタン含有粒子に医薬添加物を混合し、錠剤、カプセル、散剤、液剤、乳剤もしくは懸濁剤などの経口型の医薬組成物を得る。また、非経口剤として、注射剤、坐剤、点眼剤、鼻腔剤、吸入剤などの医薬組成物も得る事ができる。これらの製造方法は公知の方法を用いることができる。 A pharmaceutical additive is mixed with amorphous bosentan and / or amorphous bosentan-containing particles to obtain an oral pharmaceutical composition such as a tablet, capsule, powder, solution, emulsion or suspension. In addition, pharmaceutical compositions such as injections, suppositories, eye drops, nasal cavities, and inhalants can be obtained as parenterals. As these production methods, known methods can be used.
　医薬添加物としては、結合剤（例えば、カルメロース、ヒドロキシプロピルセルロース、アルギン酸、ゼラチン、部分α化澱粉、ポビドン、アラビアガム、プルラン、デキストリンなど）、賦形剤（例えば、スターチ、Ｄ－マンニトール、乳糖、トレハロース、結晶セルロース、メタケイ酸アルミン酸マグネシウム、リン酸水素カルシウム、ハイドロタルサイト、無水ケイ酸など）、崩壊剤（例えば、クロスポビドン、クロスカルメロースナトリウム、低置換度ヒドロキシプロピルセルロースなど）、界面活性剤（例えば、ポリオキシエチレン硬化ひまし油、ポリオキシエチレンポリオキシプロピレングリコール、ソルビタン脂肪酸エステル、ポリソルベート、脂肪酸グリセリンエステル、ラウリル硫酸ナトリウムなど）、滑沢剤（例えば、ショ糖脂肪酸エステル、ステアリン酸マグネシウム、タルク、フマル酸ステアリルナトリウムなど）、酸味料（例えば、クエン酸、酒石酸、リンゴ酸、アスコルビン酸など）、発泡剤（例えば炭酸水素ナトリウム、炭酸ナトリウムなど）、甘味剤（例えば、サッカリンナトリウム、グリチルリチン二カリウム、アスパルテーム、ステビア、ソーマチンなど）、香料（例えば、レモン油、オレンジ油、メントールなど）、着色剤（例えば、食用赤色２号、食用青色２号、食用黄色５号、食用レーキ色素、三二酸化鉄、アスタキサンチンなど）、安定化剤（例えば、エデト酸ナトリウム、トコフェロール、トコトリエノール、シクロデキストリンなど）、矯味剤、着香剤などが挙げられる。 Pharmaceutical additives include binders (eg, carmellose, hydroxypropyl cellulose, alginic acid, gelatin, partially pregelatinized starch, povidone, 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, etc.), lubricants (eg, Sucrose fatty acid ester, magnesium stearate, talc, sodium stearyl fumarate, etc.), acidulants (eg, citric acid, tartaric acid, malic acid, ascorbic acid, etc.), foaming agents (eg, sodium bicarbonate, sodium carbonate, etc.), sweetness Agents (eg, saccharin sodium, glycyrrhizin dipotassium, aspartame, stevia, thaumatin, etc.), flavors (eg, lemon oil, orange oil, menthol, etc.), colorants (eg, edible red No. 2, edible blue No. 2, edible yellow 5 No., edible lake pigment, iron sesquioxide, astaxanthin), stabilizers (for example, sodium edetate, tocopherol, tocotrienol, cyclodextrin, etc.), flavoring agents, flavoring agents and the like.
　これらの医薬添加物は、非晶質ボセンタン１００質量部に対して１０～２０００質量部含有させ、好ましくは２０～１５００質量部、より好ましくは２０～９００質量部含有させる。 These pharmaceutical additives are contained in an amount of 10 to 2000 parts by mass, preferably 20 to 1500 parts by mass, more preferably 20 to 900 parts by mass with respect to 100 parts by mass of amorphous bosentan.
