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WO2012002539A1 - Nouveau bosentan non cristallin et son procédé de préparation - Google Patents

Nouveau bosentan non cristallin et son procédé de préparation 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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Prior art keywords
bosentan
amorphous
minutes
spray
solvent
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Japanese (ja)
Inventor
洋介 平井
直任 尾塩
仁 坂井
田中　伸和
邦雄 真田
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Fuji Chemical Industries Co Ltd
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Fuji Chemical Industries Co Ltd
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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

L'invention concerne : un bosentan qui combine une grande solubilité dans l'eau et une stabilité à long terme ; et un procédé facile et simple de préparation du bosentan. L'invention concerne un bosentan non cristallin ayant un diamètre de particule moyen de 0,1 à 500 µm, qui est obtenu par séchage par pulvérisation d'une solution de bosentan de 0,1 à 80 % en poids dans un courant d'air à une température de 0 à 300 °C dans des conditions telles que le temps écoulé jusqu'à la transformation des gouttelettes pulvérisées en poudre soit dans une plage allant de 0,1 à 2 minutes.
PCT/JP2011/065197 2010-07-01 2011-07-01 Nouveau bosentan non cristallin et son procédé de préparation Ceased WO2012002539A1 (fr)

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JP2010-151423 2010-07-01
JP2010151423A JP5356323B2 (ja) 2010-07-01 2010-07-01 新規な非晶質ボセンタン及びその製造方法

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