　本発明の非晶質ボセンタンを含有する医薬組成物は、ボセンタンの溶解濃度向上により、投与量を減らしても、従来の結晶ボセンタンと同等の血中濃度時間曲線下面積が期待できる。ボセンタンは、エンドセリン受容体拮抗作用をもち、現在は肺動脈性肺高血圧症（ＷＨＯ機能分類クラスＩＩ、ＩＩＩ、ＩＶ）の治療薬としてのみ用いられているが、肺動脈性肺高血圧症（ＷＨＯ機能分類クラスＩ）、その他の肺高血圧症、急性及び／又は慢性腎不全、強皮症に伴う指先潰瘍、動脈硬化、慢性肺血栓塞栓症に伴う肺高血圧症、特発性肺繊維症、睡眠時無呼吸症候群、血管肥厚（再狭窄）、狭心症、心筋梗塞、慢性心不全、くも膜下出血後の脳血管攣縮などの治療薬、予防薬あるいは管理薬としても有望である。 The pharmaceutical composition containing the amorphous bosentan of the present invention can be expected to have an area under the blood concentration time curve equivalent to that of the conventional crystalline bosentan even if the dosage is reduced by improving 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, IV), but pulmonary arterial hypertension (WHO functional class) I), other pulmonary hypertension, acute and / or chronic renal failure, fingertip ulcer associated with scleroderma, arteriosclerosis, pulmonary hypertension associated with chronic pulmonary thromboembolism, idiopathic pulmonary fibrosis, sleep apnea syndrome It is also promising as a therapeutic, prophylactic or management agent for vascular thickening (restenosis), angina pectoris, myocardial infarction, chronic heart failure, cerebral vasospasm after subarachnoid hemorrhage, etc.
　また、本発明の非晶質ボセンタンは以下の薬物と組み合わせて肺動脈性肺高血圧症を含む肺高血圧症などを治療、予防又は管理するためにさらなる治療剤、例えば、Ｒｈｏ－キナーゼ阻害剤、プロスタサイクリンアゴニスト、５－ＨＴ２Ａアンタゴニスト、抗凝血剤、抗血小板薬、利尿剤、強心配糖体、カルシウムチャネル遮断剤、脂質低下剤、血管拡張剤、内皮アンタゴニスト、ホスホジエステラーゼ阻害剤、エンドペプチダーゼ阻害剤、選択的セロトニン再取込阻害剤、トロンボキサン阻害剤、血管再構築調節剤、エンドセリン受容体拮抗剤及び肺動脈圧を下げると知られている他の治療剤などと、組み合わせることができる。 In addition, the amorphous bosentan of the present invention is used in combination with the following drugs to treat, prevent or manage pulmonary hypertension including pulmonary arterial hypertension and the like, for example, Rho-kinase inhibitor, prostacyclin Agonist, 5-HT 2A antagonist, anticoagulant, antiplatelet agent, diuretic, cardiac glycoside, calcium channel blocker, lipid lowering agent, vasodilator, endothelial antagonist, phosphodiesterase inhibitor, endopeptidase inhibitor, It can be combined with selective serotonin reuptake inhibitors, thromboxane inhibitors, vascular remodeling regulators, endothelin receptor antagonists and other therapeutic agents known to lower pulmonary artery pressure.
　Ｒｈｏ－キナーゼ阻害剤としては、例えば、ファスジル、Ｙ－２７６３２及びＨ－１１５２Ｐなどである。 Examples of Rho-kinase inhibitors include fasudil, Y-27632, and H-1152P.
　プロスタサイクリンアゴニストとしては、例えば、イロプロスト、トレプロスチニル、エポプロステノール、ベラプロスト及びイロメジンなどである。 Examples of prostacyclin agonists include iloprost, treprostinil, epoprostenol, beraprost, and ilomedin.
　５－ＨＴ２Ａアンタゴニストとしては、例えば、サルポグレラートなどである。
　抗凝血剤としては、例えば、ワーファリンなどである。
　抗血小板薬としては、例えば、アスピリンなどである。 Examples of 5-HT 2A antagonists include sarpogrelate.
An example of the anticoagulant is warfarin.
Examples of the antiplatelet drug include aspirin.
　利尿剤としては、例えば、フロセミド、トリクロロメチアジド、クロルタリドン、クロロチアジド、ヒドロクロロチアジド、インダパミド、ベンチルヒドロクロロチアジド、ベンドロフルメチアジド、シクロペンチアジド、ポリチアジド、メフルシド、キシマピド、メトラゾン、スピロノラクトン及びトリアムテレンなどである。 Examples of the diuretic include furosemide, trichloromethiazide, chlorthalidone, chlorothiazide, hydrochlorothiazide, indapamide, bentlehydrochlorothiazide, bendroflumethiazide, cyclopenthiazide, polythiazide, mefurside, ximapide, metrazone, spironolactone and triamterene.
　強心配糖体としては、例えば、ジゴキシンなどである。
　カルシウムチャネル遮断剤としては、例えば、ジルチアゼム、ニフェジピン、アムロジピン、ニソルジピン、アゼルニジピン、ニカルジピン、ニモジピン、イスラジピン、ニトレンジピン、フェロジピン及びベラパミルなどである。 Examples of cardiac glycosides include digoxin.
Examples of calcium channel blockers include diltiazem, nifedipine, amlodipine, nisoldipine, azelnidipine, nicardipine, nimodipine, isradipine, nitrendipine, felodipine and verapamil.
　脂質低下剤としては、例えば、アトルバスタチン、フルバスタチン、プラバスタチン、ピタバスタチン、シンバスタチン、イタバスタチン、セリバスタチン、ロスバスタチン、ＺＤ－４５２２及びロバスタチンなどのＨＭＧ－ＣｏＡ還元酵素阻害剤などである。
　血管拡張剤としては、例えば、プロスタサイクリン及び一酸化窒素などである。 Examples of the lipid lowering agent include HMG-CoA reductase inhibitors such as atorvastatin, fluvastatin, pravastatin, pitavastatin, simvastatin, itavastatin, cerivastatin, rosuvastatin, ZD-4522 and lovastatin.
Examples of the vasodilator include prostacyclin and nitric oxide.
　ホスホジエステラーゼ阻害剤としては、例えば、アムリノン、ミルリノン及びオルプリノンなどである。ホスホジエステラーゼＩＶ阻害剤、例えば、シルデナフィル、タダラフィル及びバルデナフィルなどである。 Examples of the phosphodiesterase inhibitor include amrinone, milrinone, and olprinone. Phosphodiesterase IV inhibitors such as sildenafil, tadalafil and vardenafil.
　選択的セロトニン再取込阻害剤としては、例えば、フルオキセチン、セルツルレイン、パロキセチン及びベンラファキシンなどである。 Examples of the selective serotonin reuptake inhibitor include fluoxetine, serturlein, paroxetine, and venlafaxine.
　血管再構築調節剤としては、例えば、グリベッグなどである。
　エンドセリン受容体拮抗剤としては、例えば、ボセンタンの他に、シタキセンタン、アンブリセンタン、クラゾセンタン及びマシテンタンなどである。 Examples of the blood vessel remodeling regulator include Gleeveg.
Examples of the endothelin receptor antagonist include, besides bosentan, sitaxsentan, ambrisentan, crazosentan, and macitentan.
　肺動脈圧を下げる他の治療剤としては、例えば、エナラプリル、ラミプリル、カプトプリル、シラザプリル、トランドラプリル、ホシノプリル、キナプリル、モエキシプリル、リシノプリル及びペリンドプリルなどのＡＣＥ阻害剤、ロサルタン、カンデサルタン、イルベサルタン、エンブサルタン、バルサルタン、オルメサルタン及びテルミサルタンなどのＡＴ－ＩＩ阻害剤（ＡＲＢ剤）、イロプロスト、ベタプロスト、Ｌ－アルギニン、アデノシン、オマパトリラト、酸素、ジゴキシンなどである。 Other therapeutic agents that lower pulmonary artery pressure include, for example, 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.
　以下に、本発明を実施例により説明するが、これらの実施例は本発明の範囲を限定するものではない。 Hereinafter, the present invention will be described by way of examples, but these examples do not limit the scope of the present invention.
　［実施例１］　噴霧乾燥法
　結晶ボセンタン一水和物粉末１ｇを５０ｍＬの溶媒（塩化メチレン：エタノール＝８：２）に溶解させた。ついで、入熱温度８０℃、排熱温度５０℃、噴霧速度６ｍＬ／分で噴霧乾燥を行い、得られた粉末をさらに１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥して非晶質ボセンタンの粉末（平均粒子径４．８μｍ）を得た。この方法で、液滴が粉末化する時間は、０．１８分であった。 [Example 1] Spray drying method 1 g of crystalline bosentan monohydrate powder was dissolved in 50 mL of a solvent (methylene chloride: ethanol = 8: 2). Subsequently, spray drying was performed at a heat input temperature of 80 ° C., a waste heat temperature of 50 ° C., and a spray rate of 6 mL / min, and the resulting powder was further dried overnight at 40 ° C. under reduced pressure (5 Torr or less). Bosentan powder (average particle size 4.8 μm) was obtained. In this method, the time required for the droplets to be powdered was 0.18 minutes.
　［比較例１］　衝撃法
　結晶ボセンタン一水和物粉末１ｇを乳鉢で２．５時間すりつぶして、非晶質ボセンタンの粉末を得た。 Comparative Example 1 Impact Method 1 g of crystalline bosentan monohydrate powder was ground in a mortar for 2.5 hours to obtain amorphous bosentan powder.
　［比較例２］　析出法
　結晶ボセンタン一水和物粉末１ｇをナス型フラスコに入れ、塩化メチレン１ｍＬを加えて４０℃に加温して溶解させた。ｔ－ブチルメチルエーテル２０ｍＬを加えて温度２５℃で２時間攪拌したのち、４℃で５時間静置して固形物を析出させ、濾過を行い、得られた粉末をさらに１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥してボセンタン粉末を得た。 Comparative Example 2 Precipitation Method 1 g of crystalline bosentan monohydrate powder was placed in an eggplant type flask, 1 mL of methylene chloride was added, and the mixture was heated to 40 ° C. and dissolved. After adding 20 mL of t-butyl methyl ether and stirring at a temperature of 25 ° C. for 2 hours, the mixture was allowed to stand at 4 ° C. for 5 hours to precipitate a solid, followed by filtration. The resulting powder was further reduced under reduced pressure (over night) 5 Torr or less) and drying at 40 ° C. to obtain bosentan powder.
　［比較例３］　溶媒留去法
　結晶ボセンタン一水和物粉末１ｇを５０ｍＬのナス型フラスコに入れ、塩化メチレン２０ｍＬを加えて４０℃で溶解させた。アスピレーター減圧下、温度５０℃で溶媒を留去した後、１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥し、非晶質ボセンタンを得た。 [Comparative Example 3] Solvent evaporation method 1 g of crystalline bosentan monohydrate powder was placed in a 50 mL eggplant-shaped flask, and 20 mL of methylene chloride was added and dissolved at 40 ° C. The solvent was distilled off at a temperature of 50 ° C. under reduced pressure of an aspirator, and dried overnight at 40 ° C. under reduced pressure (5 Torr or less) to obtain amorphous bosentan.
（溶出試験）
　前述の実験で得た試料３０ｍｇを含むナス型フラスコを３７℃の温浴に浸し、３７℃の崩壊試験液第２液（ｐＨ６．８）３０ｍＬ溶液を加えてフラスコ口をパラフィン紙で閉じ、１００回／分で震盪させながら、経時的に水溶液を採取し、水溶液のボセンタン溶解濃度を測定した。採取した溶液を０．４５μｍのフィルターで篩過したのち、その溶液０．２ｍＬをメタノールで１０ｍＬに希釈し、ＵＶ測定器（ＪＡＳＣＯ－ＭＰＤ、日本分光（株）製）で２７０ｎｍの波長の吸光度を測定し溶解濃度を求めた。
　結果を表１、図１に示す。比較例４は結晶ボセンタン一水和物である。
　ここで崩壊試験液２液は、０．２Ｍリン酸二水素カリウム試液２５０ｍＬに０．２Ｎ水酸化ナトリウム試薬１１８ｍＬ及び水を加えて１０００ｍＬとすることにより調製した。この液は無色澄明で、そのｐＨは約６．８である。 (Dissolution test)
The eggplant-shaped flask containing 30 mg of the sample obtained in the above-mentioned experiment is immersed in a 37 ° C. warm bath, 30 mL of a 37 ° C. disintegration test solution second solution (pH 6.8) is added, and the flask is closed with paraffin paper. The solution was collected over time while shaking at / min, and the concentration of bosentan dissolved in the aqueous solution was measured. The collected solution is sieved with a 0.45 μm filter, 0.2 mL of the solution is diluted to 10 mL with methanol, and the absorbance at a wavelength of 270 nm is measured with a UV measuring instrument (JASCO-MPD, manufactured by JASCO Corporation). Measurement was made to determine the dissolution concentration.
The results are shown in Table 1 and FIG. Comparative Example 4 is crystalline bosentan monohydrate.
Here, 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.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　Ｘ’Ｐｅｒｔ－ＭＰＤ型（フィリップス社製）によりＸ線測定（Ｘ－ＲＤ）を、Ｔｈｅｒｍｏ　ｐｌｕｓ　ＤＳＣ８２３０（リガク社製）によりＤＳＣ（熱分析）測定を行った。実施例１、比較例１～４のＸ－ＲＤとＤＳＣの結果をそれぞれ図２、図３に示す。 X-ray measurement (X-RD) was performed by X'Pert-MPD type (manufactured by Philips), and DSC (thermal analysis) measurement was performed by Thermo plus DSC8230 (manufactured by Rigaku). The results of X-RD and DSC of Example 1 and Comparative Examples 1 to 4 are shown in FIGS. 2 and 3, respectively.
　Ｘ－ＲＤの結晶パターンでは、実施例１の本発明の製法による非晶質ボセンタン、比較例３は結晶ピークが無く非晶質状態であることが分かる。比較例１、比較例２は比較例４（結晶ボセンタン一水和物）の結晶パターンと同様であるが強度の低い結晶ピークがあり、結晶が残っていることが分かる。ＤＳＣの吸熱パターンでは、実施例１、比較例１～４は特徴的な吸熱ピークは表れていない。 In the crystal pattern of X-RD, it can be seen that amorphous bosentan according to the manufacturing method of the present invention in Example 1 and Comparative Example 3 have no crystal peak and are in an amorphous state. Comparative Example 1 and Comparative Example 2 are similar to the crystal pattern of Comparative Example 4 (crystalline bosentan monohydrate), but have a low-intensity crystal peak, indicating that crystals remain. In the endothermic pattern of DSC, the characteristic endothermic peak does not appear in Example 1 and Comparative Examples 1 to 4.
　実施例１、比較例４の粉末を示差熱熱重量同時測定装置（Seiko Instruments社製、SSC/5200）により示差熱と熱重量の測定を行った。結果を図７と図８に示す。比較例４は４０～７０℃付近に重量変化があるが、実施例１にはなく、実施例１の非晶質ボセンタンは無水物であることがわかる。 The differential heat and thermogravimetric measurements were performed on the powders of Example 1 and Comparative Example 4 using a differential thermothermogravimetric simultaneous measurement apparatus (Seiko Instruments Inc., SSC / 5200). The results are shown in FIGS. In Comparative Example 4, there is a change in weight in the vicinity of 40 to 70 ° C., but not in Example 1, and it can be seen that the amorphous bosentan of Example 1 is an anhydride.
　１２０分後の溶解濃度において、実施例１の非晶質ボセンタンの溶解濃度は１．０７ｍｇ／ｍＬであり、比較例１～２の非晶質ボセンタン、比較例４の結晶ボセンタンに対して、８倍以上の溶解濃度を示し、溶解性の向上が極めて優れていることが分かる。 At the dissolution concentration after 120 minutes, the dissolution concentration of the amorphous bosentan of Example 1 was 1.07 mg / mL, which was 8% relative to the amorphous bosentan of Comparative Examples 1 and 2 and the crystalline bosentan of Comparative Example 4. It shows that the dissolution concentration is twice or more and the improvement in solubility is extremely excellent.
（加速安定性試験及び溶出試験）
　比較例２を除く前述の実験で得た試料３０ｍｇを、開放下、温度４０℃、相対湿度７５％の条件下で７日間放置した。これらの試料を、前述の溶出試験と同じ操作で経時的に溶解濃度を測定した。溶出試験の結果を表２と図４に、Ｘ－ＲＤとＤＳＣの結果をそれぞれ図５、図６に示す。 (Accelerated stability test and dissolution test)
30 mg of the sample obtained in the above experiment except for Comparative Example 2 was left open for 7 days under conditions of a temperature of 40 ° C. and a relative humidity of 75%. The dissolution concentration of these samples was measured over time by the same operation as the above-described dissolution test. The results of the dissolution test are shown in Table 2 and FIG. 4, and the results of X-RD and DSC are shown in FIGS. 5 and 6, respectively.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　１２０分後において、実施例１の噴霧法による非晶質ボセンタンは溶解濃度は０．９２ｍｇ／ｍＬであり、噴霧法以外で製造した比較例１、３の非晶質ボセンタン及び比較例４の結晶ボセンタンよりも２倍以上溶解濃度が高い。また、比較例３の非晶質ボセンタンは６０分後から溶解濃度の低下を起こしているに対し、実施例１の噴霧法による非晶質ボセンタンは高い溶解濃度を維持している。 After 120 minutes, the amorphous bosentan by the spraying method of Example 1 had a dissolution concentration of 0.92 mg / mL, and the amorphous bosentan of Comparative Examples 1 and 3 and the crystals of Comparative Example 4 produced by a method other than the spraying method. Dissolving concentration is twice or more higher than bosentan. Further, the amorphous bosentan of Comparative Example 3 has a decrease in dissolution concentration after 60 minutes, whereas the amorphous bosentan by the spray method of Example 1 maintains a high dissolution concentration.
　加速条件により、Ｘ－ＲＤパターンでは、比較例３はわずかであるが結晶パターンが表れている。比較例１は結晶パターンが成長してきている。なお、ＤＳＣのパターンは、実施例１、比較例３とほとんど同じである。これらから、比較例３では、ＤＳＣで吸熱ピークが表れない程度であって、Ｘ－ＲＤでわずかに結晶パターンが表れる程度の微少な結晶の析出が起きている状態であることを示す。これらの微少結晶が、溶出性において、溶解度の低下要因となっている。 Depending on the acceleration conditions, in the X-RD pattern, although Comparative Example 3 is slight, a crystal pattern appears. In Comparative Example 1, the crystal pattern has grown. The DSC pattern is almost the same as in Example 1 and Comparative Example 3. From these, it is shown in Comparative Example 3 that the endothermic peak does not appear in DSC, and a minute amount of crystal precipitation occurs so that a slight crystal pattern appears in X-RD. These microcrystals are a cause of a decrease in solubility in dissolution.
　［実施例２、３］
　前記［実施例１］と同様の手法で、非晶質ボセンタンを製造した。
　結晶ボセンタン－水和物粉末１ｇを５０ｍＬの溶媒（塩化メチレン：エタノール＝８：２）に溶解させた。ついで、表３のように排熱温度と入熱温度を設定して噴霧乾燥（ビュッヒ社製：ｍｉｎｉ　ｓｐｒａｙ　ｄｒｙｅｒ　Ｂ－１９１）を行い、得られた粉末をさらに１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥して非晶質ボセンタンの粉末を得た。
　実施例２の条件における液滴が粉末化する時間は０．１８分であり、得られた非晶質ボセンタンの平均粒子径は４．３μｍであった。また実施例３の条件における液滴が粉末化する時間は０．１８分であり、得られた非晶質ボセンタンの平均粒子径は５．０μｍであった。 [Examples 2 and 3]
Amorphous bosentan was produced in the same manner as in [Example 1].
1 g of crystalline bosentan-hydrate powder was dissolved in 50 mL of a solvent (methylene chloride: ethanol = 8: 2). Then, the exhaust heat temperature and the heat input temperature were set as shown in Table 3, and spray drying (Buich: mini spray dryer B-191) was performed. The obtained powder was further reduced under reduced pressure (5 Torr or less) overnight. And dried at 40 ° C. to obtain amorphous bosentan powder.
The time required for the droplets to be powdered under the conditions of Example 2 was 0.18 minutes, and the average particle size of the obtained amorphous bosentan was 4.3 μm. The time required for the droplets to be powdered under the conditions of Example 3 was 0.18 minutes, and the average particle size of the obtained amorphous bosentan was 5.0 μm.
　実施例２及び３で得られた非晶質ボセンタンの製造時及び４０℃湿度７５％に７日間保存後の溶出試験を行った。その結果を表３及び表４に示す。 The elution test was conducted at the time of production of the amorphous bosentan obtained in Examples 2 and 3 and after storage for 7 days at 40 ° C. and 75% humidity. The results are shown in Tables 3 and 4.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　本発明の噴霧法による非晶質ボセンタンは、４０～１１０℃の幅の広い温度範囲での噴霧乾燥においても、他の製法による非晶質ボセンタンよりも、非晶質状態を長く保持でき安定性が高く、また水に溶解したとき溶解濃度を長期間にわたって維持することができる。 The amorphous bosentan produced by the spraying method of the present invention can maintain an amorphous state longer than the amorphous bosentan produced by other methods even in spray drying in a wide temperature range of 40 to 110 ° C. And when dissolved in water, the dissolution concentration can be maintained over a long period of time.
　［実施例４、５］
　前記［実施例１］と同様の手法で、非晶質ボセンタンを製造した。
結晶ボセンタン－水和物粉末１ｇを表５の溶媒５０ｍに溶解させた。ついで、入熱温度８０℃、排熱温度５０℃、噴霧速度６ｍＬ／分で噴霧乾燥を行い、得られた粉末をさらに１晩、減圧下（５Ｔｏｒｒ以下）、４０℃で乾燥して非晶質ボセンタンの粉末を得た。 [Examples 4 and 5]
Amorphous bosentan was produced in the same manner as in [Example 1].
1 g of crystalline bosentan-hydrate powder was dissolved in 50 m of the solvent shown in Table 5. Subsequently, spray drying was performed at a heat input temperature of 80 ° C., a waste heat temperature of 50 ° C., and a spray rate of 6 mL / min, and the resulting powder was further dried overnight at 40 ° C. under reduced pressure (5 Torr or less). Bosentan powder was obtained.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
　本発明の噴霧乾燥による非晶質ボセンタンは、親水性の高いエタノールから親油性の高い塩化メチレンのいずれを用いても、他の製法による非晶質ボセンタンよりも、非晶質状態を長く保持でき安定性が高く、また水に溶解したとき溶解濃度を長期間にわたって維持することができる。 Amorphous bosentan by spray drying of the present invention can maintain an amorphous state longer than amorphous bosentan by other production methods, regardless of whether the highly hydrophilic ethanol or the highly lipophilic methylene chloride is used. It has high stability and can maintain the dissolved concentration for a long period when dissolved in water.

Claims (10)

  1. 　ボセンタンを０．１～８０重量％含有する溶液を、０～３００℃の気流中に、噴霧された液滴が粉末化するまでの時間が０．１分～２分となる条件で噴霧乾燥することにより得られる、平均粒子径０．１～５００μｍの非晶質ボセンタン。 A solution containing 0.1 to 80% by weight of bosentan is spray-dried in an air stream at 0 to 300 ° C. under the condition that the time until the sprayed droplets are pulverized is 0.1 to 2 minutes. Amorphous bosentan having an average particle size of 0.1 to 500 μm.
  2. 　３７℃のｐＨ６．８のリン酸二水素カリウム－水酸化ナトリウム水溶液への溶解濃度が０．６～１０ｍｇ／ｍＬである請求項１記載の非晶質ボセンタン。 The amorphous bosentan according to claim 1, which has a solubility concentration in an aqueous solution of potassium dihydrogen phosphate-sodium hydroxide having a pH of 6.8 at 37 ° C of 0.6 to 10 mg / mL.
  3. 　温度４０℃、相対湿度７５％で７日間放置後における３７℃のｐＨ６．８のリン酸二水素カリウム－水酸化ナトリウム水溶液への溶解濃度が０．６～１０ｍｇ／ｍＬである請求項１又は２記載の非晶質ボセンタン。 The dissolution concentration in an aqueous solution of potassium dihydrogen phosphate-sodium hydroxide having a pH of 6.8 at 37 ° C after standing for 7 days at a temperature of 40 ° C and a relative humidity of 75% is 0.6 to 10 mg / mL. The amorphous bosentan described.
  4. 　粉末Ｘ線構造解析によって結晶が実質的に確認されないものである請求項１～３のいずれか１項記載の非晶質ボセンタン。 The amorphous bosentan according to any one of claims 1 to 3, wherein crystals are substantially not confirmed by powder X-ray structural analysis.
  5. 　熱分析によって１１３℃付近のピークが確認されないものである請求項１～４のいずれか１項記載の非晶質ボセンタン。 The amorphous bosentan according to any one of claims 1 to 4, wherein a peak around 113 ° C is not confirmed by thermal analysis.
  6. 　非晶質無水ボセンタンである請求項１～５のいずれか１項記載の非晶質ボセンタン。 The amorphous bosentan according to any one of claims 1 to 5, which is amorphous anhydrous bosentan.
  7. 　非晶質無水ボセンタン。 Amorphous anhydrous bosentan.
  8. 　ボセンタンを０．１～８０重量％含有する溶液を、０～３００℃の気流中に、噴霧された液滴が粉末化するまでの時間が０．１分～２分となる条件で噴霧乾燥することを特徴とする、平均粒子径０．１～５００μｍの非晶質ボセンタンの製造法。 A solution containing 0.1 to 80% by weight of bosentan is spray-dried in an air stream at 0 to 300 ° C. under the condition that the time until the sprayed droplets are pulverized is 0.1 to 2 minutes. A process for producing amorphous bosentan having an average particle size of 0.1 to 500 μm,
  9. 　ボセンタンを含有する溶液を噴霧乾燥する非晶質無水ボセンタンの製造方法。 A process for producing amorphous anhydrous bosentan by spray drying a solution containing bosentan.
  10. 　請求項１～７のいずれか１項記載の非晶質ボセンタン１００質量部に対して、医薬添加物１０～２０００質量部を含有する医薬組成物。 A pharmaceutical composition comprising 10 to 2000 parts by mass of a pharmaceutical additive based on 100 parts by mass of amorphous bosentan according to any one of claims 1 to 7.
PCT/JP2011/065197 2010-07-01 2011-07-01 Novel noncrystalline bosentan and process for preparation thereof WO2012002539A1 (en)

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